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Vaccine may blunt effects of deadly synthetic opioids
New experimental vaccines could stop the worst effects of synthetic fentanyl and carfentanil, two drugs that have been major drivers of the opioid epidemic in the United States, according to a new study published in ACS Chemical Biology on Feb. 3, 2021.
During several experiments in mice, the vaccines prevented respiratory depression, which is the main cause of overdose deaths. The vaccines also reduced the amount of drug that was distributed to the brain. Once in the brain, synthetic opioids prompt the body to slow down breathing, and when too much of the drug is consumed, breathing can stop.
“Synthetic opioids are not only extremely deadly but also addictive and easy to manufacture, making them a formidable public health threat, especially when the coronavirus crisis is negatively impacting mental health,” Kim Janda, PhD, a chemist at Scripps Research Institute in La Jolla, Calif., who developed the vaccines, said in a statement.
Fentanyl is up to 100 times stronger than morphine, and carfentanil, which is often used by veterinarians to sedate large animals such as elephants, is up to 10,000 times stronger than morphine. Carfentanil isn’t as well-known as a street drug, but it’s being used more often as an additive in heroin and cocaine.
“We’ve shown it is possible to prevent these unnecessary deaths by eliciting antibodies that stop the drug from reaching the brain,” he said.
The vaccines could be used in emergency situations to treat overdoses and as a therapy for those with substance abuse disorders, Dr. Janda said. In addition, the vaccines could protect military officers who are exposed to opioids as chemical weapons, and they may also help opioid-sniffing police dogs to train for the job.
The vaccines are still in the early stages of testing, but looking at the latest data “brings us hope that this approach will work to treat a number of opioid-related maladies,” Dr. Janda said.
In December, the CDC reported that more than 81,000 drug overdose deaths happened in the United States between May 2019 and May 2020, which was the highest number ever recorded in a 12-month period. Synthetic opioids, particularly illegally created fentanyl, were to blame.
“Unfortunately, currently battling a pandemic,” Dr. Janda said. “We look forward to continuing our vaccine research and translating it to the clinic, where we can begin to make an impact on the opioid crisis.”
A version of this article first appeared on Medscape.com.
New experimental vaccines could stop the worst effects of synthetic fentanyl and carfentanil, two drugs that have been major drivers of the opioid epidemic in the United States, according to a new study published in ACS Chemical Biology on Feb. 3, 2021.
During several experiments in mice, the vaccines prevented respiratory depression, which is the main cause of overdose deaths. The vaccines also reduced the amount of drug that was distributed to the brain. Once in the brain, synthetic opioids prompt the body to slow down breathing, and when too much of the drug is consumed, breathing can stop.
“Synthetic opioids are not only extremely deadly but also addictive and easy to manufacture, making them a formidable public health threat, especially when the coronavirus crisis is negatively impacting mental health,” Kim Janda, PhD, a chemist at Scripps Research Institute in La Jolla, Calif., who developed the vaccines, said in a statement.
Fentanyl is up to 100 times stronger than morphine, and carfentanil, which is often used by veterinarians to sedate large animals such as elephants, is up to 10,000 times stronger than morphine. Carfentanil isn’t as well-known as a street drug, but it’s being used more often as an additive in heroin and cocaine.
“We’ve shown it is possible to prevent these unnecessary deaths by eliciting antibodies that stop the drug from reaching the brain,” he said.
The vaccines could be used in emergency situations to treat overdoses and as a therapy for those with substance abuse disorders, Dr. Janda said. In addition, the vaccines could protect military officers who are exposed to opioids as chemical weapons, and they may also help opioid-sniffing police dogs to train for the job.
The vaccines are still in the early stages of testing, but looking at the latest data “brings us hope that this approach will work to treat a number of opioid-related maladies,” Dr. Janda said.
In December, the CDC reported that more than 81,000 drug overdose deaths happened in the United States between May 2019 and May 2020, which was the highest number ever recorded in a 12-month period. Synthetic opioids, particularly illegally created fentanyl, were to blame.
“Unfortunately, currently battling a pandemic,” Dr. Janda said. “We look forward to continuing our vaccine research and translating it to the clinic, where we can begin to make an impact on the opioid crisis.”
A version of this article first appeared on Medscape.com.
New experimental vaccines could stop the worst effects of synthetic fentanyl and carfentanil, two drugs that have been major drivers of the opioid epidemic in the United States, according to a new study published in ACS Chemical Biology on Feb. 3, 2021.
During several experiments in mice, the vaccines prevented respiratory depression, which is the main cause of overdose deaths. The vaccines also reduced the amount of drug that was distributed to the brain. Once in the brain, synthetic opioids prompt the body to slow down breathing, and when too much of the drug is consumed, breathing can stop.
“Synthetic opioids are not only extremely deadly but also addictive and easy to manufacture, making them a formidable public health threat, especially when the coronavirus crisis is negatively impacting mental health,” Kim Janda, PhD, a chemist at Scripps Research Institute in La Jolla, Calif., who developed the vaccines, said in a statement.
Fentanyl is up to 100 times stronger than morphine, and carfentanil, which is often used by veterinarians to sedate large animals such as elephants, is up to 10,000 times stronger than morphine. Carfentanil isn’t as well-known as a street drug, but it’s being used more often as an additive in heroin and cocaine.
“We’ve shown it is possible to prevent these unnecessary deaths by eliciting antibodies that stop the drug from reaching the brain,” he said.
The vaccines could be used in emergency situations to treat overdoses and as a therapy for those with substance abuse disorders, Dr. Janda said. In addition, the vaccines could protect military officers who are exposed to opioids as chemical weapons, and they may also help opioid-sniffing police dogs to train for the job.
The vaccines are still in the early stages of testing, but looking at the latest data “brings us hope that this approach will work to treat a number of opioid-related maladies,” Dr. Janda said.
In December, the CDC reported that more than 81,000 drug overdose deaths happened in the United States between May 2019 and May 2020, which was the highest number ever recorded in a 12-month period. Synthetic opioids, particularly illegally created fentanyl, were to blame.
“Unfortunately, currently battling a pandemic,” Dr. Janda said. “We look forward to continuing our vaccine research and translating it to the clinic, where we can begin to make an impact on the opioid crisis.”
A version of this article first appeared on Medscape.com.
Molecular insights suggest novel therapies for hidradenitis suppurativa
at the virtual annual congress of the European Academy of Dermatology and Venereology.
He presented highlights of a multicenter translational study, which utilized whole transcriptome analysis of lesional and nonlesional skin from patients with HS and normal controls along with quantitative real-time PCR and immunohistochemistry. The purpose was to further define the molecular taxonomy of this inflammatory disease. And while this objective was achieved, the results also underscored a truism regarding the painful and scarring disease: “HS is characterized by an ever-growing complexity, which translates into multiple potential mechanistic drivers,” observed Dr. da Costa, head of immunology precision medicine at AstraZeneca in Gothenburg, Sweden.
Indeed, the study identified a panel of immune-related drivers in HS that influence innate immunity and cell differentiation in follicular and epidermal keratinocytes. The research by Dr. da Costa and coinvestigators identified a broad array of promising novel therapeutic targets in HS.
“Our findings provide evidence of an inflammatory process coupled with impaired barrier function, altered epidermal cell differentiation, and possibly abnormal microbiome activity which can be seen at the follicular and epidermal keratinocytes and also to a minor degree at the level of the skin glands,” Dr. da Costa said.
There is a huge unmet need for new therapies for HS, since at present adalimumab (Humira) is the only approved medication for this debilitating inflammatory disease. Some good news that emerged from this translational study is that some of the novel molecular mediators implicated in HS are targeted by multiple Food and Drug Administration–approved therapies that have other indications. From a drug development standpoint, repurposing a commercially available drug for a novel indication is a much more efficient and less costly endeavor than is necessary to establish the safety and efficacy of an unproven new agent.
The translational work demonstrated that the proteins calgranulin-A and -B and serpin-B4 were strongly expressed in the hair root sheaths of patients with HS. Connexin-32 and koebnerisin were present in stratum granulosum, matrix metallopeptidase-9 was strongly expressed in resident monocytes, small prolin-rich protein 3 in apocrine sweat glands and ducts as well as in sebaceous glands and ducts, and transcobalamin-1 was prominent in stratum spinosum.
Of the 19 key molecular mediators of HS identified in the study, FDA-approved agents are already available that target 12 of them. For example, apremilast (Otezla) targets interferon-gamma and tumor necrosis factor–alpha. Gentamicin targets growth arrest-specific 6 (GAS6) and interleukin-17 (IL-17). Secukinumab (Cosentyx) and ixekizumab (Taltz) target IL-17A, and brodalumab (Siliq) more broadly targets IL-17A as well as all the other IL-17 receptors. Thalidomide targets hepatocyte growth factor (HGF) and TNF-alpha. Spironolactone targets androgen receptor (AR) and TNF-alpha. Colchicine targets tubulin. Anakinra (Kineret) homes in on the IL-1 receptor. And prednisone targets NFxB.
Other key molecular mediators of HS, which are targeted by commercially available drugs, include epidermal growth factor (EGF), macrophage colony-stimulating factor (MCSF), epiregulin (EREG), fibroblast growth factor 1 (FGF1), FGF2, insulin-like growth factor 2 (IGF2), and IL-6, according to Dr. da Costa.
In addition, clinical trials are underway in HS involving totally investigational agents, including several Janus kinase inhibitors and tyrosine kinase 2 inhibitors.
The work described by Dr. da Costa had multiple funding sources, including the European Hidradenitis Suppurativa Foundation, the University of Copenhagen, the Icahn School of Medicine at Mount Sinai, AstraZeneca, and the German Federal Ministry of Education and Research. Dr. da Costa is an employee of AstraZeneca, Gothenburg, Sweden.
at the virtual annual congress of the European Academy of Dermatology and Venereology.
He presented highlights of a multicenter translational study, which utilized whole transcriptome analysis of lesional and nonlesional skin from patients with HS and normal controls along with quantitative real-time PCR and immunohistochemistry. The purpose was to further define the molecular taxonomy of this inflammatory disease. And while this objective was achieved, the results also underscored a truism regarding the painful and scarring disease: “HS is characterized by an ever-growing complexity, which translates into multiple potential mechanistic drivers,” observed Dr. da Costa, head of immunology precision medicine at AstraZeneca in Gothenburg, Sweden.
Indeed, the study identified a panel of immune-related drivers in HS that influence innate immunity and cell differentiation in follicular and epidermal keratinocytes. The research by Dr. da Costa and coinvestigators identified a broad array of promising novel therapeutic targets in HS.
“Our findings provide evidence of an inflammatory process coupled with impaired barrier function, altered epidermal cell differentiation, and possibly abnormal microbiome activity which can be seen at the follicular and epidermal keratinocytes and also to a minor degree at the level of the skin glands,” Dr. da Costa said.
There is a huge unmet need for new therapies for HS, since at present adalimumab (Humira) is the only approved medication for this debilitating inflammatory disease. Some good news that emerged from this translational study is that some of the novel molecular mediators implicated in HS are targeted by multiple Food and Drug Administration–approved therapies that have other indications. From a drug development standpoint, repurposing a commercially available drug for a novel indication is a much more efficient and less costly endeavor than is necessary to establish the safety and efficacy of an unproven new agent.
The translational work demonstrated that the proteins calgranulin-A and -B and serpin-B4 were strongly expressed in the hair root sheaths of patients with HS. Connexin-32 and koebnerisin were present in stratum granulosum, matrix metallopeptidase-9 was strongly expressed in resident monocytes, small prolin-rich protein 3 in apocrine sweat glands and ducts as well as in sebaceous glands and ducts, and transcobalamin-1 was prominent in stratum spinosum.
Of the 19 key molecular mediators of HS identified in the study, FDA-approved agents are already available that target 12 of them. For example, apremilast (Otezla) targets interferon-gamma and tumor necrosis factor–alpha. Gentamicin targets growth arrest-specific 6 (GAS6) and interleukin-17 (IL-17). Secukinumab (Cosentyx) and ixekizumab (Taltz) target IL-17A, and brodalumab (Siliq) more broadly targets IL-17A as well as all the other IL-17 receptors. Thalidomide targets hepatocyte growth factor (HGF) and TNF-alpha. Spironolactone targets androgen receptor (AR) and TNF-alpha. Colchicine targets tubulin. Anakinra (Kineret) homes in on the IL-1 receptor. And prednisone targets NFxB.
Other key molecular mediators of HS, which are targeted by commercially available drugs, include epidermal growth factor (EGF), macrophage colony-stimulating factor (MCSF), epiregulin (EREG), fibroblast growth factor 1 (FGF1), FGF2, insulin-like growth factor 2 (IGF2), and IL-6, according to Dr. da Costa.
In addition, clinical trials are underway in HS involving totally investigational agents, including several Janus kinase inhibitors and tyrosine kinase 2 inhibitors.
The work described by Dr. da Costa had multiple funding sources, including the European Hidradenitis Suppurativa Foundation, the University of Copenhagen, the Icahn School of Medicine at Mount Sinai, AstraZeneca, and the German Federal Ministry of Education and Research. Dr. da Costa is an employee of AstraZeneca, Gothenburg, Sweden.
at the virtual annual congress of the European Academy of Dermatology and Venereology.
He presented highlights of a multicenter translational study, which utilized whole transcriptome analysis of lesional and nonlesional skin from patients with HS and normal controls along with quantitative real-time PCR and immunohistochemistry. The purpose was to further define the molecular taxonomy of this inflammatory disease. And while this objective was achieved, the results also underscored a truism regarding the painful and scarring disease: “HS is characterized by an ever-growing complexity, which translates into multiple potential mechanistic drivers,” observed Dr. da Costa, head of immunology precision medicine at AstraZeneca in Gothenburg, Sweden.
Indeed, the study identified a panel of immune-related drivers in HS that influence innate immunity and cell differentiation in follicular and epidermal keratinocytes. The research by Dr. da Costa and coinvestigators identified a broad array of promising novel therapeutic targets in HS.
“Our findings provide evidence of an inflammatory process coupled with impaired barrier function, altered epidermal cell differentiation, and possibly abnormal microbiome activity which can be seen at the follicular and epidermal keratinocytes and also to a minor degree at the level of the skin glands,” Dr. da Costa said.
There is a huge unmet need for new therapies for HS, since at present adalimumab (Humira) is the only approved medication for this debilitating inflammatory disease. Some good news that emerged from this translational study is that some of the novel molecular mediators implicated in HS are targeted by multiple Food and Drug Administration–approved therapies that have other indications. From a drug development standpoint, repurposing a commercially available drug for a novel indication is a much more efficient and less costly endeavor than is necessary to establish the safety and efficacy of an unproven new agent.
The translational work demonstrated that the proteins calgranulin-A and -B and serpin-B4 were strongly expressed in the hair root sheaths of patients with HS. Connexin-32 and koebnerisin were present in stratum granulosum, matrix metallopeptidase-9 was strongly expressed in resident monocytes, small prolin-rich protein 3 in apocrine sweat glands and ducts as well as in sebaceous glands and ducts, and transcobalamin-1 was prominent in stratum spinosum.
Of the 19 key molecular mediators of HS identified in the study, FDA-approved agents are already available that target 12 of them. For example, apremilast (Otezla) targets interferon-gamma and tumor necrosis factor–alpha. Gentamicin targets growth arrest-specific 6 (GAS6) and interleukin-17 (IL-17). Secukinumab (Cosentyx) and ixekizumab (Taltz) target IL-17A, and brodalumab (Siliq) more broadly targets IL-17A as well as all the other IL-17 receptors. Thalidomide targets hepatocyte growth factor (HGF) and TNF-alpha. Spironolactone targets androgen receptor (AR) and TNF-alpha. Colchicine targets tubulin. Anakinra (Kineret) homes in on the IL-1 receptor. And prednisone targets NFxB.
