User login
Rosemary, Part 2
Used as a spice in various, particularly Mediterranean, cuisines and in traditional medicine for hundreds of years, this aromatic shrub has been the focus of substantial research this century to clarify its roles in skin care. It is used broadly in cosmetic formulations, particularly to preserve the product, and acts as a skin conditioner and fragrance in safe concentrations.1 Rosemary essential oil is also a popular choice frequently used in aromatherapy.2,3 This column focuses on recent promising results supporting the antioxidant and anti-photoaging activities, especially, of rosemary.
UV Protection and Rosemary in Combination
A 2021 study in mice authored by Auh and Madhavan showed that a mixture of marigold and rosemary extracts yielded anti-photoaging effects, with the botanical formula suppressing UV-induced damage.4
Seven years earlier, Pérez-Sánchez et al. combined rosemary and citrus extracts and found that they exerted protective effects against UV damage in human HaCaT keratinocytes as well as human volunteers after oral consumption. Significant increases in minimal erythema dose (MED) were seen in participants, with daily intake of 250 mg of botanical combination, at 8 weeks (34%) and 12 weeks (56%). The investigators attributed the photoprotective effects of the formula to rosemary polyphenols and diterpenes as well as citrus flavonoids.5
Evaluation of a human skin cell model by Sánchez-Marzo et al. in 2020 revealed that rosemary diterpenes were instrumental in an herbal extract that combined citrus, olive, and rosemary in conferring genoprotection against UV-induced DNA damage. The authors note that human trials are needed to overcome the limitations of the cellular model in ascertaining whether the tested herbal formulations can yield oral and/or topical photoprotection.6
Anti-Photoaging and Anti-Pollution
In 2022, Ibrahim et al. assessed a hexane extract of rosemary leaves for anti-photoaging activity. Their evaluation showed an abundance of triterpenoids, monoterpenoids, and phenolic diterpenes in rosemary, with in vitro assays verifying the anti-aging, antioxidant, and wound healing functions of the extract. Further, topical rosemary hexane extract–loaded lipid nanocapsules protected rat skin from UV radiation, as epidermal and dermal histological parameters improved, antioxidant biochemical balance was restored, and inflammatory markers and wrinkling were diminished. The researchers concluded that the use of rosemary hexane extract represents a safe, efficient, and cost-effective way to deliver anti-aging, photoprotective functions to cosmeceutical formulations.7
In March 2021, Nobile et al. published a report on their randomized, double-blind, placebo-controlled parallel group study to investigate the efficacy of a marketed polyphenol-enriched dietary supplement (Zeropollution, which contains four standardized herbal extracts: Olea europaea leaf, Lippia citriodora, S. rosmarinus, and Sophora japonica) in diminishing pollution-induced oxidative stress and in improving skin aging in 100 White and Asian women who were outdoor workers living in a polluted environment (Milan, Italy). Statistically significant improvements in reducing wrinkle depth and hyperpigmentation, enhancing elasticity and firmness, as well as promoting skin moisturization and diminishing transepidermal water loss were noted as early as 2 weeks after product consumption began, with inter-group and intra-group analysis verifying that all skin parameters were ameliorated in Asian and White subjects.8
Previously, Nobile et al. conducted a randomized, parallel-group study on 90 subjects to evaluate the photoprotective effects of a combination of rosemary and grapefruit (Citrus paradisi) extracts (Nutroxsun). The investigators also performed a pilot, randomized crossover study on five participants. Both studies included only females with Fitzpatrick skin phototypes I-III who manifested mild to moderate chronological aging or photoaging. Within as little as 2 weeks, treated individuals exhibited reductions in UVA- and UVB-induced skin changes. Skin elasticity improved in this group, with wrinkles diminishing along with skin redness and lipoperoxides. The investigators concluded that the oral blend of rosemary and grapefruit consumed long term merits consideration as an adjuvant approach to preventing the deleterious effects of solar exposure.9
In 2021, Hoskin et al. used ex vivo human biopsies exposed to diesel engine exhaust to study the impact of spray-dried algae-rosemary particles against pollution-induced damage. The spirulina-rosemary gel that was developed lowered levels of 4-hydroxynonenal protein adducts (4HNE-PA) as well as matrix metalloproteinase-9 (MMP-9) and reduced the loss of filaggrin. The researchers concluded that their topically applied spirulina-rosemary gel was effective in mitigating or preventing skin aging and cutaneous damage caused by diesel air pollution.10
Antioxidant, Antibacterial, and Anti-Inflammatory Activity
Based on a 2023 literature search by Li Pomi et al. of in vitro as well as in vivo animal and human studies involving S. rosmarinus and the skin, researchers reported on substantial evidence buttressing the antioxidant role of the botanical agent. They cautioned that, while data support the harnessing of the bioactive constituents of rosemary to address inflammatory and infectious skin conditions, large controlled trials remain necessary to establish its potential functions in dermatologic clinical practice.11
Ten years earlier, Park et al. determined that a phenolic diterpene from rosemary (carnosic acid) prevented UV-induced expression of MMP-1, MMP-3, and MMP-9 in human skin fibroblasts and keratinocytes in a concentration-dependent manner by suppressing reactive oxygen species and blocking through the inhibition of ROS and the suppression of extracellular signal-regulated kinase (ERK)-mediated AP-1 activation.12
Around the same time, Sienkiewicz et al. showed that rosemary essential oil exhibits antibacterial activity against the standard strain Escherichia coli ATCC 25922 and 60 other clinical strains of the bacteria.13
Further, anti-inflammatory properties have been attributed to rosemary essential oil, which are thought to be due to its suppression of nuclear factor kappa B transcription and inhibition of the arachidonic acid cascade.14
Other Functions of Rosemary
In 2022, Sutkowska-Skolimowska et al. demonstrated that rosemary extract in concentrations of 50 and 100mcg/mL significantly diminished accumulated collagen in the fibroblasts of four patients with severe and fatal osteogenesis imperfecta, suggesting that the botanical agent may have a role targeting cellular stress and inducing autophagy in therapy for this condition.15
In 2015, Akbari et al. established that 0.5% and 1% concentrations of rosemary essential oil were effective in facilitating the percutaneous absorption of diclofenac sodium topical gel.16
Conclusion
In Western culture, rosemary is thought of more as a spice to add flavor to food. However, there appears to be an emerging body of evidence suggesting various possible functions for rosemary in the dermatologic armamentarium. Much more research is necessary, though, to ascertain the most appropriate and optimal roles for this popular herb in skin care.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami, Florida. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as a ecommerce solution. Write to her at [email protected].
References
1. González-Minero FJ et al. Cosmetics. 2020 Oct 3;7(4):77.
2. Sayorwan W et al. Sci Pharm. 2013 Apr-Jun;81(2):531-42.
3. Pazyar N et al. Skin Pharmacol Physiol. 2014;27(6):303-10.
4. Auh JH and Madhavan J Biomed Pharmacother. 2021 Mar;135:111178.
5. Pérez-Sánchez A et al. J Photochem Photobiol B. 2014 Jul 5;136:12-8.
6. Sánchez-Marzo N et al. Antioxidants (Basel). 2020 Mar 20;9(3):255.
7. Ibrahim N et al. Sci Rep. 2022 Jul 30;12(1):13102.
8. Nobile V et al. Food Nutr Res. 2021 Mar 29:65.
9. Nobile V et al. Food Nutr Res. 2016 Jul 1;60:31871.
10. Hoskin R et al. Molecules. 2021 Jun 22;26(13):3781.
11. Li Pomi F et al. Antioxidants (Basel). 2023 Mar 9;12(3):680.
12. Park M et al. Exp Dermatol. 2013 May;22(5):336-41.
13. Sienkiewicz M et al. Molecules. 2013 Aug 5;18(8):9334-51.
14. Borges RS et al. J Ethnopharmacol. 2019 Jan 30;229:29-45.
15. Sutkowska-Skolimowska. Int J Mol Sci. 2022 Sep 7;23(18):10341.
16. Akbari J et al. Pharm Biol. 2015;53(10):1442-7.
Used as a spice in various, particularly Mediterranean, cuisines and in traditional medicine for hundreds of years, this aromatic shrub has been the focus of substantial research this century to clarify its roles in skin care. It is used broadly in cosmetic formulations, particularly to preserve the product, and acts as a skin conditioner and fragrance in safe concentrations.1 Rosemary essential oil is also a popular choice frequently used in aromatherapy.2,3 This column focuses on recent promising results supporting the antioxidant and anti-photoaging activities, especially, of rosemary.
UV Protection and Rosemary in Combination
A 2021 study in mice authored by Auh and Madhavan showed that a mixture of marigold and rosemary extracts yielded anti-photoaging effects, with the botanical formula suppressing UV-induced damage.4
Seven years earlier, Pérez-Sánchez et al. combined rosemary and citrus extracts and found that they exerted protective effects against UV damage in human HaCaT keratinocytes as well as human volunteers after oral consumption. Significant increases in minimal erythema dose (MED) were seen in participants, with daily intake of 250 mg of botanical combination, at 8 weeks (34%) and 12 weeks (56%). The investigators attributed the photoprotective effects of the formula to rosemary polyphenols and diterpenes as well as citrus flavonoids.5
Evaluation of a human skin cell model by Sánchez-Marzo et al. in 2020 revealed that rosemary diterpenes were instrumental in an herbal extract that combined citrus, olive, and rosemary in conferring genoprotection against UV-induced DNA damage. The authors note that human trials are needed to overcome the limitations of the cellular model in ascertaining whether the tested herbal formulations can yield oral and/or topical photoprotection.6
Anti-Photoaging and Anti-Pollution
In 2022, Ibrahim et al. assessed a hexane extract of rosemary leaves for anti-photoaging activity. Their evaluation showed an abundance of triterpenoids, monoterpenoids, and phenolic diterpenes in rosemary, with in vitro assays verifying the anti-aging, antioxidant, and wound healing functions of the extract. Further, topical rosemary hexane extract–loaded lipid nanocapsules protected rat skin from UV radiation, as epidermal and dermal histological parameters improved, antioxidant biochemical balance was restored, and inflammatory markers and wrinkling were diminished. The researchers concluded that the use of rosemary hexane extract represents a safe, efficient, and cost-effective way to deliver anti-aging, photoprotective functions to cosmeceutical formulations.7
In March 2021, Nobile et al. published a report on their randomized, double-blind, placebo-controlled parallel group study to investigate the efficacy of a marketed polyphenol-enriched dietary supplement (Zeropollution, which contains four standardized herbal extracts: Olea europaea leaf, Lippia citriodora, S. rosmarinus, and Sophora japonica) in diminishing pollution-induced oxidative stress and in improving skin aging in 100 White and Asian women who were outdoor workers living in a polluted environment (Milan, Italy). Statistically significant improvements in reducing wrinkle depth and hyperpigmentation, enhancing elasticity and firmness, as well as promoting skin moisturization and diminishing transepidermal water loss were noted as early as 2 weeks after product consumption began, with inter-group and intra-group analysis verifying that all skin parameters were ameliorated in Asian and White subjects.8
Previously, Nobile et al. conducted a randomized, parallel-group study on 90 subjects to evaluate the photoprotective effects of a combination of rosemary and grapefruit (Citrus paradisi) extracts (Nutroxsun). The investigators also performed a pilot, randomized crossover study on five participants. Both studies included only females with Fitzpatrick skin phototypes I-III who manifested mild to moderate chronological aging or photoaging. Within as little as 2 weeks, treated individuals exhibited reductions in UVA- and UVB-induced skin changes. Skin elasticity improved in this group, with wrinkles diminishing along with skin redness and lipoperoxides. The investigators concluded that the oral blend of rosemary and grapefruit consumed long term merits consideration as an adjuvant approach to preventing the deleterious effects of solar exposure.9
In 2021, Hoskin et al. used ex vivo human biopsies exposed to diesel engine exhaust to study the impact of spray-dried algae-rosemary particles against pollution-induced damage. The spirulina-rosemary gel that was developed lowered levels of 4-hydroxynonenal protein adducts (4HNE-PA) as well as matrix metalloproteinase-9 (MMP-9) and reduced the loss of filaggrin. The researchers concluded that their topically applied spirulina-rosemary gel was effective in mitigating or preventing skin aging and cutaneous damage caused by diesel air pollution.10
Antioxidant, Antibacterial, and Anti-Inflammatory Activity
Based on a 2023 literature search by Li Pomi et al. of in vitro as well as in vivo animal and human studies involving S. rosmarinus and the skin, researchers reported on substantial evidence buttressing the antioxidant role of the botanical agent. They cautioned that, while data support the harnessing of the bioactive constituents of rosemary to address inflammatory and infectious skin conditions, large controlled trials remain necessary to establish its potential functions in dermatologic clinical practice.11
Ten years earlier, Park et al. determined that a phenolic diterpene from rosemary (carnosic acid) prevented UV-induced expression of MMP-1, MMP-3, and MMP-9 in human skin fibroblasts and keratinocytes in a concentration-dependent manner by suppressing reactive oxygen species and blocking through the inhibition of ROS and the suppression of extracellular signal-regulated kinase (ERK)-mediated AP-1 activation.12
Around the same time, Sienkiewicz et al. showed that rosemary essential oil exhibits antibacterial activity against the standard strain Escherichia coli ATCC 25922 and 60 other clinical strains of the bacteria.13
Further, anti-inflammatory properties have been attributed to rosemary essential oil, which are thought to be due to its suppression of nuclear factor kappa B transcription and inhibition of the arachidonic acid cascade.14
Other Functions of Rosemary
In 2022, Sutkowska-Skolimowska et al. demonstrated that rosemary extract in concentrations of 50 and 100mcg/mL significantly diminished accumulated collagen in the fibroblasts of four patients with severe and fatal osteogenesis imperfecta, suggesting that the botanical agent may have a role targeting cellular stress and inducing autophagy in therapy for this condition.15
In 2015, Akbari et al. established that 0.5% and 1% concentrations of rosemary essential oil were effective in facilitating the percutaneous absorption of diclofenac sodium topical gel.16
Conclusion
In Western culture, rosemary is thought of more as a spice to add flavor to food. However, there appears to be an emerging body of evidence suggesting various possible functions for rosemary in the dermatologic armamentarium. Much more research is necessary, though, to ascertain the most appropriate and optimal roles for this popular herb in skin care.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami, Florida. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as a ecommerce solution. Write to her at [email protected].