Other key molecular mediators of HS, which are targeted by commercially available drugs, include epidermal growth factor (EGF), macrophage colony-stimulating factor (MCSF), epiregulin (EREG), fibroblast growth factor 1 (FGF1), FGF2, insulin-like growth factor 2 (IGF2), and IL-6, according to Dr. da Costa.
In addition, clinical trials are underway in HS involving totally investigational agents, including several Janus kinase inhibitors and tyrosine kinase 2 inhibitors.
The work described by Dr. da Costa had multiple funding sources, including the European Hidradenitis Suppurativa Foundation, the University of Copenhagen, the Icahn School of Medicine at Mount Sinai, AstraZeneca, and the German Federal Ministry of Education and Research. Dr. da Costa is an employee of AstraZeneca, Gothenburg, Sweden.
FROM THE EADV CONGRESS
New approach to breast screening based on breast density at 40
The result would then be used to stratify further screening, with annual screening starting at age 40 for average-risk women who have dense breasts, and screening every 2 years starting at age 50 for women without dense breasts.
Such an approach would be cost effective and offers a more targeted risk-based strategy for the early detection of breast cancer when compared with current practices, say the authors, led by Tina Shih, PhD, University of Texas MD Anderson Cancer Center, Houston.
Their modeling study was published online in the Annals of Internal Medicine.
However, experts writing in an accompanying editorial are not persuaded. Karla Kerlikowske, MD, and Kirsten Bibbins-Domingo, MD, PhD, both from the University of California, San Francisco, point out that not all women with dense breasts are at increased risk for breast cancer. They caution against relying on breast density alone when determining screening strategies, and say age and other risk factors also need to be considered.
New approach proposed
Current recommendations from the United States Preventive Services Task Force suggest that women in their 40s can choose to undergo screening mammography based on their own personal preference, Dr. Shih explained in an interview.
However, these recommendations do not take into consideration the additional risk that breast density confers on breast cancer risk – and the only way women can know their breast density is to have a mammogram. “If you follow [current] guidelines, you would not know about your breast density until the age of 45 or 50,” she commented.
“But what if you knew about breast density earlier on and then acted on it –would that make a difference?” This was the question her team set out to explore.
For their study, the authors defined women with dense breasts as those with the Breast Imaging Reporting and Data System (BI-RADS) category C (heterogeneously dense breasts) and category D (extremely dense breasts).
The team used a computer model to compare seven different breast screening strategies:
- No screening.
- Triennial mammography from age 50 to 75 years (T50).
- Biennial mammography from age 50 to 75 years (B50).
- Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and triennial. screening from age 50 to 75 for women without dense breasts at the age of 50 (SA50T50).
- Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and biennial screening from age 50 to 75 for those without dense breast at age 50 (SA50B50).
- Stratified annual mammography from age 40 to 75 for women with dense breasts at age 49, and triennial screening from age 50 to 75 for those without dense breasts at age 40 (SA40T50).
- Stratified annual mammography from age 40 to 75 for women with dense breasts at age 40, and biennial mammography for women from age 50 to 75 without dense breasts at age 40 (SA40B50).
Compared with a no-screening strategy, the average number of mammography sessions through a woman’s lifetime would increase from seven mammograms per lifetime for the least frequent screening (T50) to 22 mammograms per lifetime for the most intensive screening schedule, the team reports.
Compared with no screening, screening would reduce breast cancer deaths by 8.6 per 1,000 women (T50)–13.2 per 1,000 women (SA40B50).
A cost-effectiveness analysis showed that the proposed new approach (SA40B50) yielded an incremental cost-effectiveness ratio of $36,200 per quality-adjusted life-year (QALY), compared with the currently recommended biennial screening strategy. This is well within the willingness-to-pay threshold of $100,000 per QALY that is generally accepted by society, the authors point out.
On the other hand, false-positive results and overdiagnosis would increase, the authors note.
The average number of false positives would increase from 141.2 per 1,000 women who underwent the least frequent triennial mammography screening schedule (T50) to 567.3 per 1,000 women with the new approach (SA40B50).
Rates of overdiagnosis would also increase from a low of 12.5% to a high of 18.6%, they add.
“With this study, we are not saying that everybody should start screening at the age of 40. We’re just saying, do a baseline mammography at 40, know your breast density status, and then we can try to modify the screening schedule based on individual risk,” Dr. Shih emphasized.
“Compared with other screening strategies examined in our study, this strategy is associated with the greatest reduction in breast cancer mortality and is cost effective, [although it] involves the most screening mammograms in a woman’s lifetime and higher rates of false-positive results and overdiagnosis,” the authors conclude.
Fundamental problem with this approach
The fundamental problem with this approach of stratifying risk on measurement of breast density – and on the basis of a single reading – is that not every woman with dense breasts is at increased risk for breast cancer, the editorialists comment.
Dr. Kerlikowske and Dr. Bibbins-Domingo point out that, in fact, only about one-quarter of women with dense breasts are at high risk for a missed invasive cancer within 1 year of a negative mammogram, and these women can be identified by using the Breast Cancer Surveillance Consortium risk model.
“This observation means that most women with dense breasts can undergo biennial screening and need not consider annual screening or supplemental imaging,” the editorialists write.
“Thus, we caution against using breast density alone to determine if a woman is at elevated risk for breast cancer,” they emphasize.
An alternative option is to focus on overall risk to select screening strategies, they suggest. For example, most guidelines recommend screening from age 50 to 74, so identifying women in their 40s who have the same risk of a woman aged 50-59 is one way to determine who may benefit from earlier initiation of screening, the editorialists observe.
“Thus, women who have a first-degree relative with breast cancer or a history of breast biopsy could be offered screening in their 40s, and, if mammography shows dense breasts, they could continue biennial screening through their 40s,” the editorialists observe. “Such women with nondense breasts could resume biennial screening at age 50 years.”
Dr. Shih told this news organization that she did not disagree with the editorialists’ suggestion that physicians could focus on overall breast cancer risk to select an appropriate screening strategy for individual patients.
“What we are suggesting is, ‘Let’s just do a baseline assessment at the age of 40 so women know their breast density instead of waiting until they are older,’ “ she said.
“But what the editorialists are suggesting is a strategy that could be even more cost effective,” she acknowledged. Dr. Shih also said that Dr. Kerlikowske and Dr. Bibbins-Domingo’s estimate that only one-quarter of women with dense breasts are actually at high risk for breast cancer likely reflects their limitation of breast density to only those women with BI-RADs category “D” – extremely dense breasts.
Yet as Dr. Shih notes, women with category C and category D breast densities are both at higher risk for breast cancer, so ignoring women with lesser degrees of breast density still doesn’t address the fact that they have a higher-than-average risk for breast cancer.
“It’s getting harder to make universal screening strategies work as we are learning more and more about breast cancer, so people are starting to talk about screening strategies based on a patient’s risk classification,” Dr. Shih noted.
“It’ll be harder to implement these kinds of strategies, but it seems like the right way to go,” she added.
The study was funded by the National Cancer Institute. Dr. Shih reports grants from the National Cancer Institute during the conduct of the study and personal fees from Pfizer and AstraZeneca outside the submitted work. Dr. Kerlikowske is an unpaid consultant for GRAIL for the STRIVE study. Dr. Bibbins-Domingo has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The result would then be used to stratify further screening, with annual screening starting at age 40 for average-risk women who have dense breasts, and screening every 2 years starting at age 50 for women without dense breasts.
Such an approach would be cost effective and offers a more targeted risk-based strategy for the early detection of breast cancer when compared with current practices, say the authors, led by Tina Shih, PhD, University of Texas MD Anderson Cancer Center, Houston.
Their modeling study was published online in the Annals of Internal Medicine.
However, experts writing in an accompanying editorial are not persuaded. Karla Kerlikowske, MD, and Kirsten Bibbins-Domingo, MD, PhD, both from the University of California, San Francisco, point out that not all women with dense breasts are at increased risk for breast cancer. They caution against relying on breast density alone when determining screening strategies, and say age and other risk factors also need to be considered.
New approach proposed
Current recommendations from the United States Preventive Services Task Force suggest that women in their 40s can choose to undergo screening mammography based on their own personal preference, Dr. Shih explained in an interview.
However, these recommendations do not take into consideration the additional risk that breast density confers on breast cancer risk – and the only way women can know their breast density is to have a mammogram. “If you follow [current] guidelines, you would not know about your breast density until the age of 45 or 50,” she commented.
“But what if you knew about breast density earlier on and then acted on it –would that make a difference?” This was the question her team set out to explore.
For their study, the authors defined women with dense breasts as those with the Breast Imaging Reporting and Data System (BI-RADS) category C (heterogeneously dense breasts) and category D (extremely dense breasts).
The team used a computer model to compare seven different breast screening strategies:
- No screening.
- Triennial mammography from age 50 to 75 years (T50).
- Biennial mammography from age 50 to 75 years (B50).
- Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and triennial. screening from age 50 to 75 for women without dense breasts at the age of 50 (SA50T50).
- Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and biennial screening from age 50 to 75 for those without dense breast at age 50 (SA50B50).
- Stratified annual mammography from age 40 to 75 for women with dense breasts at age 49, and triennial screening from age 50 to 75 for those without dense breasts at age 40 (SA40T50).
- Stratified annual mammography from age 40 to 75 for women with dense breasts at age 40, and biennial mammography for women from age 50 to 75 without dense breasts at age 40 (SA40B50).
Compared with a no-screening strategy, the average number of mammography sessions through a woman’s lifetime would increase from seven mammograms per lifetime for the least frequent screening (T50) to 22 mammograms per lifetime for the most intensive screening schedule, the team reports.
Compared with no screening, screening would reduce breast cancer deaths by 8.6 per 1,000 women (T50)–13.2 per 1,000 women (SA40B50).
A cost-effectiveness analysis showed that the proposed new approach (SA40B50) yielded an incremental cost-effectiveness ratio of $36,200 per quality-adjusted life-year (QALY), compared with the currently recommended biennial screening strategy. This is well within the willingness-to-pay threshold of $100,000 per QALY that is generally accepted by society, the authors point out.
On the other hand, false-positive results and overdiagnosis would increase, the authors note.
The average number of false positives would increase from 141.2 per 1,000 women who underwent the least frequent triennial mammography screening schedule (T50) to 567.3 per 1,000 women with the new approach (SA40B50).
Rates of overdiagnosis would also increase from a low of 12.5% to a high of 18.6%, they add.
“With this study, we are not saying that everybody should start screening at the age of 40. We’re just saying, do a baseline mammography at 40, know your breast density status, and then we can try to modify the screening schedule based on individual risk,” Dr. Shih emphasized.
“Compared with other screening strategies examined in our study, this strategy is associated with the greatest reduction in breast cancer mortality and is cost effective, [although it] involves the most screening mammograms in a woman’s lifetime and higher rates of false-positive results and overdiagnosis,” the authors conclude.
Fundamental problem with this approach
The fundamental problem with this approach of stratifying risk on measurement of breast density – and on the basis of a single reading – is that not every woman with dense breasts is at increased risk for breast cancer, the editorialists comment.
Dr. Kerlikowske and Dr. Bibbins-Domingo point out that, in fact, only about one-quarter of women with dense breasts are at high risk for a missed invasive cancer within 1 year of a negative mammogram, and these women can be identified by using the Breast Cancer Surveillance Consortium risk model.
“This observation means that most women with dense breasts can undergo biennial screening and need not consider annual screening or supplemental imaging,” the editorialists write.
“Thus, we caution against using breast density alone to determine if a woman is at elevated risk for breast cancer,” they emphasize.
An alternative option is to focus on overall risk to select screening strategies, they suggest. For example, most guidelines recommend screening from age 50 to 74, so identifying women in their 40s who have the same risk of a woman aged 50-59 is one way to determine who may benefit from earlier initiation of screening, the editorialists observe.
“Thus, women who have a first-degree relative with breast cancer or a history of breast biopsy could be offered screening in their 40s, and, if mammography shows dense breasts, they could continue biennial screening through their 40s,” the editorialists observe. “Such women with nondense breasts could resume biennial screening at age 50 years.”
Dr. Shih told this news organization that she did not disagree with the editorialists’ suggestion that physicians could focus on overall breast cancer risk to select an appropriate screening strategy for individual patients.
“What we are suggesting is, ‘Let’s just do a baseline assessment at the age of 40 so women know their breast density instead of waiting until they are older,’ “ she said.
“But what the editorialists are suggesting is a strategy that could be even more cost effective,” she acknowledged. Dr. Shih also said that Dr. Kerlikowske and Dr. Bibbins-Domingo’s estimate that only one-quarter of women with dense breasts are actually at high risk for breast cancer likely reflects their limitation of breast density to only those women with BI-RADs category “D” – extremely dense breasts.
Yet as Dr. Shih notes, women with category C and category D breast densities are both at higher risk for breast cancer, so ignoring women with lesser degrees of breast density still doesn’t address the fact that they have a higher-than-average risk for breast cancer.
“It’s getting harder to make universal screening strategies work as we are learning more and more about breast cancer, so people are starting to talk about screening strategies based on a patient’s risk classification,” Dr. Shih noted.
“It’ll be harder to implement these kinds of strategies, but it seems like the right way to go,” she added.
The study was funded by the National Cancer Institute. Dr. Shih reports grants from the National Cancer Institute during the conduct of the study and personal fees from Pfizer and AstraZeneca outside the submitted work. Dr. Kerlikowske is an unpaid consultant for GRAIL for the STRIVE study. Dr. Bibbins-Domingo has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The result would then be used to stratify further screening, with annual screening starting at age 40 for average-risk women who have dense breasts, and screening every 2 years starting at age 50 for women without dense breasts.
Such an approach would be cost effective and offers a more targeted risk-based strategy for the early detection of breast cancer when compared with current practices, say the authors, led by Tina Shih, PhD, University of Texas MD Anderson Cancer Center, Houston.
Their modeling study was published online in the Annals of Internal Medicine.
However, experts writing in an accompanying editorial are not persuaded. Karla Kerlikowske, MD, and Kirsten Bibbins-Domingo, MD, PhD, both from the University of California, San Francisco, point out that not all women with dense breasts are at increased risk for breast cancer. They caution against relying on breast density alone when determining screening strategies, and say age and other risk factors also need to be considered.
New approach proposed
Current recommendations from the United States Preventive Services Task Force suggest that women in their 40s can choose to undergo screening mammography based on their own personal preference, Dr. Shih explained in an interview.
However, these recommendations do not take into consideration the additional risk that breast density confers on breast cancer risk – and the only way women can know their breast density is to have a mammogram. “If you follow [current] guidelines, you would not know about your breast density until the age of 45 or 50,” she commented.
“But what if you knew about breast density earlier on and then acted on it –would that make a difference?” This was the question her team set out to explore.
For their study, the authors defined women with dense breasts as those with the Breast Imaging Reporting and Data System (BI-RADS) category C (heterogeneously dense breasts) and category D (extremely dense breasts).
The team used a computer model to compare seven different breast screening strategies:
- No screening.
- Triennial mammography from age 50 to 75 years (T50).
- Biennial mammography from age 50 to 75 years (B50).
- Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and triennial. screening from age 50 to 75 for women without dense breasts at the age of 50 (SA50T50).
- Stratified annual mammography from age 50 to 75 for women with dense breasts at age 50, and biennial screening from age 50 to 75 for those without dense breast at age 50 (SA50B50).
- Stratified annual mammography from age 40 to 75 for women with dense breasts at age 49, and triennial screening from age 50 to 75 for those without dense breasts at age 40 (SA40T50).
- Stratified annual mammography from age 40 to 75 for women with dense breasts at age 40, and biennial mammography for women from age 50 to 75 without dense breasts at age 40 (SA40B50).
Compared with a no-screening strategy, the average number of mammography sessions through a woman’s lifetime would increase from seven mammograms per lifetime for the least frequent screening (T50) to 22 mammograms per lifetime for the most intensive screening schedule, the team reports.
Compared with no screening, screening would reduce breast cancer deaths by 8.6 per 1,000 women (T50)–13.2 per 1,000 women (SA40B50).
A cost-effectiveness analysis showed that the proposed new approach (SA40B50) yielded an incremental cost-effectiveness ratio of $36,200 per quality-adjusted life-year (QALY), compared with the currently recommended biennial screening strategy. This is well within the willingness-to-pay threshold of $100,000 per QALY that is generally accepted by society, the authors point out.
On the other hand, false-positive results and overdiagnosis would increase, the authors note.
The average number of false positives would increase from 141.2 per 1,000 women who underwent the least frequent triennial mammography screening schedule (T50) to 567.3 per 1,000 women with the new approach (SA40B50).
Rates of overdiagnosis would also increase from a low of 12.5% to a high of 18.6%, they add.
“With this study, we are not saying that everybody should start screening at the age of 40. We’re just saying, do a baseline mammography at 40, know your breast density status, and then we can try to modify the screening schedule based on individual risk,” Dr. Shih emphasized.
“Compared with other screening strategies examined in our study, this strategy is associated with the greatest reduction in breast cancer mortality and is cost effective, [although it] involves the most screening mammograms in a woman’s lifetime and higher rates of false-positive results and overdiagnosis,” the authors conclude.
Fundamental problem with this approach
The fundamental problem with this approach of stratifying risk on measurement of breast density – and on the basis of a single reading – is that not every woman with dense breasts is at increased risk for breast cancer, the editorialists comment.
Dr. Kerlikowske and Dr. Bibbins-Domingo point out that, in fact, only about one-quarter of women with dense breasts are at high risk for a missed invasive cancer within 1 year of a negative mammogram, and these women can be identified by using the Breast Cancer Surveillance Consortium risk model.
“This observation means that most women with dense breasts can undergo biennial screening and need not consider annual screening or supplemental imaging,” the editorialists write.
“Thus, we caution against using breast density alone to determine if a woman is at elevated risk for breast cancer,” they emphasize.
An alternative option is to focus on overall risk to select screening strategies, they suggest. For example, most guidelines recommend screening from age 50 to 74, so identifying women in their 40s who have the same risk of a woman aged 50-59 is one way to determine who may benefit from earlier initiation of screening, the editorialists observe.
“Thus, women who have a first-degree relative with breast cancer or a history of breast biopsy could be offered screening in their 40s, and, if mammography shows dense breasts, they could continue biennial screening through their 40s,” the editorialists observe. “Such women with nondense breasts could resume biennial screening at age 50 years.”
Dr. Shih told this news organization that she did not disagree with the editorialists’ suggestion that physicians could focus on overall breast cancer risk to select an appropriate screening strategy for individual patients.
“What we are suggesting is, ‘Let’s just do a baseline assessment at the age of 40 so women know their breast density instead of waiting until they are older,’ “ she said.
“But what the editorialists are suggesting is a strategy that could be even more cost effective,” she acknowledged. Dr. Shih also said that Dr. Kerlikowske and Dr. Bibbins-Domingo’s estimate that only one-quarter of women with dense breasts are actually at high risk for breast cancer likely reflects their limitation of breast density to only those women with BI-RADs category “D” – extremely dense breasts.
Yet as Dr. Shih notes, women with category C and category D breast densities are both at higher risk for breast cancer, so ignoring women with lesser degrees of breast density still doesn’t address the fact that they have a higher-than-average risk for breast cancer.
“It’s getting harder to make universal screening strategies work as we are learning more and more about breast cancer, so people are starting to talk about screening strategies based on a patient’s risk classification,” Dr. Shih noted.
“It’ll be harder to implement these kinds of strategies, but it seems like the right way to go,” she added.
The study was funded by the National Cancer Institute. Dr. Shih reports grants from the National Cancer Institute during the conduct of the study and personal fees from Pfizer and AstraZeneca outside the submitted work. Dr. Kerlikowske is an unpaid consultant for GRAIL for the STRIVE study. Dr. Bibbins-Domingo has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Anybody for a nanobody? Novel psoriasis therapy impresses in phase 2b
in a phase 2b randomized trial, Kim A. Papp, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.
A nanobody is a tiny antibody fragment with a much smaller molecular weight than the monoclonal antibodies utilized today in treating psoriasis or atopic dermatitis. The sonelokinab nanobody, derived from animals in the camel family, is a recombinant sequence-optimized nanobody specific for human IL-17F, IL-17A, the heterodimer IL-17A/F, and serum albumin. The binding to serum albumin give sonelokinab a lengthy half-life of 10-12 hours, which may be therapeutically relevant, explained Dr. Papp, president and founder of Probity Medical Research in Waterloo, Ont.
He presented the 24-week results of a multicenter, double-blind, double-dummy randomized trial including 313 North American and European adults with an average 18-year history of psoriasis and a baseline Psoriasis Area and Severity Index (PASI) score of about 21. They were randomized to one of six treatment arms for the first 12 weeks: subcutaneous injection of sonelokinab at 30, 60, or 120 mg at weeks 0, 2, 4, and 8; enhanced–loading-dose sonelokinab at 120 mg every 2 weeks through week 10; the IL-17A inhibitor secukinumab (Cosentyx) at its standard dosing as an active comparator; or placebo. Data analysis was by rigorous nonresponder imputation, meaning anyone who didn’t complete the study was scored as a nonresponder.
“This yields a conservative data analysis somewhat biased against sonelokinab,” the dermatologist pointed out.
The primary outcome in the trial was the week-12 rate of an Investigator’s Global Assessment score of 0 or 1, indicative of clear or almost clear skin. This was achieved in 88.2% of patients in the highest-dose arm of sonelokinab. That group also had a week-12 PASI 90 response rate of 76.5% and a PASI 100 response rate of 33.3%. By comparison, patients on standard-dose secukinumab had a less robust week-12 IGA 0/1 rate of 77.4%, a PASI 90 of 64.2%, and a PASI 100 of 28.3%. Of note, however, this secukinumab performance was better than seen in the 30-mg sonelokinab group, and comparable to outcomes with 60 mg of sonelokinab.
Dose escalation was performed from weeks 12-24. Patients with a week-12 IGA score greater than 1 after being on sonelokinab at 30 or 60 mg were upgraded to 120 mg at week 12 and again every 4 weeks thereafter. Placebo-treated controls were switched to 120 mg at weeks 12, 14, 16, and every 4 weeks thereafter. The group on the enhanced–loading-dose sonelokinab moved to 120 mg every 4 weeks, while those who had gotten four doses of sonelokinab at 120 mg during the first 12 weeks were switched to 120 mg every 8 weeks. The secukinumab group remained on the approved dosing through week 24.
At week 24, superior outcomes were seen in the enhanced–loading-dose sonelokinab group, with an IGA 0/1 response rate of 94.2%, a PASI 90 of 90.4%, and a PASI 100 of 56.9%. The corresponding week-24 rates in patients on 120 mg of sonelokinab every 8 weeks from week 12 on were 80.4%, 79.2%, and 40.4%, outcomes similar to those seen with secukinumab.
The rapidity of response to sonelokinab at 120 mg was striking, with approximately one-third of treated patients achieving a PASI 90 response by week 4.
“This could reflect the smaller molecular profile. There is possibly rapid increased absorption or bioavailability, quicker time to achieving serum half-life, better penetration into target tissue, and perhaps more effective engagement at the target. All of those things are possibilities. These are things that are yet to be explored, but it’s very enticing to see that uncharacteristically rapid initial response. It’s all very gratifying – and tantalizing,” Dr. Papp said in response to an audience question.
The safety profile of sonelokinab was reassuring. The most common adverse events were nasopharyngitis in 13.5% of patients and pruritus in 6.7%, with most cases being mild or moderate. As with other IL-17 blockers, there was an increase in oral candidiasis. This side effect appeared to occur in dose-dependent fashion: The incidence was zero in the 30-mg group, 1.9% with 60 mg, 3.8% with sonelokinab at 120 mg without an enhanced loading dose, and 5.9% with the enhanced loading dose.
The study was conducted by Avillion in partnership with Merck. Dr. Papp reported receiving research funding from and serving as a consultant to those and numerous other pharmaceutical companies.
in a phase 2b randomized trial, Kim A. Papp, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.
A nanobody is a tiny antibody fragment with a much smaller molecular weight than the monoclonal antibodies utilized today in treating psoriasis or atopic dermatitis. The sonelokinab nanobody, derived from animals in the camel family, is a recombinant sequence-optimized nanobody specific for human IL-17F, IL-17A, the heterodimer IL-17A/F, and serum albumin. The binding to serum albumin give sonelokinab a lengthy half-life of 10-12 hours, which may be therapeutically relevant, explained Dr. Papp, president and founder of Probity Medical Research in Waterloo, Ont.
He presented the 24-week results of a multicenter, double-blind, double-dummy randomized trial including 313 North American and European adults with an average 18-year history of psoriasis and a baseline Psoriasis Area and Severity Index (PASI) score of about 21. They were randomized to one of six treatment arms for the first 12 weeks: subcutaneous injection of sonelokinab at 30, 60, or 120 mg at weeks 0, 2, 4, and 8; enhanced–loading-dose sonelokinab at 120 mg every 2 weeks through week 10; the IL-17A inhibitor secukinumab (Cosentyx) at its standard dosing as an active comparator; or placebo. Data analysis was by rigorous nonresponder imputation, meaning anyone who didn’t complete the study was scored as a nonresponder.
“This yields a conservative data analysis somewhat biased against sonelokinab,” the dermatologist pointed out.
The primary outcome in the trial was the week-12 rate of an Investigator’s Global Assessment score of 0 or 1, indicative of clear or almost clear skin. This was achieved in 88.2% of patients in the highest-dose arm of sonelokinab. That group also had a week-12 PASI 90 response rate of 76.5% and a PASI 100 response rate of 33.3%. By comparison, patients on standard-dose secukinumab had a less robust week-12 IGA 0/1 rate of 77.4%, a PASI 90 of 64.2%, and a PASI 100 of 28.3%. Of note, however, this secukinumab performance was better than seen in the 30-mg sonelokinab group, and comparable to outcomes with 60 mg of sonelokinab.
Dose escalation was performed from weeks 12-24. Patients with a week-12 IGA score greater than 1 after being on sonelokinab at 30 or 60 mg were upgraded to 120 mg at week 12 and again every 4 weeks thereafter. Placebo-treated controls were switched to 120 mg at weeks 12, 14, 16, and every 4 weeks thereafter. The group on the enhanced–loading-dose sonelokinab moved to 120 mg every 4 weeks, while those who had gotten four doses of sonelokinab at 120 mg during the first 12 weeks were switched to 120 mg every 8 weeks. The secukinumab group remained on the approved dosing through week 24.
At week 24, superior outcomes were seen in the enhanced–loading-dose sonelokinab group, with an IGA 0/1 response rate of 94.2%, a PASI 90 of 90.4%, and a PASI 100 of 56.9%. The corresponding week-24 rates in patients on 120 mg of sonelokinab every 8 weeks from week 12 on were 80.4%, 79.2%, and 40.4%, outcomes similar to those seen with secukinumab.
The rapidity of response to sonelokinab at 120 mg was striking, with approximately one-third of treated patients achieving a PASI 90 response by week 4.
“This could reflect the smaller molecular profile. There is possibly rapid increased absorption or bioavailability, quicker time to achieving serum half-life, better penetration into target tissue, and perhaps more effective engagement at the target. All of those things are possibilities. These are things that are yet to be explored, but it’s very enticing to see that uncharacteristically rapid initial response. It’s all very gratifying – and tantalizing,” Dr. Papp said in response to an audience question.
The safety profile of sonelokinab was reassuring. The most common adverse events were nasopharyngitis in 13.5% of patients and pruritus in 6.7%, with most cases being mild or moderate. As with other IL-17 blockers, there was an increase in oral candidiasis. This side effect appeared to occur in dose-dependent fashion: The incidence was zero in the 30-mg group, 1.9% with 60 mg, 3.8% with sonelokinab at 120 mg without an enhanced loading dose, and 5.9% with the enhanced loading dose.
The study was conducted by Avillion in partnership with Merck. Dr. Papp reported receiving research funding from and serving as a consultant to those and numerous other pharmaceutical companies.
in a phase 2b randomized trial, Kim A. Papp, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.
A nanobody is a tiny antibody fragment with a much smaller molecular weight than the monoclonal antibodies utilized today in treating psoriasis or atopic dermatitis. The sonelokinab nanobody, derived from animals in the camel family, is a recombinant sequence-optimized nanobody specific for human IL-17F, IL-17A, the heterodimer IL-17A/F, and serum albumin. The binding to serum albumin give sonelokinab a lengthy half-life of 10-12 hours, which may be therapeutically relevant, explained Dr. Papp, president and founder of Probity Medical Research in Waterloo, Ont.
He presented the 24-week results of a multicenter, double-blind, double-dummy randomized trial including 313 North American and European adults with an average 18-year history of psoriasis and a baseline Psoriasis Area and Severity Index (PASI) score of about 21. They were randomized to one of six treatment arms for the first 12 weeks: subcutaneous injection of sonelokinab at 30, 60, or 120 mg at weeks 0, 2, 4, and 8; enhanced–loading-dose sonelokinab at 120 mg every 2 weeks through week 10; the IL-17A inhibitor secukinumab (Cosentyx) at its standard dosing as an active comparator; or placebo. Data analysis was by rigorous nonresponder imputation, meaning anyone who didn’t complete the study was scored as a nonresponder.
“This yields a conservative data analysis somewhat biased against sonelokinab,” the dermatologist pointed out.
The primary outcome in the trial was the week-12 rate of an Investigator’s Global Assessment score of 0 or 1, indicative of clear or almost clear skin. This was achieved in 88.2% of patients in the highest-dose arm of sonelokinab. That group also had a week-12 PASI 90 response rate of 76.5% and a PASI 100 response rate of 33.3%. By comparison, patients on standard-dose secukinumab had a less robust week-12 IGA 0/1 rate of 77.4%, a PASI 90 of 64.2%, and a PASI 100 of 28.3%. Of note, however, this secukinumab performance was better than seen in the 30-mg sonelokinab group, and comparable to outcomes with 60 mg of sonelokinab.
Dose escalation was performed from weeks 12-24. Patients with a week-12 IGA score greater than 1 after being on sonelokinab at 30 or 60 mg were upgraded to 120 mg at week 12 and again every 4 weeks thereafter. Placebo-treated controls were switched to 120 mg at weeks 12, 14, 16, and every 4 weeks thereafter. The group on the enhanced–loading-dose sonelokinab moved to 120 mg every 4 weeks, while those who had gotten four doses of sonelokinab at 120 mg during the first 12 weeks were switched to 120 mg every 8 weeks. The secukinumab group remained on the approved dosing through week 24.
At week 24, superior outcomes were seen in the enhanced–loading-dose sonelokinab group, with an IGA 0/1 response rate of 94.2%, a PASI 90 of 90.4%, and a PASI 100 of 56.9%. The corresponding week-24 rates in patients on 120 mg of sonelokinab every 8 weeks from week 12 on were 80.4%, 79.2%, and 40.4%, outcomes similar to those seen with secukinumab.
The rapidity of response to sonelokinab at 120 mg was striking, with approximately one-third of treated patients achieving a PASI 90 response by week 4.
“This could reflect the smaller molecular profile. There is possibly rapid increased absorption or bioavailability, quicker time to achieving serum half-life, better penetration into target tissue, and perhaps more effective engagement at the target. All of those things are possibilities. These are things that are yet to be explored, but it’s very enticing to see that uncharacteristically rapid initial response. It’s all very gratifying – and tantalizing,” Dr. Papp said in response to an audience question.