References
1. González-Minero FJ et al. Cosmetics. 2020 Oct 3;7(4):77.
2. Sayorwan W et al. Sci Pharm. 2013 Apr-Jun;81(2):531-42.
3. Pazyar N et al. Skin Pharmacol Physiol. 2014;27(6):303-10.
4. Auh JH and Madhavan J Biomed Pharmacother. 2021 Mar;135:111178.
5. Pérez-Sánchez A et al. J Photochem Photobiol B. 2014 Jul 5;136:12-8.
6. Sánchez-Marzo N et al. Antioxidants (Basel). 2020 Mar 20;9(3):255.
7. Ibrahim N et al. Sci Rep. 2022 Jul 30;12(1):13102.
8. Nobile V et al. Food Nutr Res. 2021 Mar 29:65.
9. Nobile V et al. Food Nutr Res. 2016 Jul 1;60:31871.
10. Hoskin R et al. Molecules. 2021 Jun 22;26(13):3781.
11. Li Pomi F et al. Antioxidants (Basel). 2023 Mar 9;12(3):680.
12. Park M et al. Exp Dermatol. 2013 May;22(5):336-41.
13. Sienkiewicz M et al. Molecules. 2013 Aug 5;18(8):9334-51.
14. Borges RS et al. J Ethnopharmacol. 2019 Jan 30;229:29-45.
15. Sutkowska-Skolimowska. Int J Mol Sci. 2022 Sep 7;23(18):10341.
16. Akbari J et al. Pharm Biol. 2015;53(10):1442-7.
Used as a spice in various, particularly Mediterranean, cuisines and in traditional medicine for hundreds of years, this aromatic shrub has been the focus of substantial research this century to clarify its roles in skin care. It is used broadly in cosmetic formulations, particularly to preserve the product, and acts as a skin conditioner and fragrance in safe concentrations.1 Rosemary essential oil is also a popular choice frequently used in aromatherapy.2,3 This column focuses on recent promising results supporting the antioxidant and anti-photoaging activities, especially, of rosemary.
UV Protection and Rosemary in Combination
A 2021 study in mice authored by Auh and Madhavan showed that a mixture of marigold and rosemary extracts yielded anti-photoaging effects, with the botanical formula suppressing UV-induced damage.4
Seven years earlier, Pérez-Sánchez et al. combined rosemary and citrus extracts and found that they exerted protective effects against UV damage in human HaCaT keratinocytes as well as human volunteers after oral consumption. Significant increases in minimal erythema dose (MED) were seen in participants, with daily intake of 250 mg of botanical combination, at 8 weeks (34%) and 12 weeks (56%). The investigators attributed the photoprotective effects of the formula to rosemary polyphenols and diterpenes as well as citrus flavonoids.5
Evaluation of a human skin cell model by Sánchez-Marzo et al. in 2020 revealed that rosemary diterpenes were instrumental in an herbal extract that combined citrus, olive, and rosemary in conferring genoprotection against UV-induced DNA damage. The authors note that human trials are needed to overcome the limitations of the cellular model in ascertaining whether the tested herbal formulations can yield oral and/or topical photoprotection.6
Anti-Photoaging and Anti-Pollution
In 2022, Ibrahim et al. assessed a hexane extract of rosemary leaves for anti-photoaging activity. Their evaluation showed an abundance of triterpenoids, monoterpenoids, and phenolic diterpenes in rosemary, with in vitro assays verifying the anti-aging, antioxidant, and wound healing functions of the extract. Further, topical rosemary hexane extract–loaded lipid nanocapsules protected rat skin from UV radiation, as epidermal and dermal histological parameters improved, antioxidant biochemical balance was restored, and inflammatory markers and wrinkling were diminished. The researchers concluded that the use of rosemary hexane extract represents a safe, efficient, and cost-effective way to deliver anti-aging, photoprotective functions to cosmeceutical formulations.7
In March 2021, Nobile et al. published a report on their randomized, double-blind, placebo-controlled parallel group study to investigate the efficacy of a marketed polyphenol-enriched dietary supplement (Zeropollution, which contains four standardized herbal extracts: Olea europaea leaf, Lippia citriodora, S. rosmarinus, and Sophora japonica) in diminishing pollution-induced oxidative stress and in improving skin aging in 100 White and Asian women who were outdoor workers living in a polluted environment (Milan, Italy). Statistically significant improvements in reducing wrinkle depth and hyperpigmentation, enhancing elasticity and firmness, as well as promoting skin moisturization and diminishing transepidermal water loss were noted as early as 2 weeks after product consumption began, with inter-group and intra-group analysis verifying that all skin parameters were ameliorated in Asian and White subjects.8
Previously, Nobile et al. conducted a randomized, parallel-group study on 90 subjects to evaluate the photoprotective effects of a combination of rosemary and grapefruit (Citrus paradisi) extracts (Nutroxsun). The investigators also performed a pilot, randomized crossover study on five participants. Both studies included only females with Fitzpatrick skin phototypes I-III who manifested mild to moderate chronological aging or photoaging. Within as little as 2 weeks, treated individuals exhibited reductions in UVA- and UVB-induced skin changes. Skin elasticity improved in this group, with wrinkles diminishing along with skin redness and lipoperoxides. The investigators concluded that the oral blend of rosemary and grapefruit consumed long term merits consideration as an adjuvant approach to preventing the deleterious effects of solar exposure.9
In 2021, Hoskin et al. used ex vivo human biopsies exposed to diesel engine exhaust to study the impact of spray-dried algae-rosemary particles against pollution-induced damage. The spirulina-rosemary gel that was developed lowered levels of 4-hydroxynonenal protein adducts (4HNE-PA) as well as matrix metalloproteinase-9 (MMP-9) and reduced the loss of filaggrin. The researchers concluded that their topically applied spirulina-rosemary gel was effective in mitigating or preventing skin aging and cutaneous damage caused by diesel air pollution.10
Antioxidant, Antibacterial, and Anti-Inflammatory Activity
Based on a 2023 literature search by Li Pomi et al. of in vitro as well as in vivo animal and human studies involving S. rosmarinus and the skin, researchers reported on substantial evidence buttressing the antioxidant role of the botanical agent. They cautioned that, while data support the harnessing of the bioactive constituents of rosemary to address inflammatory and infectious skin conditions, large controlled trials remain necessary to establish its potential functions in dermatologic clinical practice.11
Ten years earlier, Park et al. determined that a phenolic diterpene from rosemary (carnosic acid) prevented UV-induced expression of MMP-1, MMP-3, and MMP-9 in human skin fibroblasts and keratinocytes in a concentration-dependent manner by suppressing reactive oxygen species and blocking through the inhibition of ROS and the suppression of extracellular signal-regulated kinase (ERK)-mediated AP-1 activation.12
Around the same time, Sienkiewicz et al. showed that rosemary essential oil exhibits antibacterial activity against the standard strain Escherichia coli ATCC 25922 and 60 other clinical strains of the bacteria.13
Further, anti-inflammatory properties have been attributed to rosemary essential oil, which are thought to be due to its suppression of nuclear factor kappa B transcription and inhibition of the arachidonic acid cascade.14
Other Functions of Rosemary
In 2022, Sutkowska-Skolimowska et al. demonstrated that rosemary extract in concentrations of 50 and 100mcg/mL significantly diminished accumulated collagen in the fibroblasts of four patients with severe and fatal osteogenesis imperfecta, suggesting that the botanical agent may have a role targeting cellular stress and inducing autophagy in therapy for this condition.15
In 2015, Akbari et al. established that 0.5% and 1% concentrations of rosemary essential oil were effective in facilitating the percutaneous absorption of diclofenac sodium topical gel.16
Conclusion
In Western culture, rosemary is thought of more as a spice to add flavor to food. However, there appears to be an emerging body of evidence suggesting various possible functions for rosemary in the dermatologic armamentarium. Much more research is necessary, though, to ascertain the most appropriate and optimal roles for this popular herb in skin care.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami, Florida. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as a ecommerce solution. Write to her at [email protected].
References
1. González-Minero FJ et al. Cosmetics. 2020 Oct 3;7(4):77.
2. Sayorwan W et al. Sci Pharm. 2013 Apr-Jun;81(2):531-42.
3. Pazyar N et al. Skin Pharmacol Physiol. 2014;27(6):303-10.
4. Auh JH and Madhavan J Biomed Pharmacother. 2021 Mar;135:111178.
5. Pérez-Sánchez A et al. J Photochem Photobiol B. 2014 Jul 5;136:12-8.
6. Sánchez-Marzo N et al. Antioxidants (Basel). 2020 Mar 20;9(3):255.
7. Ibrahim N et al. Sci Rep. 2022 Jul 30;12(1):13102.
8. Nobile V et al. Food Nutr Res. 2021 Mar 29:65.
9. Nobile V et al. Food Nutr Res. 2016 Jul 1;60:31871.
10. Hoskin R et al. Molecules. 2021 Jun 22;26(13):3781.
11. Li Pomi F et al. Antioxidants (Basel). 2023 Mar 9;12(3):680.
12. Park M et al. Exp Dermatol. 2013 May;22(5):336-41.
13. Sienkiewicz M et al. Molecules. 2013 Aug 5;18(8):9334-51.
14. Borges RS et al. J Ethnopharmacol. 2019 Jan 30;229:29-45.
15. Sutkowska-Skolimowska. Int J Mol Sci. 2022 Sep 7;23(18):10341.
16. Akbari J et al. Pharm Biol. 2015;53(10):1442-7.
Vitamin D Supplements May Be a Double-Edged Sword
This transcript has been edited for clarity.
Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.
Imagine, if you will, the great Cathedral of Our Lady of Correlation. You walk through the majestic oak doors depicting the link between ice cream sales and shark attacks, past the rose window depicting the cardiovascular benefits of red wine, and down the aisles frescoed in dramatic images showing how Facebook usage is associated with less life satisfaction. And then you reach the altar, the holy of holies where, emblazoned in shimmering pyrite, you see the patron saint of this church: vitamin D.