The safety profile of sonelokinab was reassuring. The most common adverse events were nasopharyngitis in 13.5% of patients and pruritus in 6.7%, with most cases being mild or moderate. As with other IL-17 blockers, there was an increase in oral candidiasis. This side effect appeared to occur in dose-dependent fashion: The incidence was zero in the 30-mg group, 1.9% with 60 mg, 3.8% with sonelokinab at 120 mg without an enhanced loading dose, and 5.9% with the enhanced loading dose.
The study was conducted by Avillion in partnership with Merck. Dr. Papp reported receiving research funding from and serving as a consultant to those and numerous other pharmaceutical companies.
FROM the eadv congress
Puppy love: Is losing a pet too hard for children?
The big news in the Wilkoff household is that Marilyn and I will be celebrating the arrival of a granddog into our nuclear family. Our younger daughter and her husband will be welcoming into their home a golden retriever puppy the first week in March. This may not seem like big news to some families and is certainly a step down on the priority list to the arrival of the four grandchildren that we already claim on our resume. But, you must understand that no one in our family has ever owned a dog.
Although my wife’s family had a dog, she apparently never really bonded with the canine. My pleas and occasional whining from our three children to get a dog were always met with my wife’s concerns about cleanliness and hygiene. We did have an antisocial cat who lived under a bed in the guest room or in the basement. His passing after 16 years when the kids were in college was not an event marked with any emotion beyond relief.
I think I harbored an unspoken concern about how I and our children might respond emotionally and psychologically to the inevitable death of what would likely have become our family’s best friend. Dispatching a belly-up goldfish after a month or two is small potatoes compared to putting down a tail-wagging, frisbee-catching, four-footed member of the family.
It turns out that my concerns about the mental health of our children may not have been unfounded. A recently published study from the Harvard Medical School and Massachusetts General Hospital found that children who had experienced the death of a loved pet were more likely to exhibit symptoms of psychopathology than were those who had loved a pet who was still alive (Crawford et al. Eur Child Adolesc Psychiatry. 2020 Sep 10. doi: 10.1007/s00787-020-01594-5). The observed effect of the loss was more pronounced in boys. There was also no statistical difference between the psychopathology symptoms of those children who had loved and lost and those children who had never loved a pet.
By the time I left for college I had grown up with five different dogs. I had endured the loss of sweet Mary, the boxer, when we moved to a small apartment and had to send her to a “farm.” I had watched 2-year-old Blackie experience a seizure that heralded his fatal bout with distemper. I shared the struggle with my parents as we made the decision to send my much loved inveterate car chasing “Butch” back to the pound.
However, I survived these losses and wonder whether they in some way prepared me for some of the emotional challenges that would come later in life. This study from Harvard sampled only children from birth to age 8 years. For those of us in primary care a more interesting study might be one that looked for any long-term associations between pet loss as a young child with adolescent and adult mental health. With the surge in pet ownership that has surfaced during the pandemic, there should be an abundance of clinical material to mine. The Harvard researchers’ findings should make us aware of the potential for psychopathology in a child who has suffered the loss of a pet. Each family must decide whether the plusses of pet ownership are worth the risk. However, I side with Tennyson who said it is better to have loved and lost than never to have loved at all.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
The big news in the Wilkoff household is that Marilyn and I will be celebrating the arrival of a granddog into our nuclear family. Our younger daughter and her husband will be welcoming into their home a golden retriever puppy the first week in March. This may not seem like big news to some families and is certainly a step down on the priority list to the arrival of the four grandchildren that we already claim on our resume. But, you must understand that no one in our family has ever owned a dog.
Although my wife’s family had a dog, she apparently never really bonded with the canine. My pleas and occasional whining from our three children to get a dog were always met with my wife’s concerns about cleanliness and hygiene. We did have an antisocial cat who lived under a bed in the guest room or in the basement. His passing after 16 years when the kids were in college was not an event marked with any emotion beyond relief.
I think I harbored an unspoken concern about how I and our children might respond emotionally and psychologically to the inevitable death of what would likely have become our family’s best friend. Dispatching a belly-up goldfish after a month or two is small potatoes compared to putting down a tail-wagging, frisbee-catching, four-footed member of the family.
It turns out that my concerns about the mental health of our children may not have been unfounded. A recently published study from the Harvard Medical School and Massachusetts General Hospital found that children who had experienced the death of a loved pet were more likely to exhibit symptoms of psychopathology than were those who had loved a pet who was still alive (Crawford et al. Eur Child Adolesc Psychiatry. 2020 Sep 10. doi: 10.1007/s00787-020-01594-5). The observed effect of the loss was more pronounced in boys. There was also no statistical difference between the psychopathology symptoms of those children who had loved and lost and those children who had never loved a pet.
By the time I left for college I had grown up with five different dogs. I had endured the loss of sweet Mary, the boxer, when we moved to a small apartment and had to send her to a “farm.” I had watched 2-year-old Blackie experience a seizure that heralded his fatal bout with distemper. I shared the struggle with my parents as we made the decision to send my much loved inveterate car chasing “Butch” back to the pound.
However, I survived these losses and wonder whether they in some way prepared me for some of the emotional challenges that would come later in life. This study from Harvard sampled only children from birth to age 8 years. For those of us in primary care a more interesting study might be one that looked for any long-term associations between pet loss as a young child with adolescent and adult mental health. With the surge in pet ownership that has surfaced during the pandemic, there should be an abundance of clinical material to mine. The Harvard researchers’ findings should make us aware of the potential for psychopathology in a child who has suffered the loss of a pet. Each family must decide whether the plusses of pet ownership are worth the risk. However, I side with Tennyson who said it is better to have loved and lost than never to have loved at all.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
The big news in the Wilkoff household is that Marilyn and I will be celebrating the arrival of a granddog into our nuclear family. Our younger daughter and her husband will be welcoming into their home a golden retriever puppy the first week in March. This may not seem like big news to some families and is certainly a step down on the priority list to the arrival of the four grandchildren that we already claim on our resume. But, you must understand that no one in our family has ever owned a dog.
Although my wife’s family had a dog, she apparently never really bonded with the canine. My pleas and occasional whining from our three children to get a dog were always met with my wife’s concerns about cleanliness and hygiene. We did have an antisocial cat who lived under a bed in the guest room or in the basement. His passing after 16 years when the kids were in college was not an event marked with any emotion beyond relief.
I think I harbored an unspoken concern about how I and our children might respond emotionally and psychologically to the inevitable death of what would likely have become our family’s best friend. Dispatching a belly-up goldfish after a month or two is small potatoes compared to putting down a tail-wagging, frisbee-catching, four-footed member of the family.
It turns out that my concerns about the mental health of our children may not have been unfounded. A recently published study from the Harvard Medical School and Massachusetts General Hospital found that children who had experienced the death of a loved pet were more likely to exhibit symptoms of psychopathology than were those who had loved a pet who was still alive (Crawford et al. Eur Child Adolesc Psychiatry. 2020 Sep 10. doi: 10.1007/s00787-020-01594-5). The observed effect of the loss was more pronounced in boys. There was also no statistical difference between the psychopathology symptoms of those children who had loved and lost and those children who had never loved a pet.
By the time I left for college I had grown up with five different dogs. I had endured the loss of sweet Mary, the boxer, when we moved to a small apartment and had to send her to a “farm.” I had watched 2-year-old Blackie experience a seizure that heralded his fatal bout with distemper. I shared the struggle with my parents as we made the decision to send my much loved inveterate car chasing “Butch” back to the pound.
However, I survived these losses and wonder whether they in some way prepared me for some of the emotional challenges that would come later in life. This study from Harvard sampled only children from birth to age 8 years. For those of us in primary care a more interesting study might be one that looked for any long-term associations between pet loss as a young child with adolescent and adult mental health. With the surge in pet ownership that has surfaced during the pandemic, there should be an abundance of clinical material to mine. The Harvard researchers’ findings should make us aware of the potential for psychopathology in a child who has suffered the loss of a pet. Each family must decide whether the plusses of pet ownership are worth the risk. However, I side with Tennyson who said it is better to have loved and lost than never to have loved at all.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
Glucosuria Is Not Always Due to Diabetes
Familial renal glucosuria is an uncommon, rarely documented condition wherein the absence of other renal or endocrine conditions and with a normal serum glucose level, glucosuria persists due to an isolated defect in the nephron’s proximal tubule. Seemingly, in these patients, the body’s physiologic function mimics that of sodiumglucose cotransporter-2 (SGLT2)-inhibiting medications with the glucose cotransporter being selectively targeted for promoting renal excretion of glucose. This has implications for the patient’s prospective development of hyperglycemic diseases, urinary tract infections (UTIs), and potentially even cardiovascular disease. Though it is a generally asymptomatic condition, it is one that seasoned clinicians should investigate given the future impacts and considerations required for their patients.
Case Presentation
Mr. A was a 28-year-old male with no medical history nor prescription medication use who presented to the nephrology clinic at Eglin Air Force Base, Florida, in June 2019 for a workup of asymptomatic glucosuria. The condition was discovered on a routine urinalysis in October 2015 at the initial presentation at Eglin Air Force Base, when the patient was being evaluated by his primary care physician for acute, benign headache with fever and chills. Urinalysis testing was performed in October 2015 and resulted in a urine glucose of 500 mg/dL (2+). He was directed to the emergency department for further evaluation, reciprocating the results.
On further laboratory testing in October 2015, his blood glucose was normal at 75 mg/dL; hemoglobin A1c was 5.5%. On repeat urinalysis 2 weeks later, his urinary glucose was found to be 500 mg/dL (2+). Each time, the elevated urinary glucose was the only abnormal finding: There was no concurrent hematuria, proteinuria, or ketonuria. The patient reported he had no associated symptoms, including nausea, vomiting, abdominal pain, dysuria, polyuria, and increased thirst. He was not taking any prescription medications, including SGLT2 inhibitors. His presenting headache and fever resolved with supportive care and was considered unrelated to his additional workup.
A diagnostic evaluation ensued from 2015 to 2020, including follow-up urinalyses, metabolic panels, complete blood counts, urine protein electrophoresis (UPEP), urine creatinine, urine electrolytes, 25-OH vitamin D level, κ/λ light chain panel, and serum protein electrophoresis (SPEP). The results of all diagnostic workup throughout the entirety of his evaluation were found to be normal. In 2020, his 25-OH vitamin D level was borderline low at 29.4 ng/mL. His κ/λ ratio was normal at 1.65, and his serum albumin protein electrophoresis was 4.74 g/dL, marginally elevated, but his SPEP and UPEP were normal, as were urine protein levels, total gamma globulin, and no monoclonal gamma spike noted on pathology review. Serum uric acid, and urine phosphorous were both normal. His serum creatinine and electrolytes were all within normal limits. Over the 5 years of intermittent monitoring, the maximum amount of glucosuria was 1,000 mg/dL (3+) and the minimum was 250 mg/dL (1+). There was a gap of monitoring from March 2016 until June 2019 due to the patient receiving care from offsite health care providers without shared documentation of specific laboratory values, but notes documenting persistent glucosuria (Table).
Analysis
Building the initial differential diagnosis for this patient began with confirming that he had isolated glucosuria, and not glucosuria secondary to elevated serum glucose. Additionally, conditions related to generalized proximal tubule dysfunction, acute or chronic impaired renal function, and neoplasms, including multiple myeloma (MM), were eliminated because this patient did not have the other specific findings associated with these conditions.
Proximal tubulopathies, including proximal renal tubular acidosis (type 2) and Fanconi syndrome, was initially a leading diagnosis in this patient. Isolated proximal renal tubular acidosis (RTA) (type 2) is uncommon and pathophysiologically involves reduced proximal tubular reabsorption of bicarbonate, resulting in low serum bicarbonate and metabolic acidosis. Patients with isolated proximal RTA (type 2) typically present in infancy with failure to thrive, tachypnea, recurrent vomiting, and feeding difficulties. These symptoms do not meet our patient’s clinical presentation. Fanconi syndrome involves a specific disruption in the proximal tubular apical sodium uptake mechanism affecting the transmembrane sodium gradient and the sodium-potassium- ATPase pump. Fanconi syndrome, therefore, would not only present with glucosuria, but also classically with proteinuria, hypophosphatemia, hypokalemia, and a hyperchloremic metabolic acidosis.
Chronic or acute renal disease may present with glucosuria, but one would expect additional findings including elevated serum creatinine, elevated urinary creatinine, 25-OH vitamin D deficiency, or anemia of chronic disease. Other potential diagnoses included MM and similar neoplasms. MM also would present with glucosuria with proteinuria, an elevated κ/λ light chain ratio, and an elevated SPEP and concern for bone lytic lesions, which were not present. A related disorder, monoclonal gammopathy of renal significance (MGRS), akin to monoclonal gammopathy of unknown significance (MGUS), presents with proteinuria with evidence of renal injury. While this patient had a marginally elevated κ/λ light chain ratio, the remainder of his SPEP and UPEP were normal, and evaluation by a hematologist/ oncologist and pathology review of laboratory findings confirmed no additional evidence for MM, including no monoclonal γ spike. With no evidence of renal injury with a normal serum creatinine and glomerular filtration rate, MGRS was eliminated from the differential as it did not meet the International Myeloma Working Group diagnostic criteria.1 The elevated κ/λ ratio with normal renal function is attributed to polyclonal immunoglobulin elevation, which may occur more commonly with uncomplicated acute viral illnesses.
Diagnosis
The differential homed in on a targeted defect in the proximal tubular SGLT2 gene as the final diagnosis causing isolated glucosuria. Familial renal glucosuria (FRG), a condition caused by a mutation in the SLC5A2 gene that codes for the SGLT2 has been identified in the literature as causing cases with nearly identical presentations to this patient.2,3 This condition is often found in otherwise healthy, asymptomatic patients in whom isolated glucosuria was identified on routine urinalysis testing.
Due to isolated case reports sharing this finding and the asymptomatic nature of the condition, specific data pertaining to its prevalence are not available. Case studies of other affected individuals have not noted adverse effects (AEs), such as UTIs or hypotension specifically.2,3 The patient was referred for genetic testing for this gene mutation; however, he was unable to obtain the test due to lack of insurance coverage. Mr. A has no other family members that have been evaluated for or identified as having this condition. Despite the name, FRG has an unknown inheritance pattern and is attributed to a variety of missense mutations in the SLC5A2 gene.4,5
Discussion
The SGLT2 gene believed to be mutated in this patient has recently become wellknown. The inhibition of the SGLT2 transport protein has become an important tool in the management of type 2 diabetes mellitus (T2DM) independent of the insulin pathway. The SGLT2 in the proximal convoluted tubule of the kidney reabsorbs the majority, 98%, of the renal glucose for reabsorption, and the remaining glucose is reabsorbed by the SGLT2 gene in the more distal portion of the proximal tubule in healthy individuals.4,6 The normal renal threshold for glucose reabsorption in a patient with a normal glomerular filtration rate is equivalent to a serum glucose concentration of 180 mg/dL, even higher in patients with T2DM due to upregulation of the SGLT2 inhibitors. SGLT2 inhibitors, such as canagliflozin, dapagliflozin, and empagliflozin, selectively inhibit this cotransporter, reducing the threshold from 40 to 120 mg/dL, thereby significantly increasing the renal excretion of glucose.4 The patient’s mutation in question and clinical presentation aligned with a naturally occurring mimicry of this drug’s mechanism of action (Figure).
Arguably, one of the more significant benefits to using this new class of oral antihyperglycemics, aside from the noninferior glycemic control compared with that of other first-line agents, is the added metabolic benefit. To date, SGLT2 inhibitors have been found to decrease blood pressure in all studies of the medications and promote moderate weight loss.7 SGLT2 inhibitors have not only demonstrated significant cardiovascular (CV) benefits, linked with the aforementioned metabolic benefits, but also have reduced hospitalizations for heart failure in patients with T2DM and those without.7 The EMPA-REG OUTCOME trial showed a 38% relative risk reduction in CV events in empagliflozin vs placebo.4,8 However, it is unknown whether patients with the SLC5A2 mutation also benefit from these CV benefits akin to the SGLT2 inhibiting medications, and it is and worthy of studying via longterm follow-up with patients similar to this.
This SLC5A2 mutation causing FRG selectively inhibiting SGLT2 function effectively causes this patient’s natural physiology to mimic that of these new oral antihyperglycemic medications. Patients with FRG should be counseled regarding this condition and the implications it has on their overall health. At this time, there is no formal recommendation for short-term or longterm management of patients with FRG; observation and routine preventive care monitoring based on US Preventive Services Task Force screening recommendations apply to this population in line with the general population.
This condition is not known to be associated with hypotension or hypoglycemia, and to some extent, it can be theorized that patients with this condition may have inherent protection of development of hyperglycemia. 4 Akin to patients on SGLT2 inhibitors, these patients may be at an increased risk of UTIs and genital infections, including mycotic infections due to glycemic-related imbalance in the normal flora of the urinary tract.9 Other serious AEs of SGLT2 inhibitors, such as diabetic ketoacidosis, osteoporosis and related fractures, and acute pancreatitis, should be shared with FRG patients, though they are unlikely to be at increased risk for this condition in the setting of normal serum glucose and electrolyte levels. Notably, the osteoporosis risk is small, and specific other risk factors pertinent to individual patient’s medical history, and canagliflozin exclusively. If a patient with FRG develops T2DM after diagnosis, it is imperative that they inform physicians of their condition, because SGLT2-inhibiting drugs will be ineffective in this subset of patients, necessitating increased clinical judgment in selecting an appropriate antihyperglycemic agent in this population.
Conclusions
FRG is an uncommon diagnosis of exclusion that presents with isolated glucosuria in the setting of normal serum glucose. The patient generally presents asymptomatically with a urinalysis completed for other reasons, and the patient may or may not have a family history of similar findings. The condition is of particular interest given that its SGLT2 mutation mimics the effect of SGLT2 inhibitors used for T2DM. More monitoring of patients with this condition will be required for documentation regarding long-term implications, including development of further renal disease, T2DM, or CV disease.
1. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12). doi:10.1016/s1470-2045(14)70442-5
2. Calado J, Sznajer Y, Metzger D, et al. Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion. Nephrol Dial Transplant. 2008;23(12):3874-3879. doi.org/10.1093/ndt/gfn386
3. Kim KM, Kwon SK, Kim HY. A case of isolated glycosuria mediated by an SLC5A2 gene mutation and characterized by postprandial heavy glycosuria without salt wasting. Electrolyte Blood Press. 2016;14(2):35-37. doi:10.5049/EBP.2016.14.2.35
4. Hsia DS, Grove O, Cefalu WT. An update on sodiumglucose co-transporter-2 inhibitors for the treatment of diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2017;24(1):73-79. doi:10.1097/MED.0000000000000311
5. Kleta R. Renal glucosuria due to SGLT2 mutations. Mol Genet Metab. 2004;82(1):56-58. doi:10.1016/j.ymgme.2004.01.018
6. Neumiller JJ. Empagliflozin: a new sodium-glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. Drugs Context. 2014;3:212262. doi:10.7573/dic.212262
7. Raz I, Cernea S, Cahn A. SGLT2 inhibitors for primary prevention of cardiovascular events. J Diabetes. 2020;12(1):5- 7. doi:10.1111/1753-0407.13004
8. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/nejmoa1504720
9. Mcgill JB, Subramanian S. Safety of sodium-glucose cotransporter 2 inhibitors. Am J Cardiol. 2019;124(suppl 1):S45-S52. doi:10.1016/j.amjcard.2019.10.029
Familial renal glucosuria is an uncommon, rarely documented condition wherein the absence of other renal or endocrine conditions and with a normal serum glucose level, glucosuria persists due to an isolated defect in the nephron’s proximal tubule. Seemingly, in these patients, the body’s physiologic function mimics that of sodiumglucose cotransporter-2 (SGLT2)-inhibiting medications with the glucose cotransporter being selectively targeted for promoting renal excretion of glucose. This has implications for the patient’s prospective development of hyperglycemic diseases, urinary tract infections (UTIs), and potentially even cardiovascular disease. Though it is a generally asymptomatic condition, it is one that seasoned clinicians should investigate given the future impacts and considerations required for their patients.
Case Presentation
Mr. A was a 28-year-old male with no medical history nor prescription medication use who presented to the nephrology clinic at Eglin Air Force Base, Florida, in June 2019 for a workup of asymptomatic glucosuria. The condition was discovered on a routine urinalysis in October 2015 at the initial presentation at Eglin Air Force Base, when the patient was being evaluated by his primary care physician for acute, benign headache with fever and chills. Urinalysis testing was performed in October 2015 and resulted in a urine glucose of 500 mg/dL (2+). He was directed to the emergency department for further evaluation, reciprocating the results.
On further laboratory testing in October 2015, his blood glucose was normal at 75 mg/dL; hemoglobin A1c was 5.5%. On repeat urinalysis 2 weeks later, his urinary glucose was found to be 500 mg/dL (2+). Each time, the elevated urinary glucose was the only abnormal finding: There was no concurrent hematuria, proteinuria, or ketonuria. The patient reported he had no associated symptoms, including nausea, vomiting, abdominal pain, dysuria, polyuria, and increased thirst. He was not taking any prescription medications, including SGLT2 inhibitors. His presenting headache and fever resolved with supportive care and was considered unrelated to his additional workup.
A diagnostic evaluation ensued from 2015 to 2020, including follow-up urinalyses, metabolic panels, complete blood counts, urine protein electrophoresis (UPEP), urine creatinine, urine electrolytes, 25-OH vitamin D level, κ/λ light chain panel, and serum protein electrophoresis (SPEP). The results of all diagnostic workup throughout the entirety of his evaluation were found to be normal. In 2020, his 25-OH vitamin D level was borderline low at 29.4 ng/mL. His κ/λ ratio was normal at 1.65, and his serum albumin protein electrophoresis was 4.74 g/dL, marginally elevated, but his SPEP and UPEP were normal, as were urine protein levels, total gamma globulin, and no monoclonal gamma spike noted on pathology review. Serum uric acid, and urine phosphorous were both normal. His serum creatinine and electrolytes were all within normal limits. Over the 5 years of intermittent monitoring, the maximum amount of glucosuria was 1,000 mg/dL (3+) and the minimum was 250 mg/dL (1+). There was a gap of monitoring from March 2016 until June 2019 due to the patient receiving care from offsite health care providers without shared documentation of specific laboratory values, but notes documenting persistent glucosuria (Table).
Analysis
Building the initial differential diagnosis for this patient began with confirming that he had isolated glucosuria, and not glucosuria secondary to elevated serum glucose. Additionally, conditions related to generalized proximal tubule dysfunction, acute or chronic impaired renal function, and neoplasms, including multiple myeloma (MM), were eliminated because this patient did not have the other specific findings associated with these conditions.
Proximal tubulopathies, including proximal renal tubular acidosis (type 2) and Fanconi syndrome, was initially a leading diagnosis in this patient. Isolated proximal renal tubular acidosis (RTA) (type 2) is uncommon and pathophysiologically involves reduced proximal tubular reabsorption of bicarbonate, resulting in low serum bicarbonate and metabolic acidosis. Patients with isolated proximal RTA (type 2) typically present in infancy with failure to thrive, tachypnea, recurrent vomiting, and feeding difficulties. These symptoms do not meet our patient’s clinical presentation. Fanconi syndrome involves a specific disruption in the proximal tubular apical sodium uptake mechanism affecting the transmembrane sodium gradient and the sodium-potassium- ATPase pump. Fanconi syndrome, therefore, would not only present with glucosuria, but also classically with proteinuria, hypophosphatemia, hypokalemia, and a hyperchloremic metabolic acidosis.
Chronic or acute renal disease may present with glucosuria, but one would expect additional findings including elevated serum creatinine, elevated urinary creatinine, 25-OH vitamin D deficiency, or anemia of chronic disease. Other potential diagnoses included MM and similar neoplasms. MM also would present with glucosuria with proteinuria, an elevated κ/λ light chain ratio, and an elevated SPEP and concern for bone lytic lesions, which were not present. A related disorder, monoclonal gammopathy of renal significance (MGRS), akin to monoclonal gammopathy of unknown significance (MGUS), presents with proteinuria with evidence of renal injury. While this patient had a marginally elevated κ/λ light chain ratio, the remainder of his SPEP and UPEP were normal, and evaluation by a hematologist/ oncologist and pathology review of laboratory findings confirmed no additional evidence for MM, including no monoclonal γ spike. With no evidence of renal injury with a normal serum creatinine and glomerular filtration rate, MGRS was eliminated from the differential as it did not meet the International Myeloma Working Group diagnostic criteria.1 The elevated κ/λ ratio with normal renal function is attributed to polyclonal immunoglobulin elevation, which may occur more commonly with uncomplicated acute viral illnesses.
Diagnosis
The differential homed in on a targeted defect in the proximal tubular SGLT2 gene as the final diagnosis causing isolated glucosuria. Familial renal glucosuria (FRG), a condition caused by a mutation in the SLC5A2 gene that codes for the SGLT2 has been identified in the literature as causing cases with nearly identical presentations to this patient.2,3 This condition is often found in otherwise healthy, asymptomatic patients in whom isolated glucosuria was identified on routine urinalysis testing.
Due to isolated case reports sharing this finding and the asymptomatic nature of the condition, specific data pertaining to its prevalence are not available. Case studies of other affected individuals have not noted adverse effects (AEs), such as UTIs or hypotension specifically.2,3 The patient was referred for genetic testing for this gene mutation; however, he was unable to obtain the test due to lack of insurance coverage. Mr. A has no other family members that have been evaluated for or identified as having this condition. Despite the name, FRG has an unknown inheritance pattern and is attributed to a variety of missense mutations in the SLC5A2 gene.4,5
Discussion
The SGLT2 gene believed to be mutated in this patient has recently become wellknown. The inhibition of the SGLT2 transport protein has become an important tool in the management of type 2 diabetes mellitus (T2DM) independent of the insulin pathway. The SGLT2 in the proximal convoluted tubule of the kidney reabsorbs the majority, 98%, of the renal glucose for reabsorption, and the remaining glucose is reabsorbed by the SGLT2 gene in the more distal portion of the proximal tubule in healthy individuals.4,6 The normal renal threshold for glucose reabsorption in a patient with a normal glomerular filtration rate is equivalent to a serum glucose concentration of 180 mg/dL, even higher in patients with T2DM due to upregulation of the SGLT2 inhibitors. SGLT2 inhibitors, such as canagliflozin, dapagliflozin, and empagliflozin, selectively inhibit this cotransporter, reducing the threshold from 40 to 120 mg/dL, thereby significantly increasing the renal excretion of glucose.4 The patient’s mutation in question and clinical presentation aligned with a naturally occurring mimicry of this drug’s mechanism of action (Figure).
Arguably, one of the more significant benefits to using this new class of oral antihyperglycemics, aside from the noninferior glycemic control compared with that of other first-line agents, is the added metabolic benefit. To date, SGLT2 inhibitors have been found to decrease blood pressure in all studies of the medications and promote moderate weight loss.7 SGLT2 inhibitors have not only demonstrated significant cardiovascular (CV) benefits, linked with the aforementioned metabolic benefits, but also have reduced hospitalizations for heart failure in patients with T2DM and those without.7 The EMPA-REG OUTCOME trial showed a 38% relative risk reduction in CV events in empagliflozin vs placebo.4,8 However, it is unknown whether patients with the SLC5A2 mutation also benefit from these CV benefits akin to the SGLT2 inhibiting medications, and it is and worthy of studying via longterm follow-up with patients similar to this.
This SLC5A2 mutation causing FRG selectively inhibiting SGLT2 function effectively causes this patient’s natural physiology to mimic that of these new oral antihyperglycemic medications. Patients with FRG should be counseled regarding this condition and the implications it has on their overall health. At this time, there is no formal recommendation for short-term or longterm management of patients with FRG; observation and routine preventive care monitoring based on US Preventive Services Task Force screening recommendations apply to this population in line with the general population.
This condition is not known to be associated with hypotension or hypoglycemia, and to some extent, it can be theorized that patients with this condition may have inherent protection of development of hyperglycemia. 4 Akin to patients on SGLT2 inhibitors, these patients may be at an increased risk of UTIs and genital infections, including mycotic infections due to glycemic-related imbalance in the normal flora of the urinary tract.9 Other serious AEs of SGLT2 inhibitors, such as diabetic ketoacidosis, osteoporosis and related fractures, and acute pancreatitis, should be shared with FRG patients, though they are unlikely to be at increased risk for this condition in the setting of normal serum glucose and electrolyte levels. Notably, the osteoporosis risk is small, and specific other risk factors pertinent to individual patient’s medical history, and canagliflozin exclusively. If a patient with FRG develops T2DM after diagnosis, it is imperative that they inform physicians of their condition, because SGLT2-inhibiting drugs will be ineffective in this subset of patients, necessitating increased clinical judgment in selecting an appropriate antihyperglycemic agent in this population.
Conclusions
FRG is an uncommon diagnosis of exclusion that presents with isolated glucosuria in the setting of normal serum glucose. The patient generally presents asymptomatically with a urinalysis completed for other reasons, and the patient may or may not have a family history of similar findings. The condition is of particular interest given that its SGLT2 mutation mimics the effect of SGLT2 inhibitors used for T2DM. More monitoring of patients with this condition will be required for documentation regarding long-term implications, including development of further renal disease, T2DM, or CV disease.
Familial renal glucosuria is an uncommon, rarely documented condition wherein the absence of other renal or endocrine conditions and with a normal serum glucose level, glucosuria persists due to an isolated defect in the nephron’s proximal tubule. Seemingly, in these patients, the body’s physiologic function mimics that of sodiumglucose cotransporter-2 (SGLT2)-inhibiting medications with the glucose cotransporter being selectively targeted for promoting renal excretion of glucose. This has implications for the patient’s prospective development of hyperglycemic diseases, urinary tract infections (UTIs), and potentially even cardiovascular disease. Though it is a generally asymptomatic condition, it is one that seasoned clinicians should investigate given the future impacts and considerations required for their patients.
Case Presentation
Mr. A was a 28-year-old male with no medical history nor prescription medication use who presented to the nephrology clinic at Eglin Air Force Base, Florida, in June 2019 for a workup of asymptomatic glucosuria. The condition was discovered on a routine urinalysis in October 2015 at the initial presentation at Eglin Air Force Base, when the patient was being evaluated by his primary care physician for acute, benign headache with fever and chills. Urinalysis testing was performed in October 2015 and resulted in a urine glucose of 500 mg/dL (2+). He was directed to the emergency department for further evaluation, reciprocating the results.
On further laboratory testing in October 2015, his blood glucose was normal at 75 mg/dL; hemoglobin A1c was 5.5%. On repeat urinalysis 2 weeks later, his urinary glucose was found to be 500 mg/dL (2+). Each time, the elevated urinary glucose was the only abnormal finding: There was no concurrent hematuria, proteinuria, or ketonuria. The patient reported he had no associated symptoms, including nausea, vomiting, abdominal pain, dysuria, polyuria, and increased thirst. He was not taking any prescription medications, including SGLT2 inhibitors. His presenting headache and fever resolved with supportive care and was considered unrelated to his additional workup.