Yes, if you’ve watched this space, then you know that I have little truck with the wildly popular supplement. In all of clinical research, I believe that there is no molecule with stronger data for correlation and weaker data for causation.
Low serum vitamin D levels have been linked to higher risks for heart disease, cancer, falls, COVID, dementia, C diff, and others. And yet, when we do randomized trials of vitamin D supplementation — the thing that can prove that the low level was causally linked to the outcome of interest — we get negative results.
Trials aren’t perfect, of course, and we’ll talk in a moment about a big one that had some issues. But we are at a point where we need to either be vitamin D apologists, saying, “Forget what those lying RCTs tell you and buy this supplement” — an $800 million-a-year industry, by the way — or conclude that vitamin D levels are a convenient marker of various lifestyle factors that are associated with better outcomes: markers of exercise, getting outside, eating a varied diet.
Or perhaps vitamin D supplements have real effects. It’s just that the beneficial effects are matched by the harmful ones. Stay tuned.
The Women’s Health Initiative remains among the largest randomized trials of vitamin D and calcium supplementation ever conducted — and a major contributor to the negative outcomes of vitamin D trials.
But if you dig into the inclusion and exclusion criteria for this trial, you’ll find that individuals were allowed to continue taking vitamins and supplements while they were in the trial, regardless of their randomization status. In fact, the majority took supplements at baseline, and more took supplements over time.
That means, of course, that people in the placebo group, who were getting sugar pills instead of vitamin D and calcium, may have been taking vitamin D and calcium on the side. That would certainly bias the results of the trial toward the null, which is what the primary analyses showed. To wit, the original analysis of the Women’s Health Initiative trial showed no effect of randomization to vitamin D supplementation on improving cancer or cardiovascular outcomes.
But the Women’s Health Initiative trial started 30 years ago. Today, with the benefit of decades of follow-up, we can re-investigate — and perhaps re-litigate — those findings, courtesy of this study, “Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women” appearing in Annals of Internal Medicine.
Dr Cynthia Thomson, of the Mel and Enid Zuckerman College of Public Health at the University of Arizona, and colleagues led this updated analysis focused on two findings that had been hinted at, but not statistically confirmed, in other vitamin D studies: a potential for the supplement to reduce the risk for cancer, and a potential for it to increase the risk for heart disease.
The randomized trial itself only lasted 7 years. What we are seeing in this analysis of 36,282 women is outcomes that happened at any time from randomization to the end of 2023 — around 20 years after the randomization to supplementation stopped. But, the researchers would argue, that’s probably okay. Cancer and heart disease take time to develop; we see lung cancer long after people stop smoking. So a history of consistent vitamin D supplementation may indeed be protective — or harmful.
Here are the top-line results. Those randomized to vitamin D and calcium supplementation had a 7% reduction in the rate of death from cancer, driven primarily by a reduction in colorectal cancer. This was statistically significant. Also statistically significant? Those randomized to supplementation had a 6% increase in the rate of death from cardiovascular disease. Put those findings together and what do you get? Stone-cold nothing, in terms of overall mortality.
Okay, you say, but what about all that supplementation that was happening outside of the context of the trial, biasing our results toward the null?
The researchers finally clue us in.
First of all, I’ll tell you that, yes, people who were supplementing outside of the trial had higher baseline vitamin D levels — a median of 54.5 nmol/L vs 32.8 nmol/L. This may be because they were supplementing with vitamin D, but it could also be because people who take supplements tend to do other healthy things — another correlation to add to the great cathedral.
To get a better view of the real effects of randomization, the authors restricted the analysis to just those who did not use outside supplements. If vitamin D supplements help, then these are the people they should help. This group had about a 11% reduction in the incidence of cancer — statistically significant — and a 7% reduction in cancer mortality that did not meet the bar for statistical significance.
There was no increase in cardiovascular disease among this group. But this small effect on cancer was nowhere near enough to significantly reduce the rate of all-cause mortality.
Among those using supplements, vitamin D supplementation didn’t really move the needle on any outcome.
I know what you’re thinking: How many of these women were vitamin D deficient when we got started? These results may simply be telling us that people who have normal vitamin D levels are fine to go without supplementation.
Nearly three fourths of women who were not taking supplements entered the trial with vitamin D levels below the 50 nmol/L cutoff that the authors suggest would qualify for deficiency. Around half of those who used supplements were deficient. And yet, frustratingly, I could not find data on the effect of randomization to supplementation stratified by baseline vitamin D level. I even reached out to Dr Thomson to ask about this. She replied, “We did not stratify on baseline values because the numbers are too small statistically to test this.” Sorry.
In the meantime, I can tell you that for your “average woman,” vitamin D supplementation likely has no effect on mortality. It might modestly reduce the risk for certain cancers while increasing the risk for heart disease (probably through coronary calcification). So, there might be some room for personalization here. Perhaps women with a strong family history of cancer or other risk factors would do better with supplements, and those with a high risk for heart disease would do worse. Seems like a strategy that could be tested in a clinical trial. But maybe we could ask the participants to give up their extracurricular supplement use before they enter the trial. F. Perry Wilson, MD, MSCE, has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @fperrywilson and his book, How Medicine Works and When It Doesn’t, is available now.
This transcript has been edited for clarity.
Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.
Imagine, if you will, the great Cathedral of Our Lady of Correlation. You walk through the majestic oak doors depicting the link between ice cream sales and shark attacks, past the rose window depicting the cardiovascular benefits of red wine, and down the aisles frescoed in dramatic images showing how Facebook usage is associated with less life satisfaction. And then you reach the altar, the holy of holies where, emblazoned in shimmering pyrite, you see the patron saint of this church: vitamin D.
Yes, if you’ve watched this space, then you know that I have little truck with the wildly popular supplement. In all of clinical research, I believe that there is no molecule with stronger data for correlation and weaker data for causation.
Low serum vitamin D levels have been linked to higher risks for heart disease, cancer, falls, COVID, dementia, C diff, and others. And yet, when we do randomized trials of vitamin D supplementation — the thing that can prove that the low level was causally linked to the outcome of interest — we get negative results.
Trials aren’t perfect, of course, and we’ll talk in a moment about a big one that had some issues. But we are at a point where we need to either be vitamin D apologists, saying, “Forget what those lying RCTs tell you and buy this supplement” — an $800 million-a-year industry, by the way — or conclude that vitamin D levels are a convenient marker of various lifestyle factors that are associated with better outcomes: markers of exercise, getting outside, eating a varied diet.
Or perhaps vitamin D supplements have real effects. It’s just that the beneficial effects are matched by the harmful ones. Stay tuned.
The Women’s Health Initiative remains among the largest randomized trials of vitamin D and calcium supplementation ever conducted — and a major contributor to the negative outcomes of vitamin D trials.
But if you dig into the inclusion and exclusion criteria for this trial, you’ll find that individuals were allowed to continue taking vitamins and supplements while they were in the trial, regardless of their randomization status. In fact, the majority took supplements at baseline, and more took supplements over time.
That means, of course, that people in the placebo group, who were getting sugar pills instead of vitamin D and calcium, may have been taking vitamin D and calcium on the side. That would certainly bias the results of the trial toward the null, which is what the primary analyses showed. To wit, the original analysis of the Women’s Health Initiative trial showed no effect of randomization to vitamin D supplementation on improving cancer or cardiovascular outcomes.
But the Women’s Health Initiative trial started 30 years ago. Today, with the benefit of decades of follow-up, we can re-investigate — and perhaps re-litigate — those findings, courtesy of this study, “Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women” appearing in Annals of Internal Medicine.
Dr Cynthia Thomson, of the Mel and Enid Zuckerman College of Public Health at the University of Arizona, and colleagues led this updated analysis focused on two findings that had been hinted at, but not statistically confirmed, in other vitamin D studies: a potential for the supplement to reduce the risk for cancer, and a potential for it to increase the risk for heart disease.
The randomized trial itself only lasted 7 years. What we are seeing in this analysis of 36,282 women is outcomes that happened at any time from randomization to the end of 2023 — around 20 years after the randomization to supplementation stopped. But, the researchers would argue, that’s probably okay. Cancer and heart disease take time to develop; we see lung cancer long after people stop smoking. So a history of consistent vitamin D supplementation may indeed be protective — or harmful.
Here are the top-line results. Those randomized to vitamin D and calcium supplementation had a 7% reduction in the rate of death from cancer, driven primarily by a reduction in colorectal cancer. This was statistically significant. Also statistically significant? Those randomized to supplementation had a 6% increase in the rate of death from cardiovascular disease. Put those findings together and what do you get? Stone-cold nothing, in terms of overall mortality.
Okay, you say, but what about all that supplementation that was happening outside of the context of the trial, biasing our results toward the null?
The researchers finally clue us in.
First of all, I’ll tell you that, yes, people who were supplementing outside of the trial had higher baseline vitamin D levels — a median of 54.5 nmol/L vs 32.8 nmol/L. This may be because they were supplementing with vitamin D, but it could also be because people who take supplements tend to do other healthy things — another correlation to add to the great cathedral.
To get a better view of the real effects of randomization, the authors restricted the analysis to just those who did not use outside supplements. If vitamin D supplements help, then these are the people they should help. This group had about a 11% reduction in the incidence of cancer — statistically significant — and a 7% reduction in cancer mortality that did not meet the bar for statistical significance.
There was no increase in cardiovascular disease among this group. But this small effect on cancer was nowhere near enough to significantly reduce the rate of all-cause mortality.
Among those using supplements, vitamin D supplementation didn’t really move the needle on any outcome.
I know what you’re thinking: How many of these women were vitamin D deficient when we got started? These results may simply be telling us that people who have normal vitamin D levels are fine to go without supplementation.
Nearly three fourths of women who were not taking supplements entered the trial with vitamin D levels below the 50 nmol/L cutoff that the authors suggest would qualify for deficiency. Around half of those who used supplements were deficient. And yet, frustratingly, I could not find data on the effect of randomization to supplementation stratified by baseline vitamin D level. I even reached out to Dr Thomson to ask about this. She replied, “We did not stratify on baseline values because the numbers are too small statistically to test this.” Sorry.
In the meantime, I can tell you that for your “average woman,” vitamin D supplementation likely has no effect on mortality. It might modestly reduce the risk for certain cancers while increasing the risk for heart disease (probably through coronary calcification). So, there might be some room for personalization here. Perhaps women with a strong family history of cancer or other risk factors would do better with supplements, and those with a high risk for heart disease would do worse. Seems like a strategy that could be tested in a clinical trial. But maybe we could ask the participants to give up their extracurricular supplement use before they enter the trial. F. Perry Wilson, MD, MSCE, has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @fperrywilson and his book, How Medicine Works and When It Doesn’t, is available now.
This transcript has been edited for clarity.
Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.
Imagine, if you will, the great Cathedral of Our Lady of Correlation. You walk through the majestic oak doors depicting the link between ice cream sales and shark attacks, past the rose window depicting the cardiovascular benefits of red wine, and down the aisles frescoed in dramatic images showing how Facebook usage is associated with less life satisfaction. And then you reach the altar, the holy of holies where, emblazoned in shimmering pyrite, you see the patron saint of this church: vitamin D.
Yes, if you’ve watched this space, then you know that I have little truck with the wildly popular supplement. In all of clinical research, I believe that there is no molecule with stronger data for correlation and weaker data for causation.
Low serum vitamin D levels have been linked to higher risks for heart disease, cancer, falls, COVID, dementia, C diff, and others. And yet, when we do randomized trials of vitamin D supplementation — the thing that can prove that the low level was causally linked to the outcome of interest — we get negative results.
Trials aren’t perfect, of course, and we’ll talk in a moment about a big one that had some issues. But we are at a point where we need to either be vitamin D apologists, saying, “Forget what those lying RCTs tell you and buy this supplement” — an $800 million-a-year industry, by the way — or conclude that vitamin D levels are a convenient marker of various lifestyle factors that are associated with better outcomes: markers of exercise, getting outside, eating a varied diet.
Or perhaps vitamin D supplements have real effects. It’s just that the beneficial effects are matched by the harmful ones. Stay tuned.
The Women’s Health Initiative remains among the largest randomized trials of vitamin D and calcium supplementation ever conducted — and a major contributor to the negative outcomes of vitamin D trials.
But if you dig into the inclusion and exclusion criteria for this trial, you’ll find that individuals were allowed to continue taking vitamins and supplements while they were in the trial, regardless of their randomization status. In fact, the majority took supplements at baseline, and more took supplements over time.
That means, of course, that people in the placebo group, who were getting sugar pills instead of vitamin D and calcium, may have been taking vitamin D and calcium on the side. That would certainly bias the results of the trial toward the null, which is what the primary analyses showed. To wit, the original analysis of the Women’s Health Initiative trial showed no effect of randomization to vitamin D supplementation on improving cancer or cardiovascular outcomes.
But the Women’s Health Initiative trial started 30 years ago. Today, with the benefit of decades of follow-up, we can re-investigate — and perhaps re-litigate — those findings, courtesy of this study, “Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women” appearing in Annals of Internal Medicine.
Dr Cynthia Thomson, of the Mel and Enid Zuckerman College of Public Health at the University of Arizona, and colleagues led this updated analysis focused on two findings that had been hinted at, but not statistically confirmed, in other vitamin D studies: a potential for the supplement to reduce the risk for cancer, and a potential for it to increase the risk for heart disease.
The randomized trial itself only lasted 7 years. What we are seeing in this analysis of 36,282 women is outcomes that happened at any time from randomization to the end of 2023 — around 20 years after the randomization to supplementation stopped. But, the researchers would argue, that’s probably okay. Cancer and heart disease take time to develop; we see lung cancer long after people stop smoking. So a history of consistent vitamin D supplementation may indeed be protective — or harmful.
Here are the top-line results. Those randomized to vitamin D and calcium supplementation had a 7% reduction in the rate of death from cancer, driven primarily by a reduction in colorectal cancer. This was statistically significant. Also statistically significant? Those randomized to supplementation had a 6% increase in the rate of death from cardiovascular disease. Put those findings together and what do you get? Stone-cold nothing, in terms of overall mortality.
Okay, you say, but what about all that supplementation that was happening outside of the context of the trial, biasing our results toward the null?
The researchers finally clue us in.
First of all, I’ll tell you that, yes, people who were supplementing outside of the trial had higher baseline vitamin D levels — a median of 54.5 nmol/L vs 32.8 nmol/L. This may be because they were supplementing with vitamin D, but it could also be because people who take supplements tend to do other healthy things — another correlation to add to the great cathedral.
To get a better view of the real effects of randomization, the authors restricted the analysis to just those who did not use outside supplements. If vitamin D supplements help, then these are the people they should help. This group had about a 11% reduction in the incidence of cancer — statistically significant — and a 7% reduction in cancer mortality that did not meet the bar for statistical significance.
There was no increase in cardiovascular disease among this group. But this small effect on cancer was nowhere near enough to significantly reduce the rate of all-cause mortality.
Among those using supplements, vitamin D supplementation didn’t really move the needle on any outcome.
I know what you’re thinking: How many of these women were vitamin D deficient when we got started? These results may simply be telling us that people who have normal vitamin D levels are fine to go without supplementation.
Nearly three fourths of women who were not taking supplements entered the trial with vitamin D levels below the 50 nmol/L cutoff that the authors suggest would qualify for deficiency. Around half of those who used supplements were deficient. And yet, frustratingly, I could not find data on the effect of randomization to supplementation stratified by baseline vitamin D level. I even reached out to Dr Thomson to ask about this. She replied, “We did not stratify on baseline values because the numbers are too small statistically to test this.” Sorry.
In the meantime, I can tell you that for your “average woman,” vitamin D supplementation likely has no effect on mortality. It might modestly reduce the risk for certain cancers while increasing the risk for heart disease (probably through coronary calcification). So, there might be some room for personalization here. Perhaps women with a strong family history of cancer or other risk factors would do better with supplements, and those with a high risk for heart disease would do worse. Seems like a strategy that could be tested in a clinical trial. But maybe we could ask the participants to give up their extracurricular supplement use before they enter the trial. F. Perry Wilson, MD, MSCE, has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @fperrywilson and his book, How Medicine Works and When It Doesn’t, is available now.
Survival Advantage of Adjuvant IO ‘Big News’ in Renal Cancer
This transcript has been edited for clarity.
Hi. I’m Brian Rini. I’m an Ingram Professor of Medicine at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. I think there’s three main areas: adjuvant therapy in kidney cancer, frontline therapy in advanced disease, and the refractory space.
To open with adjuvant therapy, the biggest news in kidney cancer, and probably all of GU cancer at ASCO GU this year, was the adjuvant pembrolizumab overall survival data. This KEYNOTE study had previously shown disease-free survival advantages over placebo in a population with high-risk resected kidney cancer. There was a trend toward overall survival, but it was not significant in those early analyses.
Now with nearly 5 years of follow-up, we see an overall survival advantage, with a hazard ratio in the 0.6 range — so, about a 40% reduction in the risk for death among these patients receiving adjuvant pembrolizumab (pembro). This was really important for the field. It’s been difficult to show a survival advantage, even in diseases like melanoma, which is considered at least as much, if not more immune responsive, and I think puts into perspective whether to offer this drug to high-risk resected patients. And it certainly needs to be considered for this population.
I think the balance on that — and this came out in some of the questions after the session — was around how many of the placebo recipients got salvage immune therapy, which would be a standard of care. But in the countries where this was done, it’s not really clear how many actually got therapy. We know most patients got some salvage therapy, be it local or systemic, and about half the patients got immune therapy. But some more granular detail would be necessary.
The other thing I would mention is that this was paired with the previous presentation, which was adjuvant nivolumab. It was a very similar study, a similar drug in a similar setting, but it did not show any advantages of either disease-free or overall survival. This comes on the heels of other negative studies and a negative ipilimumab/nivolumab (ipi/nivo) study in this setting, part of the same study.
The reasons for these discrepancies are not entirely clear. There’s differences in populations and duration of therapy and mechanism, and all sorts of things. I don’t think anybody’s really been able to come up with one reason why we have some negative immune trials in kidney cancer and one shiningly positive one. But be that as it may, I think the take-home was that adjuvant pembro is certainly a standard of care in high-risk disease, and a benefit/risk discussion needs to be had with each individual patient. And I think pembro will be the building block for future studies, some of which are ongoing.
The second major area of update was in frontline kidney cancer. There weren’t a lot of new data, but there were updates to the existing trials. As you may know, frontline immune-based doublet is a standard of care in this disease: either ipi/nivo or one of the immuno-oncology/tyrosine kinase inhibitor (IO/TKI) regimens. We had two updates. One was an 8-year update on ipi/nivo. It’s a really long follow-up for these patients now, and what was observed was that these results remain remarkably consistent.
The hazard ratios for benefit in terms of survival and durability of response are really consistent over the past several years — again, a hallmark of immune therapy. Over half the responders are still responding now, many years later. I think that only strengthens the position of ipi/nivo as a choice for advanced clear cell kidney cancer patients. Again, there are good long-term toxicity data, and some patients can remain off treatment in what’s called treatment-free survival. So, an important update. We look forward to future, probably 10-year, data.
The CheckMate 9ER cabozantinib/nivolumab (cabo/nivo) study was updated now with many years of follow-up, as some of the other IO/TKI regimens have as well. And I think there is a similar theme, although a few years behind in maturity from the ipi/nivo data. It shows persistence of benefit. With IO/TKI regimens, a lot of the benefit is up front. It’s high response rates. It’s progression-free survival (PFS). But we’re starting to see some of that durability.
Where it’ll land, if there will be a tail of the curve and where it will be, is unclear, but these updates are important in terms of counseling patients. Patients want to know not just what’s going to happen at their first scan but also years from now. And they’re planning to be around years from now. So, I think these data are important.
The last thing I’ll mention is a health-related quality-of-life update from what was called the 005 trial of belzutifan, an oral HIF inhibitor, compared with everolimus. We heard data at the European Society for Medical Oncology (ESMO) Congress 2023 on a PFS and response-rate advantage. The drug was approved by the US Food and Drug Administration (FDA) in late December, and now we see some quality-of-life data.
Quality-of-life questionnaires and scales have a lot of imperfections. I don’t think they necessarily capture everything we want. But in this case, it was fairly clean in that belzutifan is known to be a well-tolerated agent. The toxicity profile is clean. It’s been used for years in patients with Von Hippel-Lindau syndrome, certainly in the trials for years, and has shown good tolerance over time. So, I view these data as complementary to what we already knew about the drug, but they’re nice to see.
It’s nice to see datasets come together and show the same thing: Not only is the drug active in a refractory renal cell carcinoma (RCC) setting, but also it’s really well tolerated and does not adversely impact patients› quality of life. I use this drug a lot in refractory kidney cancer, and because it’s so well tolerated. That means it’s also combinable. And there are some very large studies in the front-end second-line space combining it, in a space where people believe that it has more activity. But there are some complementary data as we wait for the overall survival signal, hopefully, from this regimen.
So, there have been some exciting updates, mostly in the adjuvant space but also in some other spaces in kidney cancer and building upon some of the clinical advances that we had seen from previous meetings. I’m Brian Rini, and I appreciate you attending.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Hi. I’m Brian Rini. I’m an Ingram Professor of Medicine at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. I think there’s three main areas: adjuvant therapy in kidney cancer, frontline therapy in advanced disease, and the refractory space.
To open with adjuvant therapy, the biggest news in kidney cancer, and probably all of GU cancer at ASCO GU this year, was the adjuvant pembrolizumab overall survival data. This KEYNOTE study had previously shown disease-free survival advantages over placebo in a population with high-risk resected kidney cancer. There was a trend toward overall survival, but it was not significant in those early analyses.
Now with nearly 5 years of follow-up, we see an overall survival advantage, with a hazard ratio in the 0.6 range — so, about a 40% reduction in the risk for death among these patients receiving adjuvant pembrolizumab (pembro). This was really important for the field. It’s been difficult to show a survival advantage, even in diseases like melanoma, which is considered at least as much, if not more immune responsive, and I think puts into perspective whether to offer this drug to high-risk resected patients. And it certainly needs to be considered for this population.
I think the balance on that — and this came out in some of the questions after the session — was around how many of the placebo recipients got salvage immune therapy, which would be a standard of care. But in the countries where this was done, it’s not really clear how many actually got therapy. We know most patients got some salvage therapy, be it local or systemic, and about half the patients got immune therapy. But some more granular detail would be necessary.
The other thing I would mention is that this was paired with the previous presentation, which was adjuvant nivolumab. It was a very similar study, a similar drug in a similar setting, but it did not show any advantages of either disease-free or overall survival. This comes on the heels of other negative studies and a negative ipilimumab/nivolumab (ipi/nivo) study in this setting, part of the same study.
The reasons for these discrepancies are not entirely clear. There’s differences in populations and duration of therapy and mechanism, and all sorts of things. I don’t think anybody’s really been able to come up with one reason why we have some negative immune trials in kidney cancer and one shiningly positive one. But be that as it may, I think the take-home was that adjuvant pembro is certainly a standard of care in high-risk disease, and a benefit/risk discussion needs to be had with each individual patient. And I think pembro will be the building block for future studies, some of which are ongoing.
The second major area of update was in frontline kidney cancer. There weren’t a lot of new data, but there were updates to the existing trials. As you may know, frontline immune-based doublet is a standard of care in this disease: either ipi/nivo or one of the immuno-oncology/tyrosine kinase inhibitor (IO/TKI) regimens. We had two updates. One was an 8-year update on ipi/nivo. It’s a really long follow-up for these patients now, and what was observed was that these results remain remarkably consistent.
The hazard ratios for benefit in terms of survival and durability of response are really consistent over the past several years — again, a hallmark of immune therapy. Over half the responders are still responding now, many years later. I think that only strengthens the position of ipi/nivo as a choice for advanced clear cell kidney cancer patients. Again, there are good long-term toxicity data, and some patients can remain off treatment in what’s called treatment-free survival. So, an important update. We look forward to future, probably 10-year, data.