A diagnostic evaluation ensued from 2015 to 2020, including follow-up urinalyses, metabolic panels, complete blood counts, urine protein electrophoresis (UPEP), urine creatinine, urine electrolytes, 25-OH vitamin D level, κ/λ light chain panel, and serum protein electrophoresis (SPEP). The results of all diagnostic workup throughout the entirety of his evaluation were found to be normal. In 2020, his 25-OH vitamin D level was borderline low at 29.4 ng/mL. His κ/λ ratio was normal at 1.65, and his serum albumin protein electrophoresis was 4.74 g/dL, marginally elevated, but his SPEP and UPEP were normal, as were urine protein levels, total gamma globulin, and no monoclonal gamma spike noted on pathology review. Serum uric acid, and urine phosphorous were both normal. His serum creatinine and electrolytes were all within normal limits. Over the 5 years of intermittent monitoring, the maximum amount of glucosuria was 1,000 mg/dL (3+) and the minimum was 250 mg/dL (1+). There was a gap of monitoring from March 2016 until June 2019 due to the patient receiving care from offsite health care providers without shared documentation of specific laboratory values, but notes documenting persistent glucosuria (Table).
Analysis
Building the initial differential diagnosis for this patient began with confirming that he had isolated glucosuria, and not glucosuria secondary to elevated serum glucose. Additionally, conditions related to generalized proximal tubule dysfunction, acute or chronic impaired renal function, and neoplasms, including multiple myeloma (MM), were eliminated because this patient did not have the other specific findings associated with these conditions.
Proximal tubulopathies, including proximal renal tubular acidosis (type 2) and Fanconi syndrome, was initially a leading diagnosis in this patient. Isolated proximal renal tubular acidosis (RTA) (type 2) is uncommon and pathophysiologically involves reduced proximal tubular reabsorption of bicarbonate, resulting in low serum bicarbonate and metabolic acidosis. Patients with isolated proximal RTA (type 2) typically present in infancy with failure to thrive, tachypnea, recurrent vomiting, and feeding difficulties. These symptoms do not meet our patient’s clinical presentation. Fanconi syndrome involves a specific disruption in the proximal tubular apical sodium uptake mechanism affecting the transmembrane sodium gradient and the sodium-potassium- ATPase pump. Fanconi syndrome, therefore, would not only present with glucosuria, but also classically with proteinuria, hypophosphatemia, hypokalemia, and a hyperchloremic metabolic acidosis.
Chronic or acute renal disease may present with glucosuria, but one would expect additional findings including elevated serum creatinine, elevated urinary creatinine, 25-OH vitamin D deficiency, or anemia of chronic disease. Other potential diagnoses included MM and similar neoplasms. MM also would present with glucosuria with proteinuria, an elevated κ/λ light chain ratio, and an elevated SPEP and concern for bone lytic lesions, which were not present. A related disorder, monoclonal gammopathy of renal significance (MGRS), akin to monoclonal gammopathy of unknown significance (MGUS), presents with proteinuria with evidence of renal injury. While this patient had a marginally elevated κ/λ light chain ratio, the remainder of his SPEP and UPEP were normal, and evaluation by a hematologist/ oncologist and pathology review of laboratory findings confirmed no additional evidence for MM, including no monoclonal γ spike. With no evidence of renal injury with a normal serum creatinine and glomerular filtration rate, MGRS was eliminated from the differential as it did not meet the International Myeloma Working Group diagnostic criteria.1 The elevated κ/λ ratio with normal renal function is attributed to polyclonal immunoglobulin elevation, which may occur more commonly with uncomplicated acute viral illnesses.
Diagnosis
The differential homed in on a targeted defect in the proximal tubular SGLT2 gene as the final diagnosis causing isolated glucosuria. Familial renal glucosuria (FRG), a condition caused by a mutation in the SLC5A2 gene that codes for the SGLT2 has been identified in the literature as causing cases with nearly identical presentations to this patient.2,3 This condition is often found in otherwise healthy, asymptomatic patients in whom isolated glucosuria was identified on routine urinalysis testing.
Due to isolated case reports sharing this finding and the asymptomatic nature of the condition, specific data pertaining to its prevalence are not available. Case studies of other affected individuals have not noted adverse effects (AEs), such as UTIs or hypotension specifically.2,3 The patient was referred for genetic testing for this gene mutation; however, he was unable to obtain the test due to lack of insurance coverage. Mr. A has no other family members that have been evaluated for or identified as having this condition. Despite the name, FRG has an unknown inheritance pattern and is attributed to a variety of missense mutations in the SLC5A2 gene.4,5
Discussion
The SGLT2 gene believed to be mutated in this patient has recently become wellknown. The inhibition of the SGLT2 transport protein has become an important tool in the management of type 2 diabetes mellitus (T2DM) independent of the insulin pathway. The SGLT2 in the proximal convoluted tubule of the kidney reabsorbs the majority, 98%, of the renal glucose for reabsorption, and the remaining glucose is reabsorbed by the SGLT2 gene in the more distal portion of the proximal tubule in healthy individuals.4,6 The normal renal threshold for glucose reabsorption in a patient with a normal glomerular filtration rate is equivalent to a serum glucose concentration of 180 mg/dL, even higher in patients with T2DM due to upregulation of the SGLT2 inhibitors. SGLT2 inhibitors, such as canagliflozin, dapagliflozin, and empagliflozin, selectively inhibit this cotransporter, reducing the threshold from 40 to 120 mg/dL, thereby significantly increasing the renal excretion of glucose.4 The patient’s mutation in question and clinical presentation aligned with a naturally occurring mimicry of this drug’s mechanism of action (Figure).
Arguably, one of the more significant benefits to using this new class of oral antihyperglycemics, aside from the noninferior glycemic control compared with that of other first-line agents, is the added metabolic benefit. To date, SGLT2 inhibitors have been found to decrease blood pressure in all studies of the medications and promote moderate weight loss.7 SGLT2 inhibitors have not only demonstrated significant cardiovascular (CV) benefits, linked with the aforementioned metabolic benefits, but also have reduced hospitalizations for heart failure in patients with T2DM and those without.7 The EMPA-REG OUTCOME trial showed a 38% relative risk reduction in CV events in empagliflozin vs placebo.4,8 However, it is unknown whether patients with the SLC5A2 mutation also benefit from these CV benefits akin to the SGLT2 inhibiting medications, and it is and worthy of studying via longterm follow-up with patients similar to this.
This SLC5A2 mutation causing FRG selectively inhibiting SGLT2 function effectively causes this patient’s natural physiology to mimic that of these new oral antihyperglycemic medications. Patients with FRG should be counseled regarding this condition and the implications it has on their overall health. At this time, there is no formal recommendation for short-term or longterm management of patients with FRG; observation and routine preventive care monitoring based on US Preventive Services Task Force screening recommendations apply to this population in line with the general population.
This condition is not known to be associated with hypotension or hypoglycemia, and to some extent, it can be theorized that patients with this condition may have inherent protection of development of hyperglycemia. 4 Akin to patients on SGLT2 inhibitors, these patients may be at an increased risk of UTIs and genital infections, including mycotic infections due to glycemic-related imbalance in the normal flora of the urinary tract.9 Other serious AEs of SGLT2 inhibitors, such as diabetic ketoacidosis, osteoporosis and related fractures, and acute pancreatitis, should be shared with FRG patients, though they are unlikely to be at increased risk for this condition in the setting of normal serum glucose and electrolyte levels. Notably, the osteoporosis risk is small, and specific other risk factors pertinent to individual patient’s medical history, and canagliflozin exclusively. If a patient with FRG develops T2DM after diagnosis, it is imperative that they inform physicians of their condition, because SGLT2-inhibiting drugs will be ineffective in this subset of patients, necessitating increased clinical judgment in selecting an appropriate antihyperglycemic agent in this population.
Conclusions
FRG is an uncommon diagnosis of exclusion that presents with isolated glucosuria in the setting of normal serum glucose. The patient generally presents asymptomatically with a urinalysis completed for other reasons, and the patient may or may not have a family history of similar findings. The condition is of particular interest given that its SGLT2 mutation mimics the effect of SGLT2 inhibitors used for T2DM. More monitoring of patients with this condition will be required for documentation regarding long-term implications, including development of further renal disease, T2DM, or CV disease.
1. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12). doi:10.1016/s1470-2045(14)70442-5
2. Calado J, Sznajer Y, Metzger D, et al. Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion. Nephrol Dial Transplant. 2008;23(12):3874-3879. doi.org/10.1093/ndt/gfn386
3. Kim KM, Kwon SK, Kim HY. A case of isolated glycosuria mediated by an SLC5A2 gene mutation and characterized by postprandial heavy glycosuria without salt wasting. Electrolyte Blood Press. 2016;14(2):35-37. doi:10.5049/EBP.2016.14.2.35
4. Hsia DS, Grove O, Cefalu WT. An update on sodiumglucose co-transporter-2 inhibitors for the treatment of diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2017;24(1):73-79. doi:10.1097/MED.0000000000000311
5. Kleta R. Renal glucosuria due to SGLT2 mutations. Mol Genet Metab. 2004;82(1):56-58. doi:10.1016/j.ymgme.2004.01.018
6. Neumiller JJ. Empagliflozin: a new sodium-glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. Drugs Context. 2014;3:212262. doi:10.7573/dic.212262
7. Raz I, Cernea S, Cahn A. SGLT2 inhibitors for primary prevention of cardiovascular events. J Diabetes. 2020;12(1):5- 7. doi:10.1111/1753-0407.13004
8. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/nejmoa1504720
9. Mcgill JB, Subramanian S. Safety of sodium-glucose cotransporter 2 inhibitors. Am J Cardiol. 2019;124(suppl 1):S45-S52. doi:10.1016/j.amjcard.2019.10.029
1. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12). doi:10.1016/s1470-2045(14)70442-5
2. Calado J, Sznajer Y, Metzger D, et al. Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion. Nephrol Dial Transplant. 2008;23(12):3874-3879. doi.org/10.1093/ndt/gfn386
3. Kim KM, Kwon SK, Kim HY. A case of isolated glycosuria mediated by an SLC5A2 gene mutation and characterized by postprandial heavy glycosuria without salt wasting. Electrolyte Blood Press. 2016;14(2):35-37. doi:10.5049/EBP.2016.14.2.35
4. Hsia DS, Grove O, Cefalu WT. An update on sodiumglucose co-transporter-2 inhibitors for the treatment of diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2017;24(1):73-79. doi:10.1097/MED.0000000000000311
5. Kleta R. Renal glucosuria due to SGLT2 mutations. Mol Genet Metab. 2004;82(1):56-58. doi:10.1016/j.ymgme.2004.01.018
6. Neumiller JJ. Empagliflozin: a new sodium-glucose co-transporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. Drugs Context. 2014;3:212262. doi:10.7573/dic.212262
7. Raz I, Cernea S, Cahn A. SGLT2 inhibitors for primary prevention of cardiovascular events. J Diabetes. 2020;12(1):5- 7. doi:10.1111/1753-0407.13004
8. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/nejmoa1504720
9. Mcgill JB, Subramanian S. Safety of sodium-glucose cotransporter 2 inhibitors. Am J Cardiol. 2019;124(suppl 1):S45-S52. doi:10.1016/j.amjcard.2019.10.029
Reminders of our mortality can come when physicians least expect it
This time of year I spend weekend afternoons in my hot tub, catching up on medical journals, CME, paperbacks, and generally anything worth reading that shows up in my mailbox.
One of those items was the alumni news from my medical school. As usual, I leafed through it, reading articles of interest and glancing at updates on any classmates that were featured.
Then I stopped.
There, in the back of the magazine, was an obituary on the first of my classmates to pass (that I’m aware of).
I reread it a few times in disbelief. Maybe it was on her taking a new job or being promoted, and was in the wrong section. Nope.
I put the magazine down. She was 1 year younger than me and had gone into internal medicine. Not someone I’d kept in touch with, but certainly was friendly with during those 4 years and frequently chatted with in hallways or between classes. I remember meeting her during the first week of school, when I got her name mixed up with another girl’s in our class. I saw her at parties, meetings, and I think even played doubles tennis with her once, though who we played against I have no idea anymore.
She was at our 20th reunion, and we’d talked for a few minutes. We caught up on our lives since graduation and, as people do at these things, moved on to chat with others.
No details were given as to her death, and it really doesn’t matter.
. For most of each day it’s a fact in the back of our minds, behind the daily activities of working, shopping, doing laundry, commuting, and cooking dinner. After all, it’s really what we do while here that matters, no matter how mundane it may seem.
But sometimes something will push that realization to the front, and make us remember how important every minute really is.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
This time of year I spend weekend afternoons in my hot tub, catching up on medical journals, CME, paperbacks, and generally anything worth reading that shows up in my mailbox.
One of those items was the alumni news from my medical school. As usual, I leafed through it, reading articles of interest and glancing at updates on any classmates that were featured.
Then I stopped.
There, in the back of the magazine, was an obituary on the first of my classmates to pass (that I’m aware of).
I reread it a few times in disbelief. Maybe it was on her taking a new job or being promoted, and was in the wrong section. Nope.
I put the magazine down. She was 1 year younger than me and had gone into internal medicine. Not someone I’d kept in touch with, but certainly was friendly with during those 4 years and frequently chatted with in hallways or between classes. I remember meeting her during the first week of school, when I got her name mixed up with another girl’s in our class. I saw her at parties, meetings, and I think even played doubles tennis with her once, though who we played against I have no idea anymore.
She was at our 20th reunion, and we’d talked for a few minutes. We caught up on our lives since graduation and, as people do at these things, moved on to chat with others.
No details were given as to her death, and it really doesn’t matter.
. For most of each day it’s a fact in the back of our minds, behind the daily activities of working, shopping, doing laundry, commuting, and cooking dinner. After all, it’s really what we do while here that matters, no matter how mundane it may seem.
But sometimes something will push that realization to the front, and make us remember how important every minute really is.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
This time of year I spend weekend afternoons in my hot tub, catching up on medical journals, CME, paperbacks, and generally anything worth reading that shows up in my mailbox.
One of those items was the alumni news from my medical school. As usual, I leafed through it, reading articles of interest and glancing at updates on any classmates that were featured.
Then I stopped.
There, in the back of the magazine, was an obituary on the first of my classmates to pass (that I’m aware of).
I reread it a few times in disbelief. Maybe it was on her taking a new job or being promoted, and was in the wrong section. Nope.
I put the magazine down. She was 1 year younger than me and had gone into internal medicine. Not someone I’d kept in touch with, but certainly was friendly with during those 4 years and frequently chatted with in hallways or between classes. I remember meeting her during the first week of school, when I got her name mixed up with another girl’s in our class. I saw her at parties, meetings, and I think even played doubles tennis with her once, though who we played against I have no idea anymore.
She was at our 20th reunion, and we’d talked for a few minutes. We caught up on our lives since graduation and, as people do at these things, moved on to chat with others.
No details were given as to her death, and it really doesn’t matter.
. For most of each day it’s a fact in the back of our minds, behind the daily activities of working, shopping, doing laundry, commuting, and cooking dinner. After all, it’s really what we do while here that matters, no matter how mundane it may seem.
But sometimes something will push that realization to the front, and make us remember how important every minute really is.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Neoadjuvant immunotherapy shows promise in stage III melanoma
The next dramatic , John M. Kirkwood, MD, predicted at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.
These agents have already demonstrated profound efficacy, first in stage IV metastatic disease and more recently as adjuvant therapy for resected stage III melanoma. Now, there is a great interest in learning whether by prescribing them preoperatively, patients might reduce their risk of advancing to metastatic disease. And neoadjuvant therapy offers an extremely attractive feature: It yields results in an accelerated fashion.