The CheckMate 9ER cabozantinib/nivolumab (cabo/nivo) study was updated now with many years of follow-up, as some of the other IO/TKI regimens have as well. And I think there is a similar theme, although a few years behind in maturity from the ipi/nivo data. It shows persistence of benefit. With IO/TKI regimens, a lot of the benefit is up front. It’s high response rates. It’s progression-free survival (PFS). But we’re starting to see some of that durability.
Where it’ll land, if there will be a tail of the curve and where it will be, is unclear, but these updates are important in terms of counseling patients. Patients want to know not just what’s going to happen at their first scan but also years from now. And they’re planning to be around years from now. So, I think these data are important.
The last thing I’ll mention is a health-related quality-of-life update from what was called the 005 trial of belzutifan, an oral HIF inhibitor, compared with everolimus. We heard data at the European Society for Medical Oncology (ESMO) Congress 2023 on a PFS and response-rate advantage. The drug was approved by the US Food and Drug Administration (FDA) in late December, and now we see some quality-of-life data.
Quality-of-life questionnaires and scales have a lot of imperfections. I don’t think they necessarily capture everything we want. But in this case, it was fairly clean in that belzutifan is known to be a well-tolerated agent. The toxicity profile is clean. It’s been used for years in patients with Von Hippel-Lindau syndrome, certainly in the trials for years, and has shown good tolerance over time. So, I view these data as complementary to what we already knew about the drug, but they’re nice to see.
It’s nice to see datasets come together and show the same thing: Not only is the drug active in a refractory renal cell carcinoma (RCC) setting, but also it’s really well tolerated and does not adversely impact patients› quality of life. I use this drug a lot in refractory kidney cancer, and because it’s so well tolerated. That means it’s also combinable. And there are some very large studies in the front-end second-line space combining it, in a space where people believe that it has more activity. But there are some complementary data as we wait for the overall survival signal, hopefully, from this regimen.
So, there have been some exciting updates, mostly in the adjuvant space but also in some other spaces in kidney cancer and building upon some of the clinical advances that we had seen from previous meetings. I’m Brian Rini, and I appreciate you attending.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Hi. I’m Brian Rini. I’m an Ingram Professor of Medicine at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. I think there’s three main areas: adjuvant therapy in kidney cancer, frontline therapy in advanced disease, and the refractory space.
To open with adjuvant therapy, the biggest news in kidney cancer, and probably all of GU cancer at ASCO GU this year, was the adjuvant pembrolizumab overall survival data. This KEYNOTE study had previously shown disease-free survival advantages over placebo in a population with high-risk resected kidney cancer. There was a trend toward overall survival, but it was not significant in those early analyses.
Now with nearly 5 years of follow-up, we see an overall survival advantage, with a hazard ratio in the 0.6 range — so, about a 40% reduction in the risk for death among these patients receiving adjuvant pembrolizumab (pembro). This was really important for the field. It’s been difficult to show a survival advantage, even in diseases like melanoma, which is considered at least as much, if not more immune responsive, and I think puts into perspective whether to offer this drug to high-risk resected patients. And it certainly needs to be considered for this population.
I think the balance on that — and this came out in some of the questions after the session — was around how many of the placebo recipients got salvage immune therapy, which would be a standard of care. But in the countries where this was done, it’s not really clear how many actually got therapy. We know most patients got some salvage therapy, be it local or systemic, and about half the patients got immune therapy. But some more granular detail would be necessary.
The other thing I would mention is that this was paired with the previous presentation, which was adjuvant nivolumab. It was a very similar study, a similar drug in a similar setting, but it did not show any advantages of either disease-free or overall survival. This comes on the heels of other negative studies and a negative ipilimumab/nivolumab (ipi/nivo) study in this setting, part of the same study.
The reasons for these discrepancies are not entirely clear. There’s differences in populations and duration of therapy and mechanism, and all sorts of things. I don’t think anybody’s really been able to come up with one reason why we have some negative immune trials in kidney cancer and one shiningly positive one. But be that as it may, I think the take-home was that adjuvant pembro is certainly a standard of care in high-risk disease, and a benefit/risk discussion needs to be had with each individual patient. And I think pembro will be the building block for future studies, some of which are ongoing.
The second major area of update was in frontline kidney cancer. There weren’t a lot of new data, but there were updates to the existing trials. As you may know, frontline immune-based doublet is a standard of care in this disease: either ipi/nivo or one of the immuno-oncology/tyrosine kinase inhibitor (IO/TKI) regimens. We had two updates. One was an 8-year update on ipi/nivo. It’s a really long follow-up for these patients now, and what was observed was that these results remain remarkably consistent.
The hazard ratios for benefit in terms of survival and durability of response are really consistent over the past several years — again, a hallmark of immune therapy. Over half the responders are still responding now, many years later. I think that only strengthens the position of ipi/nivo as a choice for advanced clear cell kidney cancer patients. Again, there are good long-term toxicity data, and some patients can remain off treatment in what’s called treatment-free survival. So, an important update. We look forward to future, probably 10-year, data.
The CheckMate 9ER cabozantinib/nivolumab (cabo/nivo) study was updated now with many years of follow-up, as some of the other IO/TKI regimens have as well. And I think there is a similar theme, although a few years behind in maturity from the ipi/nivo data. It shows persistence of benefit. With IO/TKI regimens, a lot of the benefit is up front. It’s high response rates. It’s progression-free survival (PFS). But we’re starting to see some of that durability.
Where it’ll land, if there will be a tail of the curve and where it will be, is unclear, but these updates are important in terms of counseling patients. Patients want to know not just what’s going to happen at their first scan but also years from now. And they’re planning to be around years from now. So, I think these data are important.
The last thing I’ll mention is a health-related quality-of-life update from what was called the 005 trial of belzutifan, an oral HIF inhibitor, compared with everolimus. We heard data at the European Society for Medical Oncology (ESMO) Congress 2023 on a PFS and response-rate advantage. The drug was approved by the US Food and Drug Administration (FDA) in late December, and now we see some quality-of-life data.
Quality-of-life questionnaires and scales have a lot of imperfections. I don’t think they necessarily capture everything we want. But in this case, it was fairly clean in that belzutifan is known to be a well-tolerated agent. The toxicity profile is clean. It’s been used for years in patients with Von Hippel-Lindau syndrome, certainly in the trials for years, and has shown good tolerance over time. So, I view these data as complementary to what we already knew about the drug, but they’re nice to see.
It’s nice to see datasets come together and show the same thing: Not only is the drug active in a refractory renal cell carcinoma (RCC) setting, but also it’s really well tolerated and does not adversely impact patients› quality of life. I use this drug a lot in refractory kidney cancer, and because it’s so well tolerated. That means it’s also combinable. And there are some very large studies in the front-end second-line space combining it, in a space where people believe that it has more activity. But there are some complementary data as we wait for the overall survival signal, hopefully, from this regimen.
So, there have been some exciting updates, mostly in the adjuvant space but also in some other spaces in kidney cancer and building upon some of the clinical advances that we had seen from previous meetings. I’m Brian Rini, and I appreciate you attending.
A version of this article first appeared on Medscape.com.
The Urethra Is a Sex Organ; Why This Matters in Incontinence
This transcript has been edited for clarity.
Rachel S. Rubin, MD: I’m Dr. Rachel Rubin, urologist and sexual medicine specialist in the Washington, DC, area. We are coming to you live from the Mayo Clinic Urology Conference in Maui, Hawaii, with the world’s leading experts in men’s health, sexual health, and quality of life. I’m bringing in Dr. Allen Morey from the North Dallas area, one of the world’s leading experts in reconstructive urology. He deals with all things urinary incontinence, penile curvature, and sexual health.
Dr. Morey said something at this conference that really put my chin on the floor. He said, So, Dr. Morey, tell us more about why you made that comment and about the incontinence in men that you deal with all the time.
Allen F. Morey, MD: For many years, I’ve worked at cancer centers where, through the various treatments for prostate cancer, the men suffered from urinary incontinence and we put a lot of artificial urinary sphincters in those patients. I had one patient who asked, “Why do I keep having this erosion?” Of course, the erosion is where the cuff compresses the tissue surrounding the urethra, and the tissue gives way, leaving a hole in the urethra. I looked at him and noticed that he was pale. And I thought, Let me check his testosterone level. We started checking it on everybody who had this problem, and sure enough, the ones who had the cup erosion — who had the atrophic tissue around the urethra — most of them had low testosterone levels. Some of this was due to the cancer treatment, but in other men, it was just due to old age.
We started thinking that this is a causal relationship. And we tested it. I had a fellow who was a board-certified pathologist before becoming a urologist. He obtained some specimens from the urethra and did very sophisticated, elegant stains on that tissue. We found that it’s just erectile tissue surrounding the urethra. That’s why I call it a sex organ. I tell my patients, “When you are a teenager, this tissue is thin, like on your pinky finger. As you get older, it becomes thicker. And then as you get even older, and you may be having cancer treatment, that tissue is gone.” You can show them your little finger; it’s about that size. All the meat is off the bone. There’s nothing left protecting the urinary mucosa from the device.
That’s why it’s important to maintain the optimal health of those tissues and for them to remain dry. Because let’s face it: Urinary incontinence is a horrible quality of life. These are my happiest patients when we fix it. Before that, when they go on vacation, they have a separate suitcase filled with diapers. They can’t go anywhere. They can’t do anything. When they become incontinent after the prostatectomy, they gain weight. And when you put in the device to treat it, they lose weight and you can track it. The urinary incontinence patients really suffer. And we need to consider the medical optimization of those patients.
Dr. Rubin: It’s so important, and I love how analogous this is to our female patients. We know that incontinence is devastating to our female patients as well, and there’s a lot of hope. As we get older we start to pee every time we cough, laugh, or sneeze. Men are a little more bothered by it when it happens; they don’t expect it. Among women, it’s thought of as normal, but it’s not normal. There is so much we can do to help these patients, ranging from conservative treatment to surgical therapies.
The connection between hormones and urethral health is true on the female side as well. As you go through menopause, the urethral tissue thins out, gets dry, gets irritated, and can cause worsening incontinence, pain with sex, and genital urinary syndrome of menopause. It’s really important.
For our primary care doctors, how should we talk about stress incontinence in men? How do we diagnose it?
Dr. Morey: It’s easy to diagnose. Just do a quick history. Find out how many pads a day they are using. You have to ask the question, and then you have them stand up and look inside their underwear. You’ll see what kind of pad they are wearing. Is it just a shield or are they actually wearing full diapers? Then I have them do a standing cough test. I stand off to the side, holding a couple of towels, and have the patient cough four times. I can tell if it’s a full stream or just a couple of drops. Is it nothing but they are wearing a pad? You match up what you see with their experience, and in an instant it tells you how severe their problem is and it helps you direct them on to further treatment, because many patients have treatment fatigue. They’ve already been through the system. They have really suffered and they don’t know which way to go. They don’t know what’s available.
Dr. Rubin: On the female side, we have pelvic floor physical therapy. We have pads and devices that you can wear, and pessaries. We have surgical options, like bulking agents into the urethra as well as urethral slings, which can be quite helpful for women. So there’s a lot of hope out there for women, and from what I learned from you at this conference, there’s a lot of hope for men as well. So talk us through treatment, from conservative to surgical options.
Dr. Morey: There hasn’t been much innovation in male incontinence treatment over the past few decades, but we’re starting to see signs of new products appearing on the horizon, so I’m very optimistic that in the next 5 or 10 years, we’ll have more. But right now it comes down to slings and artificial sphincters, which are devices with little pumps and hydraulics, and they’re very good. But they’ve been around for 50 years, and they have this other potential risk factor of the erosion of the tissue.
We don’t have a pill that we can give the patient to tighten up those muscles. We can help them with overactive bladder. But maybe the hormonal influence is a way to optimize the health of the tissue so that these surgical treatments can really deliver the best outcomes. And as I always say, and having treated so many of these patients, it’s really a game of millimeters — how much coaptation you get. If you’re off by the slightest amount, that’s an unhappy patient. So it doesn’t take much to make it a lot better.
Dr. Rubin: There’s so much hope for our patients, and this can really have an effect on sexual health. You know the benefits you see in their quality of life and sexual health when you can stop leakage.
Dr. Morey: I always take care of the waterworks first. Many of the men have both urinary problems and erectile problems. Nobody feels sexy when they’re leaking urine all over their partner. So first we take care of that. And then, in the motivated younger patients, we bring them back and talk to them about potentially having a second operation.
Dr. Rubin: And so similarly, in women with urinary incontinence, it can have a major impact on sexual health — how they show up and how they talk to their partner. So, it is really important for our primary care docs to talk to patients about urinary incontinence and not just say, “Oh, well, you’re getting older. There’s nothing that you can do.” There’s actually no age at which there is nothing that we can do. And it’s really important to refer patients to those urologists who have extra training in incontinence and sexual health, because we do care about these quality-of-life measures and there is a lot we can do, ranging from conservative to more invasive treatments. But patients really should have options.
Dr. Morey: I heard during this meeting that urinary incontinence was the number-one source of treatment regret among patients who had their prostate treated for cancer. So, this is a really big deal for our patients. And it impacts wellness, quality of life, and overall well-being.
Dr. Rubin: When we are counseling patients for cancer surgeries or cancer treatments such as radiation therapy, it’s really hard for the patients who have never had urinary incontinence to imagine what that might be like. When you’re telling them they could have a stroke or a heart attack, or they could have erectile dysfunction or urinary incontinence, it all sounds similar to them. It could happen to someone else. It’s very hard to truly counsel patients on these quality-of-life issues that they’ve never encountered before.
Dr. Morey: We have found that it takes a long time for patients to get into our office for treatment, and it’s unbelievable — often 5 years in diapers before they find us.
Dr. Rubin: Hopefully videos like this will teach our docs and our patients that there is hope out there, that you don’t need to wait through years of suffering from incontinence. So, how does somebody find a reconstructive urologist or a sexual medicine urologist?
Dr. Morey: There are a couple of good websites out there, such as fixincontinence.com and edcure.org. The device manufacturers have pretty good information for patients.
Dr. Rubin: The Sexual Medicine Society of North America (SMSNA) has a great find-a-provider website, which provides a list of urologists who are trained in both sexual health and urinary incontinence, because they both matter. Our patients deeply care about these issues.
Rachel S. Rubin, MD, has disclosed the following relevant financial relationships: Serve(d) as a speaker for Sprout; received research grant from Maternal Medical; received income in an amount equal to or greater than $250 from Absorption Pharmaceuticals, GSK, Endo.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
Rachel S. Rubin, MD: I’m Dr. Rachel Rubin, urologist and sexual medicine specialist in the Washington, DC, area. We are coming to you live from the Mayo Clinic Urology Conference in Maui, Hawaii, with the world’s leading experts in men’s health, sexual health, and quality of life. I’m bringing in Dr. Allen Morey from the North Dallas area, one of the world’s leading experts in reconstructive urology. He deals with all things urinary incontinence, penile curvature, and sexual health.
Dr. Morey said something at this conference that really put my chin on the floor. He said, So, Dr. Morey, tell us more about why you made that comment and about the incontinence in men that you deal with all the time.
Allen F. Morey, MD: For many years, I’ve worked at cancer centers where, through the various treatments for prostate cancer, the men suffered from urinary incontinence and we put a lot of artificial urinary sphincters in those patients. I had one patient who asked, “Why do I keep having this erosion?” Of course, the erosion is where the cuff compresses the tissue surrounding the urethra, and the tissue gives way, leaving a hole in the urethra. I looked at him and noticed that he was pale. And I thought, Let me check his testosterone level. We started checking it on everybody who had this problem, and sure enough, the ones who had the cup erosion — who had the atrophic tissue around the urethra — most of them had low testosterone levels. Some of this was due to the cancer treatment, but in other men, it was just due to old age.
We started thinking that this is a causal relationship. And we tested it. I had a fellow who was a board-certified pathologist before becoming a urologist. He obtained some specimens from the urethra and did very sophisticated, elegant stains on that tissue. We found that it’s just erectile tissue surrounding the urethra. That’s why I call it a sex organ. I tell my patients, “When you are a teenager, this tissue is thin, like on your pinky finger. As you get older, it becomes thicker. And then as you get even older, and you may be having cancer treatment, that tissue is gone.” You can show them your little finger; it’s about that size. All the meat is off the bone. There’s nothing left protecting the urinary mucosa from the device.
That’s why it’s important to maintain the optimal health of those tissues and for them to remain dry. Because let’s face it: Urinary incontinence is a horrible quality of life. These are my happiest patients when we fix it. Before that, when they go on vacation, they have a separate suitcase filled with diapers. They can’t go anywhere. They can’t do anything. When they become incontinent after the prostatectomy, they gain weight. And when you put in the device to treat it, they lose weight and you can track it. The urinary incontinence patients really suffer. And we need to consider the medical optimization of those patients.
Dr. Rubin: It’s so important, and I love how analogous this is to our female patients. We know that incontinence is devastating to our female patients as well, and there’s a lot of hope. As we get older we start to pee every time we cough, laugh, or sneeze. Men are a little more bothered by it when it happens; they don’t expect it. Among women, it’s thought of as normal, but it’s not normal. There is so much we can do to help these patients, ranging from conservative treatment to surgical therapies.
The connection between hormones and urethral health is true on the female side as well. As you go through menopause, the urethral tissue thins out, gets dry, gets irritated, and can cause worsening incontinence, pain with sex, and genital urinary syndrome of menopause. It’s really important.
For our primary care doctors, how should we talk about stress incontinence in men? How do we diagnose it?
Dr. Morey: It’s easy to diagnose. Just do a quick history. Find out how many pads a day they are using. You have to ask the question, and then you have them stand up and look inside their underwear. You’ll see what kind of pad they are wearing. Is it just a shield or are they actually wearing full diapers? Then I have them do a standing cough test. I stand off to the side, holding a couple of towels, and have the patient cough four times. I can tell if it’s a full stream or just a couple of drops. Is it nothing but they are wearing a pad? You match up what you see with their experience, and in an instant it tells you how severe their problem is and it helps you direct them on to further treatment, because many patients have treatment fatigue. They’ve already been through the system. They have really suffered and they don’t know which way to go. They don’t know what’s available.
Dr. Rubin: On the female side, we have pelvic floor physical therapy. We have pads and devices that you can wear, and pessaries. We have surgical options, like bulking agents into the urethra as well as urethral slings, which can be quite helpful for women. So there’s a lot of hope out there for women, and from what I learned from you at this conference, there’s a lot of hope for men as well. So talk us through treatment, from conservative to surgical options.
Dr. Morey: There hasn’t been much innovation in male incontinence treatment over the past few decades, but we’re starting to see signs of new products appearing on the horizon, so I’m very optimistic that in the next 5 or 10 years, we’ll have more. But right now it comes down to slings and artificial sphincters, which are devices with little pumps and hydraulics, and they’re very good. But they’ve been around for 50 years, and they have this other potential risk factor of the erosion of the tissue.
We don’t have a pill that we can give the patient to tighten up those muscles. We can help them with overactive bladder. But maybe the hormonal influence is a way to optimize the health of the tissue so that these surgical treatments can really deliver the best outcomes. And as I always say, and having treated so many of these patients, it’s really a game of millimeters — how much coaptation you get. If you’re off by the slightest amount, that’s an unhappy patient. So it doesn’t take much to make it a lot better.
Dr. Rubin: There’s so much hope for our patients, and this can really have an effect on sexual health. You know the benefits you see in their quality of life and sexual health when you can stop leakage.
Dr. Morey: I always take care of the waterworks first. Many of the men have both urinary problems and erectile problems. Nobody feels sexy when they’re leaking urine all over their partner. So first we take care of that. And then, in the motivated younger patients, we bring them back and talk to them about potentially having a second operation.
Dr. Rubin: And so similarly, in women with urinary incontinence, it can have a major impact on sexual health — how they show up and how they talk to their partner. So, it is really important for our primary care docs to talk to patients about urinary incontinence and not just say, “Oh, well, you’re getting older. There’s nothing that you can do.” There’s actually no age at which there is nothing that we can do. And it’s really important to refer patients to those urologists who have extra training in incontinence and sexual health, because we do care about these quality-of-life measures and there is a lot we can do, ranging from conservative to more invasive treatments. But patients really should have options.
Dr. Morey: I heard during this meeting that urinary incontinence was the number-one source of treatment regret among patients who had their prostate treated for cancer. So, this is a really big deal for our patients. And it impacts wellness, quality of life, and overall well-being.
Dr. Rubin: When we are counseling patients for cancer surgeries or cancer treatments such as radiation therapy, it’s really hard for the patients who have never had urinary incontinence to imagine what that might be like. When you’re telling them they could have a stroke or a heart attack, or they could have erectile dysfunction or urinary incontinence, it all sounds similar to them. It could happen to someone else. It’s very hard to truly counsel patients on these quality-of-life issues that they’ve never encountered before.
Dr. Morey: We have found that it takes a long time for patients to get into our office for treatment, and it’s unbelievable — often 5 years in diapers before they find us.
Dr. Rubin: Hopefully videos like this will teach our docs and our patients that there is hope out there, that you don’t need to wait through years of suffering from incontinence. So, how does somebody find a reconstructive urologist or a sexual medicine urologist?
Dr. Morey: There are a couple of good websites out there, such as fixincontinence.com and edcure.org. The device manufacturers have pretty good information for patients.
Dr. Rubin: The Sexual Medicine Society of North America (SMSNA) has a great find-a-provider website, which provides a list of urologists who are trained in both sexual health and urinary incontinence, because they both matter. Our patients deeply care about these issues.
Rachel S. Rubin, MD, has disclosed the following relevant financial relationships: Serve(d) as a speaker for Sprout; received research grant from Maternal Medical; received income in an amount equal to or greater than $250 from Absorption Pharmaceuticals, GSK, Endo.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
Rachel S. Rubin, MD: I’m Dr. Rachel Rubin, urologist and sexual medicine specialist in the Washington, DC, area. We are coming to you live from the Mayo Clinic Urology Conference in Maui, Hawaii, with the world’s leading experts in men’s health, sexual health, and quality of life. I’m bringing in Dr. Allen Morey from the North Dallas area, one of the world’s leading experts in reconstructive urology. He deals with all things urinary incontinence, penile curvature, and sexual health.
Dr. Morey said something at this conference that really put my chin on the floor. He said, So, Dr. Morey, tell us more about why you made that comment and about the incontinence in men that you deal with all the time.
Allen F. Morey, MD: For many years, I’ve worked at cancer centers where, through the various treatments for prostate cancer, the men suffered from urinary incontinence and we put a lot of artificial urinary sphincters in those patients. I had one patient who asked, “Why do I keep having this erosion?” Of course, the erosion is where the cuff compresses the tissue surrounding the urethra, and the tissue gives way, leaving a hole in the urethra. I looked at him and noticed that he was pale. And I thought, Let me check his testosterone level. We started checking it on everybody who had this problem, and sure enough, the ones who had the cup erosion — who had the atrophic tissue around the urethra — most of them had low testosterone levels. Some of this was due to the cancer treatment, but in other men, it was just due to old age.
We started thinking that this is a causal relationship. And we tested it. I had a fellow who was a board-certified pathologist before becoming a urologist. He obtained some specimens from the urethra and did very sophisticated, elegant stains on that tissue. We found that it’s just erectile tissue surrounding the urethra. That’s why I call it a sex organ. I tell my patients, “When you are a teenager, this tissue is thin, like on your pinky finger. As you get older, it becomes thicker. And then as you get even older, and you may be having cancer treatment, that tissue is gone.” You can show them your little finger; it’s about that size. All the meat is off the bone. There’s nothing left protecting the urinary mucosa from the device.