“The major problem with postoperative adjuvant trials in melanoma since 1984 is the long time to maturity. Many of us don’t want to wait the full 9 or 10 years for a full-bore, phase 3 adjuvant trial in stage III melanoma to mature,” explained Dr. Kirkwood, professor of medicine, dermatology, and translational science and coleader of the melanoma and skin cancer program at the University of Pittsburgh. “The opportunity to treat a patient who presents with a bulky lymph node, has a biopsy, and then can be treated for 3 or 6 weeks or sometimes even longer periods with a therapy that’s promising allows us to ask what’s going on in the tumor tissue, what’s going on in the clinical response at 3 or 6 weeks, and if there’s pathological complete or near-complete response under the microscope.”
Because pathological complete response is a strong predictor of relapse-free survival, this neoadjuvant-forward therapeutic strategy has the potential to provide patients and their physicians with an early forecast of likely clinical outcome only 4-6 weeks into treatment. Also, there is both preclinical and clinical evidence that neoadjuvant therapy may offer a survival advantage over adjuvant therapy, perhaps as a result of early treatment of micrometastatic disease. Another benefit of neoadjuvant therapy for melanoma is the resultant tumor shrinkage, which can permit less extensive surgery.
Dr. Kirkwood highlighted a phase 2 clinical trial conducted at the University of Pittsburgh to illustrate the potential of neoadjuvant therapy in melanoma. The ongoing single-arm study includes 32 patients with stage IIIB or IIIC resectable melanoma along with accessible tumor for biopsy and intratumoral injections of CMP-001, a toll-like receptor 9 agonist. According to the Eighth Edition of the American Joint Committee on Cancer staging manual, stage IIIB melanoma has a 10-year mortality of 23%, and stage IIIC disease has 40%.
CMP-001 triggers type 1 interferon production through activation of plasmacytoid dendritic cells. The resultant inflammatory response draws T cells into the tumor to enhance the response to immunotherapy, which in this study was nivolumab (Opdivo), a human programmed death ligand 1 (PD-L1)–blocking antibody. The neoadjuvant regimen consisted of seven once-weekly intratumoral injections of CMP-001, plus three 240-mg doses of nivolumab given at 2-week intervals. This was followed by resection, then 1 year of adjuvant therapy with nivolumab at 480 mg every 4 weeks and intratumoral CMP-001 every 4 weeks.
In an interim analysis, a major pathologic response occurred in an impressive 15 of 21 patients (71%) after 6 weeks of neoadjuvant therapy. Thirteen of the 15 had a pathologic complete response. Encouragingly, no one with a pathologic complete or near-complete response has relapsed to date.
“A pathologic complete response or near-complete response with neoadjuvant therapy appears to be a biomarker of durable disease control and is associated with excellent outcomes,” Dr. Kirkwood observed, adding that the Pittsburgh experience has been mirrored in reports from the Netherlands, Australia, and University of Texas M.D. Anderson Cancer Center, Houston, involving other neoadjuvant agents.
Other potential early biomarkers of favorable outcome with neoadjuvant therapy include CD8+ T cells in the tumor at baseline, tumor mutational burden, T-cell clonality, and a T-cell–inflamed gene-expression profile.
There were no dose-limiting toxicities or delays in surgery related to the neoadjuvant treatment.
Of note, imaging often inaccurately showed only a partial response in patients who actually had a pathologic complete response, meaning totally devoid of tumor, Dr. Kirkwood said.
Corroboration of these findings is planned in the national multicenter ECOG-ACRIN neoadjuvant trial EA6194.
“Consider referring to this trial any patients who present with bulky nodal disease for whom a treatment assessment at 4-6 weeks is desired in order to predict what the outcome may be,” he suggested.
Dr. Kirkwood reported receiving research grants from Amgen, BMS, Castle Biosciences, Checkmate, Immunocore, Iovance, and Novartis and serving as a consultant to a handful of companies.
Global Academy for Medical Education and this news organization are owned by the same company.
The next dramatic , John M. Kirkwood, MD, predicted at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.
These agents have already demonstrated profound efficacy, first in stage IV metastatic disease and more recently as adjuvant therapy for resected stage III melanoma. Now, there is a great interest in learning whether by prescribing them preoperatively, patients might reduce their risk of advancing to metastatic disease. And neoadjuvant therapy offers an extremely attractive feature: It yields results in an accelerated fashion.
“The major problem with postoperative adjuvant trials in melanoma since 1984 is the long time to maturity. Many of us don’t want to wait the full 9 or 10 years for a full-bore, phase 3 adjuvant trial in stage III melanoma to mature,” explained Dr. Kirkwood, professor of medicine, dermatology, and translational science and coleader of the melanoma and skin cancer program at the University of Pittsburgh. “The opportunity to treat a patient who presents with a bulky lymph node, has a biopsy, and then can be treated for 3 or 6 weeks or sometimes even longer periods with a therapy that’s promising allows us to ask what’s going on in the tumor tissue, what’s going on in the clinical response at 3 or 6 weeks, and if there’s pathological complete or near-complete response under the microscope.”
Because pathological complete response is a strong predictor of relapse-free survival, this neoadjuvant-forward therapeutic strategy has the potential to provide patients and their physicians with an early forecast of likely clinical outcome only 4-6 weeks into treatment. Also, there is both preclinical and clinical evidence that neoadjuvant therapy may offer a survival advantage over adjuvant therapy, perhaps as a result of early treatment of micrometastatic disease. Another benefit of neoadjuvant therapy for melanoma is the resultant tumor shrinkage, which can permit less extensive surgery.
Dr. Kirkwood highlighted a phase 2 clinical trial conducted at the University of Pittsburgh to illustrate the potential of neoadjuvant therapy in melanoma. The ongoing single-arm study includes 32 patients with stage IIIB or IIIC resectable melanoma along with accessible tumor for biopsy and intratumoral injections of CMP-001, a toll-like receptor 9 agonist. According to the Eighth Edition of the American Joint Committee on Cancer staging manual, stage IIIB melanoma has a 10-year mortality of 23%, and stage IIIC disease has 40%.
CMP-001 triggers type 1 interferon production through activation of plasmacytoid dendritic cells. The resultant inflammatory response draws T cells into the tumor to enhance the response to immunotherapy, which in this study was nivolumab (Opdivo), a human programmed death ligand 1 (PD-L1)–blocking antibody. The neoadjuvant regimen consisted of seven once-weekly intratumoral injections of CMP-001, plus three 240-mg doses of nivolumab given at 2-week intervals. This was followed by resection, then 1 year of adjuvant therapy with nivolumab at 480 mg every 4 weeks and intratumoral CMP-001 every 4 weeks.
In an interim analysis, a major pathologic response occurred in an impressive 15 of 21 patients (71%) after 6 weeks of neoadjuvant therapy. Thirteen of the 15 had a pathologic complete response. Encouragingly, no one with a pathologic complete or near-complete response has relapsed to date.
“A pathologic complete response or near-complete response with neoadjuvant therapy appears to be a biomarker of durable disease control and is associated with excellent outcomes,” Dr. Kirkwood observed, adding that the Pittsburgh experience has been mirrored in reports from the Netherlands, Australia, and University of Texas M.D. Anderson Cancer Center, Houston, involving other neoadjuvant agents.
Other potential early biomarkers of favorable outcome with neoadjuvant therapy include CD8+ T cells in the tumor at baseline, tumor mutational burden, T-cell clonality, and a T-cell–inflamed gene-expression profile.
There were no dose-limiting toxicities or delays in surgery related to the neoadjuvant treatment.
Of note, imaging often inaccurately showed only a partial response in patients who actually had a pathologic complete response, meaning totally devoid of tumor, Dr. Kirkwood said.
Corroboration of these findings is planned in the national multicenter ECOG-ACRIN neoadjuvant trial EA6194.
“Consider referring to this trial any patients who present with bulky nodal disease for whom a treatment assessment at 4-6 weeks is desired in order to predict what the outcome may be,” he suggested.
Dr. Kirkwood reported receiving research grants from Amgen, BMS, Castle Biosciences, Checkmate, Immunocore, Iovance, and Novartis and serving as a consultant to a handful of companies.
Global Academy for Medical Education and this news organization are owned by the same company.
The next dramatic , John M. Kirkwood, MD, predicted at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.
These agents have already demonstrated profound efficacy, first in stage IV metastatic disease and more recently as adjuvant therapy for resected stage III melanoma. Now, there is a great interest in learning whether by prescribing them preoperatively, patients might reduce their risk of advancing to metastatic disease. And neoadjuvant therapy offers an extremely attractive feature: It yields results in an accelerated fashion.
“The major problem with postoperative adjuvant trials in melanoma since 1984 is the long time to maturity. Many of us don’t want to wait the full 9 or 10 years for a full-bore, phase 3 adjuvant trial in stage III melanoma to mature,” explained Dr. Kirkwood, professor of medicine, dermatology, and translational science and coleader of the melanoma and skin cancer program at the University of Pittsburgh. “The opportunity to treat a patient who presents with a bulky lymph node, has a biopsy, and then can be treated for 3 or 6 weeks or sometimes even longer periods with a therapy that’s promising allows us to ask what’s going on in the tumor tissue, what’s going on in the clinical response at 3 or 6 weeks, and if there’s pathological complete or near-complete response under the microscope.”
Because pathological complete response is a strong predictor of relapse-free survival, this neoadjuvant-forward therapeutic strategy has the potential to provide patients and their physicians with an early forecast of likely clinical outcome only 4-6 weeks into treatment. Also, there is both preclinical and clinical evidence that neoadjuvant therapy may offer a survival advantage over adjuvant therapy, perhaps as a result of early treatment of micrometastatic disease. Another benefit of neoadjuvant therapy for melanoma is the resultant tumor shrinkage, which can permit less extensive surgery.
Dr. Kirkwood highlighted a phase 2 clinical trial conducted at the University of Pittsburgh to illustrate the potential of neoadjuvant therapy in melanoma. The ongoing single-arm study includes 32 patients with stage IIIB or IIIC resectable melanoma along with accessible tumor for biopsy and intratumoral injections of CMP-001, a toll-like receptor 9 agonist. According to the Eighth Edition of the American Joint Committee on Cancer staging manual, stage IIIB melanoma has a 10-year mortality of 23%, and stage IIIC disease has 40%.
CMP-001 triggers type 1 interferon production through activation of plasmacytoid dendritic cells. The resultant inflammatory response draws T cells into the tumor to enhance the response to immunotherapy, which in this study was nivolumab (Opdivo), a human programmed death ligand 1 (PD-L1)–blocking antibody. The neoadjuvant regimen consisted of seven once-weekly intratumoral injections of CMP-001, plus three 240-mg doses of nivolumab given at 2-week intervals. This was followed by resection, then 1 year of adjuvant therapy with nivolumab at 480 mg every 4 weeks and intratumoral CMP-001 every 4 weeks.
In an interim analysis, a major pathologic response occurred in an impressive 15 of 21 patients (71%) after 6 weeks of neoadjuvant therapy. Thirteen of the 15 had a pathologic complete response. Encouragingly, no one with a pathologic complete or near-complete response has relapsed to date.
“A pathologic complete response or near-complete response with neoadjuvant therapy appears to be a biomarker of durable disease control and is associated with excellent outcomes,” Dr. Kirkwood observed, adding that the Pittsburgh experience has been mirrored in reports from the Netherlands, Australia, and University of Texas M.D. Anderson Cancer Center, Houston, involving other neoadjuvant agents.
Other potential early biomarkers of favorable outcome with neoadjuvant therapy include CD8+ T cells in the tumor at baseline, tumor mutational burden, T-cell clonality, and a T-cell–inflamed gene-expression profile.
There were no dose-limiting toxicities or delays in surgery related to the neoadjuvant treatment.
Of note, imaging often inaccurately showed only a partial response in patients who actually had a pathologic complete response, meaning totally devoid of tumor, Dr. Kirkwood said.
Corroboration of these findings is planned in the national multicenter ECOG-ACRIN neoadjuvant trial EA6194.
“Consider referring to this trial any patients who present with bulky nodal disease for whom a treatment assessment at 4-6 weeks is desired in order to predict what the outcome may be,” he suggested.
Dr. Kirkwood reported receiving research grants from Amgen, BMS, Castle Biosciences, Checkmate, Immunocore, Iovance, and Novartis and serving as a consultant to a handful of companies.
Global Academy for Medical Education and this news organization are owned by the same company.
FROM THE CUTANEOUS MALIGNANCIES FORUM
Study: COVID cases have been ‘severely undercounted’
Large numbers of COVID-19 cases have been undetected and unreported, which has resulted in severe undercounting of the total number of people who have been infected during the pandemic, according to a new study published Monday in the journal PLOS ONE.
In the United States, the number of COVID-19 cases is likely three times that of reported cases. According to the study, more than 71 million Americans have contracted the virus during the pandemic, and 7 million were infected or potentially contagious last week.
Public health officials rely on case counts to guide decisions, so the undercounting should be considered while trying to end the pandemic.
“The estimates of actual infections reveal for the first time the true severity of COVID-19 across the U.S. and in countries worldwide,” Jungsik Noh, PhD, a bioinformatics professor at the University of Texas Southwestern Medical Center, said in a statement.
Dr. Noh and colleague Gaudenz Danuser created a computational model that uses machine-learning strategies to estimate the actual number of daily cases in the United States and the 50 most-infected countries.
The model pulls data from the Johns Hopkins University database and the COVID Tracking Project, as well as large-scale surveys conducted by the CDC and several states. The algorithm uses the number of reported deaths, which is thought to be more accurate than the number of lab-confirmed cases, as the basis for calculations.
In 25 of the 50 countries, the “actual” cumulative cases were estimated to be 5-20 times greater than the confirmed cases. In the United States, Belgium, and Brazil, about 10% of the population has contracted the coronavirus, according to the model. At the beginning of February, about 11% of the population in Pennsylvania had current infections, which was the highest rate of any state. About 0.15% of residents in Minnesota had infections, and about 2.5% of residents in New York and Texas had infections.
“Knowing the true severity in different regions will help us effectively fight against the virus spreading,” Dr. Noh said. “The currently infected population is the cause of future infections and deaths. Its actual size in a region is a crucial variable required when determining the severity of COVID-19 and building strategies against regional outbreaks.”
A version of this article first appeared on WebMD.com.
Large numbers of COVID-19 cases have been undetected and unreported, which has resulted in severe undercounting of the total number of people who have been infected during the pandemic, according to a new study published Monday in the journal PLOS ONE.
In the United States, the number of COVID-19 cases is likely three times that of reported cases. According to the study, more than 71 million Americans have contracted the virus during the pandemic, and 7 million were infected or potentially contagious last week.
Public health officials rely on case counts to guide decisions, so the undercounting should be considered while trying to end the pandemic.
“The estimates of actual infections reveal for the first time the true severity of COVID-19 across the U.S. and in countries worldwide,” Jungsik Noh, PhD, a bioinformatics professor at the University of Texas Southwestern Medical Center, said in a statement.
Dr. Noh and colleague Gaudenz Danuser created a computational model that uses machine-learning strategies to estimate the actual number of daily cases in the United States and the 50 most-infected countries.
The model pulls data from the Johns Hopkins University database and the COVID Tracking Project, as well as large-scale surveys conducted by the CDC and several states. The algorithm uses the number of reported deaths, which is thought to be more accurate than the number of lab-confirmed cases, as the basis for calculations.
In 25 of the 50 countries, the “actual” cumulative cases were estimated to be 5-20 times greater than the confirmed cases. In the United States, Belgium, and Brazil, about 10% of the population has contracted the coronavirus, according to the model. At the beginning of February, about 11% of the population in Pennsylvania had current infections, which was the highest rate of any state. About 0.15% of residents in Minnesota had infections, and about 2.5% of residents in New York and Texas had infections.
“Knowing the true severity in different regions will help us effectively fight against the virus spreading,” Dr. Noh said. “The currently infected population is the cause of future infections and deaths. Its actual size in a region is a crucial variable required when determining the severity of COVID-19 and building strategies against regional outbreaks.”
A version of this article first appeared on WebMD.com.
Large numbers of COVID-19 cases have been undetected and unreported, which has resulted in severe undercounting of the total number of people who have been infected during the pandemic, according to a new study published Monday in the journal PLOS ONE.
In the United States, the number of COVID-19 cases is likely three times that of reported cases. According to the study, more than 71 million Americans have contracted the virus during the pandemic, and 7 million were infected or potentially contagious last week.
Public health officials rely on case counts to guide decisions, so the undercounting should be considered while trying to end the pandemic.
“The estimates of actual infections reveal for the first time the true severity of COVID-19 across the U.S. and in countries worldwide,” Jungsik Noh, PhD, a bioinformatics professor at the University of Texas Southwestern Medical Center, said in a statement.
Dr. Noh and colleague Gaudenz Danuser created a computational model that uses machine-learning strategies to estimate the actual number of daily cases in the United States and the 50 most-infected countries.
The model pulls data from the Johns Hopkins University database and the COVID Tracking Project, as well as large-scale surveys conducted by the CDC and several states. The algorithm uses the number of reported deaths, which is thought to be more accurate than the number of lab-confirmed cases, as the basis for calculations.
In 25 of the 50 countries, the “actual” cumulative cases were estimated to be 5-20 times greater than the confirmed cases. In the United States, Belgium, and Brazil, about 10% of the population has contracted the coronavirus, according to the model. At the beginning of February, about 11% of the population in Pennsylvania had current infections, which was the highest rate of any state. About 0.15% of residents in Minnesota had infections, and about 2.5% of residents in New York and Texas had infections.
“Knowing the true severity in different regions will help us effectively fight against the virus spreading,” Dr. Noh said. “The currently infected population is the cause of future infections and deaths. Its actual size in a region is a crucial variable required when determining the severity of COVID-19 and building strategies against regional outbreaks.”
A version of this article first appeared on WebMD.com.
COVID-19: Peginterferon lambda may prevent clinical deterioration, shorten viral shedding
and shorten the duration of viral shedding, according to results of a double-blind, placebo-controlled trial (NCT04354259).
Reductions in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA were greater with peginterferon lambda than with placebo from day 3 onward in the phase 2 study led by Jordan J. Feld, MD, of the Toronto Centre for Liver Disease. The findings were reported in The Lancet Respiratory Medicine.
Fewer side effects
To date in randomized clinical trials, efficacy in treatment of COVID-19 has been shown only for remdesivir and dexamethasone in hospitalized patients, and in an interim analysis of accelerated viral clearance for a monoclonal antibody infusion in outpatients.
Activity against respiratory pathogens has been demonstrated for interferon lambda-1, a type III interferon shown to be involved in innate antiviral responses. Interferons, Dr. Feld and coauthors stated, drive induction of genes with antiviral, antiproliferative and immunoregulatory properties, and early treatment with interferons might halt clinical progression and shorten the duration of viral shedding with reduced onward transmission. In addition, interferon lambdas (type III) use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, leading to fewer side effects than other interferons, including avoiding risk of promoting cytokine storm syndrome.
The researchers investigated peginterferon lambda safety and efficacy in treatment of patients with laboratory-confirmed, mild to moderate COVID-19. Sixty patients (median age 46 years, about 60% female, about 50% White) were recruited from outpatient testing centers at six institutions in Toronto, and referred to a single ambulatory site. Patients were randomly assigned 1:1 to a single subcutaneous injection of peginterferon lambda 180 mcg or placebo within 7 days of symptom onset or, if asymptomatic, of their first positive swab. Mean time from symptom onset to injection was about 4.5 days, and about 18.5% were asymptomatic. The primary outcome was the proportion of patients negative for SARS-CoV-2 RNA on day 7 after the injection.
Greater benefit with higher baseline load
A higher baseline SARS-CoV-2 RNA concentration found in the peginterferon lambda group was found to be significantly associated with day 7 clearance (odds ratio [OR] 0.69 [95% confidence interval 0.51-0.87]; P = ·001). In the peginterferon lambda group, also, the mean decline in SARS-CoV-2 RNA was significantly larger than in the placebo group across all time points (days 3, 5, 7, and14). While viral load decline was 0.81 log greater in the treatment group (P = .14) by day 3, viral load decline increased to 1.67 log copies per mL by day 5 (P = .013) and 2.42 log copies per mL by day 7 (P = .0041). At day 14, the viral decline was 1.77 log copies per mL larger in the peginterferon lambda group (P = .048). The investigators pointed out that the difference in viral load decline between groups was greater in patients with high baseline viral load (at or above 106 copies per mL). In the peginterferon lambda high baseline viral load group, the reduction was 7.17 log copies per mL, versus 4.92 log copies per mL in the placebo group (P = .004).
More patients SARS-CoV-2 RNA negative
By day 7, 80% of patients in the peginterferon lambda group were negative for SARS-CoV-2 RNA, compared with 63% in the placebo group (P = .15). After baseline load adjustment, however, the peginterferon lambda treatment was significantly associated with day 7 clearance (OR 4·12 [95% CI 1·15-16·73]; P = .029).
Respiratory symptoms improved faster
Most symptoms in both groups were mild to moderate, without difference in frequency or severity. While symptom improvement was generally similar over time for both groups, respiratory symptoms improved faster with peginterferon lambda, with the effect more pronounced in the high baseline viral load group (OR 5·88 (0·81-42·46; P =. 079).
Laboratory adverse events, similar for both groups, were mild.
“Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding,” the investigators concluded.
“This clinical trial is important” because it suggests that a single intravenous dose of peginterferon lambda administered to outpatients with a positive SARS-CoV-2 nasopharyngeal swab speeds reduction of SARS-CoV-2 viral load, David L. Bowton, MD, FCCP, professor emeritus, Wake Forest Baptist Health, Winston-Salem, N.C., said in an interview. He observed that the smaller viral load difference observed at day 14 likely reflects host immune responses.
Dr. Bowton also noted that two placebo group baseline characteristics (five placebo group patients with anti-SARS-CoV-2 S protein IgG antibodies; two times more undetectable SARS-CoV-2 RNA at baseline assessment) would tend to reduce differences between the peginterferon lambda and placebo groups. He added that the study findings were concordant with another phase 2 trial of hospitalized COVID-19 patients receiving inhaled interferon beta-1a.
“Thus, interferons may find a place in the treatment of COVID-19 and perhaps other severe viral illnesses,” Dr. Bowton said.
The study was funded by the Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.
Dr. Bowton had no disclosures. Disclosures for Dr. Feld and coauthors are listed on the Lancet Respiratory Medicine website.
and shorten the duration of viral shedding, according to results of a double-blind, placebo-controlled trial (NCT04354259).
Reductions in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA were greater with peginterferon lambda than with placebo from day 3 onward in the phase 2 study led by Jordan J. Feld, MD, of the Toronto Centre for Liver Disease. The findings were reported in The Lancet Respiratory Medicine.
Fewer side effects
To date in randomized clinical trials, efficacy in treatment of COVID-19 has been shown only for remdesivir and dexamethasone in hospitalized patients, and in an interim analysis of accelerated viral clearance for a monoclonal antibody infusion in outpatients.
Activity against respiratory pathogens has been demonstrated for interferon lambda-1, a type III interferon shown to be involved in innate antiviral responses. Interferons, Dr. Feld and coauthors stated, drive induction of genes with antiviral, antiproliferative and immunoregulatory properties, and early treatment with interferons might halt clinical progression and shorten the duration of viral shedding with reduced onward transmission. In addition, interferon lambdas (type III) use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, leading to fewer side effects than other interferons, including avoiding risk of promoting cytokine storm syndrome.
The researchers investigated peginterferon lambda safety and efficacy in treatment of patients with laboratory-confirmed, mild to moderate COVID-19. Sixty patients (median age 46 years, about 60% female, about 50% White) were recruited from outpatient testing centers at six institutions in Toronto, and referred to a single ambulatory site. Patients were randomly assigned 1:1 to a single subcutaneous injection of peginterferon lambda 180 mcg or placebo within 7 days of symptom onset or, if asymptomatic, of their first positive swab. Mean time from symptom onset to injection was about 4.5 days, and about 18.5% were asymptomatic. The primary outcome was the proportion of patients negative for SARS-CoV-2 RNA on day 7 after the injection.
Greater benefit with higher baseline load
A higher baseline SARS-CoV-2 RNA concentration found in the peginterferon lambda group was found to be significantly associated with day 7 clearance (odds ratio [OR] 0.69 [95% confidence interval 0.51-0.87]; P = ·001). In the peginterferon lambda group, also, the mean decline in SARS-CoV-2 RNA was significantly larger than in the placebo group across all time points (days 3, 5, 7, and14). While viral load decline was 0.81 log greater in the treatment group (P = .14) by day 3, viral load decline increased to 1.67 log copies per mL by day 5 (P = .013) and 2.42 log copies per mL by day 7 (P = .0041). At day 14, the viral decline was 1.77 log copies per mL larger in the peginterferon lambda group (P = .048). The investigators pointed out that the difference in viral load decline between groups was greater in patients with high baseline viral load (at or above 106 copies per mL). In the peginterferon lambda high baseline viral load group, the reduction was 7.17 log copies per mL, versus 4.92 log copies per mL in the placebo group (P = .004).
More patients SARS-CoV-2 RNA negative
By day 7, 80% of patients in the peginterferon lambda group were negative for SARS-CoV-2 RNA, compared with 63% in the placebo group (P = .15). After baseline load adjustment, however, the peginterferon lambda treatment was significantly associated with day 7 clearance (OR 4·12 [95% CI 1·15-16·73]; P = .029).
Respiratory symptoms improved faster
Most symptoms in both groups were mild to moderate, without difference in frequency or severity. While symptom improvement was generally similar over time for both groups, respiratory symptoms improved faster with peginterferon lambda, with the effect more pronounced in the high baseline viral load group (OR 5·88 (0·81-42·46; P =. 079).
Laboratory adverse events, similar for both groups, were mild.
“Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding,” the investigators concluded.
“This clinical trial is important” because it suggests that a single intravenous dose of peginterferon lambda administered to outpatients with a positive SARS-CoV-2 nasopharyngeal swab speeds reduction of SARS-CoV-2 viral load, David L. Bowton, MD, FCCP, professor emeritus, Wake Forest Baptist Health, Winston-Salem, N.C., said in an interview. He observed that the smaller viral load difference observed at day 14 likely reflects host immune responses.
Dr. Bowton also noted that two placebo group baseline characteristics (five placebo group patients with anti-SARS-CoV-2 S protein IgG antibodies; two times more undetectable SARS-CoV-2 RNA at baseline assessment) would tend to reduce differences between the peginterferon lambda and placebo groups. He added that the study findings were concordant with another phase 2 trial of hospitalized COVID-19 patients receiving inhaled interferon beta-1a.
“Thus, interferons may find a place in the treatment of COVID-19 and perhaps other severe viral illnesses,” Dr. Bowton said.
The study was funded by the Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.
Dr. Bowton had no disclosures. Disclosures for Dr. Feld and coauthors are listed on the Lancet Respiratory Medicine website.
and shorten the duration of viral shedding, according to results of a double-blind, placebo-controlled trial (NCT04354259).
Reductions in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA were greater with peginterferon lambda than with placebo from day 3 onward in the phase 2 study led by Jordan J. Feld, MD, of the Toronto Centre for Liver Disease. The findings were reported in The Lancet Respiratory Medicine.
Fewer side effects
To date in randomized clinical trials, efficacy in treatment of COVID-19 has been shown only for remdesivir and dexamethasone in hospitalized patients, and in an interim analysis of accelerated viral clearance for a monoclonal antibody infusion in outpatients.
Activity against respiratory pathogens has been demonstrated for interferon lambda-1, a type III interferon shown to be involved in innate antiviral responses. Interferons, Dr. Feld and coauthors stated, drive induction of genes with antiviral, antiproliferative and immunoregulatory properties, and early treatment with interferons might halt clinical progression and shorten the duration of viral shedding with reduced onward transmission. In addition, interferon lambdas (type III) use a distinct receptor complex with high expression levels limited to epithelial cells in the lung, liver, and intestine, leading to fewer side effects than other interferons, including avoiding risk of promoting cytokine storm syndrome.
The researchers investigated peginterferon lambda safety and efficacy in treatment of patients with laboratory-confirmed, mild to moderate COVID-19. Sixty patients (median age 46 years, about 60% female, about 50% White) were recruited from outpatient testing centers at six institutions in Toronto, and referred to a single ambulatory site. Patients were randomly assigned 1:1 to a single subcutaneous injection of peginterferon lambda 180 mcg or placebo within 7 days of symptom onset or, if asymptomatic, of their first positive swab. Mean time from symptom onset to injection was about 4.5 days, and about 18.5% were asymptomatic. The primary outcome was the proportion of patients negative for SARS-CoV-2 RNA on day 7 after the injection.
Greater benefit with higher baseline load
A higher baseline SARS-CoV-2 RNA concentration found in the peginterferon lambda group was found to be significantly associated with day 7 clearance (odds ratio [OR] 0.69 [95% confidence interval 0.51-0.87]; P = ·001). In the peginterferon lambda group, also, the mean decline in SARS-CoV-2 RNA was significantly larger than in the placebo group across all time points (days 3, 5, 7, and14). While viral load decline was 0.81 log greater in the treatment group (P = .14) by day 3, viral load decline increased to 1.67 log copies per mL by day 5 (P = .013) and 2.42 log copies per mL by day 7 (P = .0041). At day 14, the viral decline was 1.77 log copies per mL larger in the peginterferon lambda group (P = .048). The investigators pointed out that the difference in viral load decline between groups was greater in patients with high baseline viral load (at or above 106 copies per mL). In the peginterferon lambda high baseline viral load group, the reduction was 7.17 log copies per mL, versus 4.92 log copies per mL in the placebo group (P = .004).
More patients SARS-CoV-2 RNA negative
By day 7, 80% of patients in the peginterferon lambda group were negative for SARS-CoV-2 RNA, compared with 63% in the placebo group (P = .15). After baseline load adjustment, however, the peginterferon lambda treatment was significantly associated with day 7 clearance (OR 4·12 [95% CI 1·15-16·73]; P = .029).
Respiratory symptoms improved faster
Most symptoms in both groups were mild to moderate, without difference in frequency or severity. While symptom improvement was generally similar over time for both groups, respiratory symptoms improved faster with peginterferon lambda, with the effect more pronounced in the high baseline viral load group (OR 5·88 (0·81-42·46; P =. 079).
Laboratory adverse events, similar for both groups, were mild.
“Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding,” the investigators concluded.
“This clinical trial is important” because it suggests that a single intravenous dose of peginterferon lambda administered to outpatients with a positive SARS-CoV-2 nasopharyngeal swab speeds reduction of SARS-CoV-2 viral load, David L. Bowton, MD, FCCP, professor emeritus, Wake Forest Baptist Health, Winston-Salem, N.C., said in an interview. He observed that the smaller viral load difference observed at day 14 likely reflects host immune responses.
Dr. Bowton also noted that two placebo group baseline characteristics (five placebo group patients with anti-SARS-CoV-2 S protein IgG antibodies; two times more undetectable SARS-CoV-2 RNA at baseline assessment) would tend to reduce differences between the peginterferon lambda and placebo groups. He added that the study findings were concordant with another phase 2 trial of hospitalized COVID-19 patients receiving inhaled interferon beta-1a.
“Thus, interferons may find a place in the treatment of COVID-19 and perhaps other severe viral illnesses,” Dr. Bowton said.
The study was funded by the Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.
Dr. Bowton had no disclosures. Disclosures for Dr. Feld and coauthors are listed on the Lancet Respiratory Medicine website.
FROM THE LANCET RESPIRATORY MEDICINE