That’s why it’s important to maintain the optimal health of those tissues and for them to remain dry. Because let’s face it: Urinary incontinence is a horrible quality of life. These are my happiest patients when we fix it. Before that, when they go on vacation, they have a separate suitcase filled with diapers. They can’t go anywhere. They can’t do anything. When they become incontinent after the prostatectomy, they gain weight. And when you put in the device to treat it, they lose weight and you can track it. The urinary incontinence patients really suffer. And we need to consider the medical optimization of those patients.
Dr. Rubin: It’s so important, and I love how analogous this is to our female patients. We know that incontinence is devastating to our female patients as well, and there’s a lot of hope. As we get older we start to pee every time we cough, laugh, or sneeze. Men are a little more bothered by it when it happens; they don’t expect it. Among women, it’s thought of as normal, but it’s not normal. There is so much we can do to help these patients, ranging from conservative treatment to surgical therapies.
The connection between hormones and urethral health is true on the female side as well. As you go through menopause, the urethral tissue thins out, gets dry, gets irritated, and can cause worsening incontinence, pain with sex, and genital urinary syndrome of menopause. It’s really important.
For our primary care doctors, how should we talk about stress incontinence in men? How do we diagnose it?
Dr. Morey: It’s easy to diagnose. Just do a quick history. Find out how many pads a day they are using. You have to ask the question, and then you have them stand up and look inside their underwear. You’ll see what kind of pad they are wearing. Is it just a shield or are they actually wearing full diapers? Then I have them do a standing cough test. I stand off to the side, holding a couple of towels, and have the patient cough four times. I can tell if it’s a full stream or just a couple of drops. Is it nothing but they are wearing a pad? You match up what you see with their experience, and in an instant it tells you how severe their problem is and it helps you direct them on to further treatment, because many patients have treatment fatigue. They’ve already been through the system. They have really suffered and they don’t know which way to go. They don’t know what’s available.
Dr. Rubin: On the female side, we have pelvic floor physical therapy. We have pads and devices that you can wear, and pessaries. We have surgical options, like bulking agents into the urethra as well as urethral slings, which can be quite helpful for women. So there’s a lot of hope out there for women, and from what I learned from you at this conference, there’s a lot of hope for men as well. So talk us through treatment, from conservative to surgical options.
Dr. Morey: There hasn’t been much innovation in male incontinence treatment over the past few decades, but we’re starting to see signs of new products appearing on the horizon, so I’m very optimistic that in the next 5 or 10 years, we’ll have more. But right now it comes down to slings and artificial sphincters, which are devices with little pumps and hydraulics, and they’re very good. But they’ve been around for 50 years, and they have this other potential risk factor of the erosion of the tissue.
We don’t have a pill that we can give the patient to tighten up those muscles. We can help them with overactive bladder. But maybe the hormonal influence is a way to optimize the health of the tissue so that these surgical treatments can really deliver the best outcomes. And as I always say, and having treated so many of these patients, it’s really a game of millimeters — how much coaptation you get. If you’re off by the slightest amount, that’s an unhappy patient. So it doesn’t take much to make it a lot better.
Dr. Rubin: There’s so much hope for our patients, and this can really have an effect on sexual health. You know the benefits you see in their quality of life and sexual health when you can stop leakage.
Dr. Morey: I always take care of the waterworks first. Many of the men have both urinary problems and erectile problems. Nobody feels sexy when they’re leaking urine all over their partner. So first we take care of that. And then, in the motivated younger patients, we bring them back and talk to them about potentially having a second operation.
Dr. Rubin: And so similarly, in women with urinary incontinence, it can have a major impact on sexual health — how they show up and how they talk to their partner. So, it is really important for our primary care docs to talk to patients about urinary incontinence and not just say, “Oh, well, you’re getting older. There’s nothing that you can do.” There’s actually no age at which there is nothing that we can do. And it’s really important to refer patients to those urologists who have extra training in incontinence and sexual health, because we do care about these quality-of-life measures and there is a lot we can do, ranging from conservative to more invasive treatments. But patients really should have options.
Dr. Morey: I heard during this meeting that urinary incontinence was the number-one source of treatment regret among patients who had their prostate treated for cancer. So, this is a really big deal for our patients. And it impacts wellness, quality of life, and overall well-being.
Dr. Rubin: When we are counseling patients for cancer surgeries or cancer treatments such as radiation therapy, it’s really hard for the patients who have never had urinary incontinence to imagine what that might be like. When you’re telling them they could have a stroke or a heart attack, or they could have erectile dysfunction or urinary incontinence, it all sounds similar to them. It could happen to someone else. It’s very hard to truly counsel patients on these quality-of-life issues that they’ve never encountered before.
Dr. Morey: We have found that it takes a long time for patients to get into our office for treatment, and it’s unbelievable — often 5 years in diapers before they find us.
Dr. Rubin: Hopefully videos like this will teach our docs and our patients that there is hope out there, that you don’t need to wait through years of suffering from incontinence. So, how does somebody find a reconstructive urologist or a sexual medicine urologist?
Dr. Morey: There are a couple of good websites out there, such as fixincontinence.com and edcure.org. The device manufacturers have pretty good information for patients.
Dr. Rubin: The Sexual Medicine Society of North America (SMSNA) has a great find-a-provider website, which provides a list of urologists who are trained in both sexual health and urinary incontinence, because they both matter. Our patients deeply care about these issues.
Rachel S. Rubin, MD, has disclosed the following relevant financial relationships: Serve(d) as a speaker for Sprout; received research grant from Maternal Medical; received income in an amount equal to or greater than $250 from Absorption Pharmaceuticals, GSK, Endo.
A version of this article appeared on Medscape.com.
The Paradox of Achalasia Symptoms
In contrast to most diseases, as achalasia progresses, the symptoms improve. Specifically, reduction of symptoms of dysphagia lulls the gastroenterologist into thinking their patients are doing well.
This improvement in dysphagia is likely due to two mechanisms. The first is that as the esophagus dilates, there is a greater capacity for food accumulation before sensation occurs. Whether this is completely a volume issue or whether there is a contribution from increased esophageal body distensibility is unclear. Similarly, as achalasia results from inflammation and destruction of the motor neurons of the myenteric plexus, sensory neurons are also damaged. As a result, the patient’s ability to sense food retention lessens. To some degree, this explains the phenomenon of patients presenting with megaesophagus; after years of initially diminishing or stable symptoms managed with patient accommodation, patients present with end-stage disease manifested by a food-impacted esophagus, nocturnal aspiration, and weight loss.
This aspect of the natural history of achalasia has led esophagologists to follow patients with achalasia after treatment at regular intervals with objective examinations such as timed esophagography to mitigate against this worsening yet symptomatically stable course.
Dr. Katzka is based in the Division of Digestive and Liver Diseases, Columbia University Medical Center, New York. He receives research support from Medtronic and is an associate editor for GI & Hepatology News. Previously published in Gastro Hep Advances. 2024 Jan 19. doi: 10.1016/j.gastha.2024.01.006.
In contrast to most diseases, as achalasia progresses, the symptoms improve. Specifically, reduction of symptoms of dysphagia lulls the gastroenterologist into thinking their patients are doing well.
This improvement in dysphagia is likely due to two mechanisms. The first is that as the esophagus dilates, there is a greater capacity for food accumulation before sensation occurs. Whether this is completely a volume issue or whether there is a contribution from increased esophageal body distensibility is unclear. Similarly, as achalasia results from inflammation and destruction of the motor neurons of the myenteric plexus, sensory neurons are also damaged. As a result, the patient’s ability to sense food retention lessens. To some degree, this explains the phenomenon of patients presenting with megaesophagus; after years of initially diminishing or stable symptoms managed with patient accommodation, patients present with end-stage disease manifested by a food-impacted esophagus, nocturnal aspiration, and weight loss.
This aspect of the natural history of achalasia has led esophagologists to follow patients with achalasia after treatment at regular intervals with objective examinations such as timed esophagography to mitigate against this worsening yet symptomatically stable course.
Dr. Katzka is based in the Division of Digestive and Liver Diseases, Columbia University Medical Center, New York. He receives research support from Medtronic and is an associate editor for GI & Hepatology News. Previously published in Gastro Hep Advances. 2024 Jan 19. doi: 10.1016/j.gastha.2024.01.006.
In contrast to most diseases, as achalasia progresses, the symptoms improve. Specifically, reduction of symptoms of dysphagia lulls the gastroenterologist into thinking their patients are doing well.
This improvement in dysphagia is likely due to two mechanisms. The first is that as the esophagus dilates, there is a greater capacity for food accumulation before sensation occurs. Whether this is completely a volume issue or whether there is a contribution from increased esophageal body distensibility is unclear. Similarly, as achalasia results from inflammation and destruction of the motor neurons of the myenteric plexus, sensory neurons are also damaged. As a result, the patient’s ability to sense food retention lessens. To some degree, this explains the phenomenon of patients presenting with megaesophagus; after years of initially diminishing or stable symptoms managed with patient accommodation, patients present with end-stage disease manifested by a food-impacted esophagus, nocturnal aspiration, and weight loss.
This aspect of the natural history of achalasia has led esophagologists to follow patients with achalasia after treatment at regular intervals with objective examinations such as timed esophagography to mitigate against this worsening yet symptomatically stable course.
Dr. Katzka is based in the Division of Digestive and Liver Diseases, Columbia University Medical Center, New York. He receives research support from Medtronic and is an associate editor for GI & Hepatology News. Previously published in Gastro Hep Advances. 2024 Jan 19. doi: 10.1016/j.gastha.2024.01.006.
Residents Unionizing: What Are the Benefits, the Downsides?
This transcript has been edited for clarity.
Hospital administrators and some department heads have been vocal about the potential for unions to affect both the attending-resident relationship and the ability for residents to directly discuss concerns and educational plans.
Sometimes, there are institution-specific issues as well. One example was at Loma Linda. They argued that unionization would go against their religious principles. They filed a lawsuit. That didn’t go through, and the residents won a few months later.
I know there’s always that one senior, older doctor who says, “Back in our day, we just worked, and we never complained.”
Look at the current situation that residents are facing now, with housing and rent prices and increasing costs of childcare. Sprinkle in some inflation, poor hospital staffing, increasing workload, and add in the fact that the average first-year resident salary in 2023 was around $64,000.
Now, if you look back to 2012, the average salary was around $55,000. If you adjust that for inflation, it would be around $75,000 today, which is more than what the average resident is getting paid.
Then, there are hospital administrators who say that the hospital does not have the money to meet these demands; meanwhile, hospital graduate medical education (GME) offices receive about $150,000 of Medicare funds per resident.
Obviously, there are additional costs when it comes to training and supporting residents. In general, unionizing freaks out the people handling all the cash.
There’s also the threat of a strike, which no hospital wants on their public record. A recent highly publicized event happened at New York’s Elmhurst Hospital, when 160 residents went on strike for 3 days until a deal was made.
Critics of unionizing also cite a particular study in JAMA, which included a survey of 5700 general surgery residents at 285 programs. It found that while unions helped with vacation time and housing stipends, the unions were not associated with improved burnout rates, suicidality, job satisfaction, duty hour violations, mistreatment, educational environment, or salary.
Now, granted, this isn’t the strongest study. It only sampled one group of residents, so I wouldn’t generalize these findings, but it’s still commonly cited by anti-union advocates.
Another potential downside, which is purely anecdotal because I can’t find any data to support this, is potential retaliation against residents or harm to the attending-resident relationship.
I’m an attending. I don’t really understand this one. I don’t exactly own stock in my hospital, nor am I making millions of dollars by siphoning GME money. I’m just trying to focus on educating and supporting my residents the best I can.
Dr. Patel is Clinical Instructor, Department of Pediatrics, Columbia University College of Physicians and Surgeons; Pediatric Hospitalist, Morgan Stanley Children’s Hospital of NewYork–Presbyterian, and Benioff Children’s Hospital, University of California San Francisco. He disclosed ties with Medumo Inc.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Hospital administrators and some department heads have been vocal about the potential for unions to affect both the attending-resident relationship and the ability for residents to directly discuss concerns and educational plans.
Sometimes, there are institution-specific issues as well. One example was at Loma Linda. They argued that unionization would go against their religious principles. They filed a lawsuit. That didn’t go through, and the residents won a few months later.
I know there’s always that one senior, older doctor who says, “Back in our day, we just worked, and we never complained.”
Look at the current situation that residents are facing now, with housing and rent prices and increasing costs of childcare. Sprinkle in some inflation, poor hospital staffing, increasing workload, and add in the fact that the average first-year resident salary in 2023 was around $64,000.
Now, if you look back to 2012, the average salary was around $55,000. If you adjust that for inflation, it would be around $75,000 today, which is more than what the average resident is getting paid.
Then, there are hospital administrators who say that the hospital does not have the money to meet these demands; meanwhile, hospital graduate medical education (GME) offices receive about $150,000 of Medicare funds per resident.
Obviously, there are additional costs when it comes to training and supporting residents. In general, unionizing freaks out the people handling all the cash.
There’s also the threat of a strike, which no hospital wants on their public record. A recent highly publicized event happened at New York’s Elmhurst Hospital, when 160 residents went on strike for 3 days until a deal was made.
Critics of unionizing also cite a particular study in JAMA, which included a survey of 5700 general surgery residents at 285 programs. It found that while unions helped with vacation time and housing stipends, the unions were not associated with improved burnout rates, suicidality, job satisfaction, duty hour violations, mistreatment, educational environment, or salary.
Now, granted, this isn’t the strongest study. It only sampled one group of residents, so I wouldn’t generalize these findings, but it’s still commonly cited by anti-union advocates.
Another potential downside, which is purely anecdotal because I can’t find any data to support this, is potential retaliation against residents or harm to the attending-resident relationship.
I’m an attending. I don’t really understand this one. I don’t exactly own stock in my hospital, nor am I making millions of dollars by siphoning GME money. I’m just trying to focus on educating and supporting my residents the best I can.
Dr. Patel is Clinical Instructor, Department of Pediatrics, Columbia University College of Physicians and Surgeons; Pediatric Hospitalist, Morgan Stanley Children’s Hospital of NewYork–Presbyterian, and Benioff Children’s Hospital, University of California San Francisco. He disclosed ties with Medumo Inc.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Hospital administrators and some department heads have been vocal about the potential for unions to affect both the attending-resident relationship and the ability for residents to directly discuss concerns and educational plans.
Sometimes, there are institution-specific issues as well. One example was at Loma Linda. They argued that unionization would go against their religious principles. They filed a lawsuit. That didn’t go through, and the residents won a few months later.
I know there’s always that one senior, older doctor who says, “Back in our day, we just worked, and we never complained.”
Look at the current situation that residents are facing now, with housing and rent prices and increasing costs of childcare. Sprinkle in some inflation, poor hospital staffing, increasing workload, and add in the fact that the average first-year resident salary in 2023 was around $64,000.
Now, if you look back to 2012, the average salary was around $55,000. If you adjust that for inflation, it would be around $75,000 today, which is more than what the average resident is getting paid.
Then, there are hospital administrators who say that the hospital does not have the money to meet these demands; meanwhile, hospital graduate medical education (GME) offices receive about $150,000 of Medicare funds per resident.
Obviously, there are additional costs when it comes to training and supporting residents. In general, unionizing freaks out the people handling all the cash.
There’s also the threat of a strike, which no hospital wants on their public record. A recent highly publicized event happened at New York’s Elmhurst Hospital, when 160 residents went on strike for 3 days until a deal was made.
Critics of unionizing also cite a particular study in JAMA, which included a survey of 5700 general surgery residents at 285 programs. It found that while unions helped with vacation time and housing stipends, the unions were not associated with improved burnout rates, suicidality, job satisfaction, duty hour violations, mistreatment, educational environment, or salary.
Now, granted, this isn’t the strongest study. It only sampled one group of residents, so I wouldn’t generalize these findings, but it’s still commonly cited by anti-union advocates.
Another potential downside, which is purely anecdotal because I can’t find any data to support this, is potential retaliation against residents or harm to the attending-resident relationship.
I’m an attending. I don’t really understand this one. I don’t exactly own stock in my hospital, nor am I making millions of dollars by siphoning GME money. I’m just trying to focus on educating and supporting my residents the best I can.
Dr. Patel is Clinical Instructor, Department of Pediatrics, Columbia University College of Physicians and Surgeons; Pediatric Hospitalist, Morgan Stanley Children’s Hospital of NewYork–Presbyterian, and Benioff Children’s Hospital, University of California San Francisco. He disclosed ties with Medumo Inc.
A version of this article first appeared on Medscape.com.
Myasthenia Gravis: 5 Things to Know
Myasthenia gravis (MG) is a rare autoimmune neurologic disorder that occurs when the transmission between nerves and muscles is disrupted. It is caused by autoantibodies against acetylcholine receptors (AChRs), which results in muscle weakness that is often fatigable and affects various muscles in the body, including those that move the eyes, eyelids, and limbs. Ocular MG affects only the muscles that move the eyes and eyelids, whereas generalized MG (gMG) affects muscles throughout the body. When MG occurs with a thymoma, it is called thymoma-associated MG and is considered a paraneoplastic disease. In severe cases of MG, patients can experience a myasthenic crisis (MC), during which respiratory muscles weaken and necessitate mechanical ventilation. Diagnosis of MG is based on clinical examination, and laboratory tests are used to confirm the diagnosis. Treatment options include cholinesterase enzyme inhibitors and immunosuppressive agents, which aim to either reduce symptoms or cause nonspecific immunosuppression, respectively, but do not target the pathogenetic autoantibodies that characterize the disease.
1. The most common age at onset of gMG is the second and third decades in women and the seventh and eighth decades in men.
MG has an annual incidence of approximately four to 30 new cases per million population. Prevalence rates range from 150 to 200 cases per million population, and they have steadily increased over the past 50 years. This increase in prevalence is probably the result of better disease recognition, aging of the population, and an increased life span in patients.
MG can occur at any age; however, onset is more common in females in the second and third decades and is more common in males in the seventh to eighth decades. Before age 40 years, the female-to-male ratio is 3:1, and after age 50 years, the female-to-male ratio is 3:2.
2. gMG commonly weakens muscles responsible for eye movement, facial expressions, and functions such as chewing, swallowing, and speaking.
gMG typically manifests as muscle weakness that worsens with repeated use. Patients often report that their function is best in the morning, with more pronounced weakness at the end of the day. Permanent muscle damage is rare, however, and maximal muscle strength is often good.
Extraocular muscles are more commonly affected, as twitch fibers in these muscles develop tension faster, have a higher frequency of synaptic firing than limb muscles, and have fewer AChRs, making them more susceptible to fatigue. Patients present asymmetrically; intermittent drooping of the upper eyelid (ptosis) and double vision (diplopia) are the most common symptoms.
Muscles innervated by the cranial nerves (bulbar muscles) are involved in 60% of patients with gMG and can lead to fatigable chewing, reduced facial expression, speech difficulties (dysarthria), and weakness of swallowing (dysphagia). Up to 15% of patients initially present with bulbar muscle involvement, including dysarthria and painless dysphagia.
3. Emotional stress can trigger an MC.
MC is a complication of MG characterized by worsening muscle weakness that results in respiratory failure and necessitates mechanical ventilation.
MC is often the result of respiratory muscle weakness but can also be due to bulbar weakness with upper airway collapse. MC can occur in 15%-20% of patients within the first 2-3 years of the disease; however, it can also be the first presentation of MG in 18%-28% of cases.
MC can be triggered by multiple causes, including emotional or physical stress. The most common precipitant is infection; other precipitants include surgery, pregnancy, perimenstrual state, certain medications, tapering of immune-modulating medications, exposure to temperature extremes, pain, and sleep deprivation. Approximately one third to one half of patients with MC may have no obvious cause.
4. High levels of anti-AChR antibodies strongly indicate MG, but normal levels do not rule it out.
All patients with a clinical history suggestive of MG should be tested for antibodies for confirmation. Most patients have anti-AChR antibodies (~85%), and those without have anti–muscle-specific kinase (MuSK antibodies) (6%) and anti–lipoprotein receptor-related protein 4 (LRP4) antibodies (2%).
The sensitivity of anti-AChR antibodies varies depending on whether the antibody is binding, modulating, or blocking the AChR. Binding antibody is the most common, and when combined with blocking antibodies, has a high sensitivity (99.6%) and is typically tested first. Higher AChR antibody titers are more specific for the diagnosis of MG than are low titers, but they do not correlate with disease severity.
For patients who do not have anti-AChR antibodies but do have clinical features of MG, anti-MuSK antibodies and anti-LRP4 antibodies are measured to increase diagnostic sensitivity. For symptomatic patients who do not have any autoantibodies (seronegative), electrodiagnostic testing that shows evidence of impaired signal transmission at the neuromuscular junction is used to confirm the diagnosis of MG.
5. Studies suggest that over 75% of seropositive MG patients show distinct thymus abnormalities.
More than 75% of patients with AChR antibody–positive MG have abnormalities in their thymus, and up to 40% of patients with a thymoma have MG. Among those with thymic pathology, thymic hyperplasia is the most common type (85%), but other thymic tumors (mainly thymoma) can be present in up to 15% of cases. Thymomas are typically noninvasive and cortical, but in some rare cases, invasive thymic carcinoma can occur.
Given this overlap in presentation, it is recommended that patients with seronegative and seropositive MG undergo chest CT or MRI for evaluation of their anterior mediastinal anatomy and to detect the presence of a thymoma. For patients with MG and a thymoma, as well as selected (nonthymomatous) patients with seropositive or seronegative MG, therapeutic thymectomy is recommended.
Myasthenia gravis (MG) is a rare autoimmune neurologic disorder that occurs when the transmission between nerves and muscles is disrupted. It is caused by autoantibodies against acetylcholine receptors (AChRs), which results in muscle weakness that is often fatigable and affects various muscles in the body, including those that move the eyes, eyelids, and limbs. Ocular MG affects only the muscles that move the eyes and eyelids, whereas generalized MG (gMG) affects muscles throughout the body. When MG occurs with a thymoma, it is called thymoma-associated MG and is considered a paraneoplastic disease. In severe cases of MG, patients can experience a myasthenic crisis (MC), during which respiratory muscles weaken and necessitate mechanical ventilation. Diagnosis of MG is based on clinical examination, and laboratory tests are used to confirm the diagnosis. Treatment options include cholinesterase enzyme inhibitors and immunosuppressive agents, which aim to either reduce symptoms or cause nonspecific immunosuppression, respectively, but do not target the pathogenetic autoantibodies that characterize the disease.
1. The most common age at onset of gMG is the second and third decades in women and the seventh and eighth decades in men.
MG has an annual incidence of approximately four to 30 new cases per million population. Prevalence rates range from 150 to 200 cases per million population, and they have steadily increased over the past 50 years. This increase in prevalence is probably the result of better disease recognition, aging of the population, and an increased life span in patients.
MG can occur at any age; however, onset is more common in females in the second and third decades and is more common in males in the seventh to eighth decades. Before age 40 years, the female-to-male ratio is 3:1, and after age 50 years, the female-to-male ratio is 3:2.
2. gMG commonly weakens muscles responsible for eye movement, facial expressions, and functions such as chewing, swallowing, and speaking.
gMG typically manifests as muscle weakness that worsens with repeated use. Patients often report that their function is best in the morning, with more pronounced weakness at the end of the day. Permanent muscle damage is rare, however, and maximal muscle strength is often good.
Extraocular muscles are more commonly affected, as twitch fibers in these muscles develop tension faster, have a higher frequency of synaptic firing than limb muscles, and have fewer AChRs, making them more susceptible to fatigue. Patients present asymmetrically; intermittent drooping of the upper eyelid (ptosis) and double vision (diplopia) are the most common symptoms.
Muscles innervated by the cranial nerves (bulbar muscles) are involved in 60% of patients with gMG and can lead to fatigable chewing, reduced facial expression, speech difficulties (dysarthria), and weakness of swallowing (dysphagia). Up to 15% of patients initially present with bulbar muscle involvement, including dysarthria and painless dysphagia.
3. Emotional stress can trigger an MC.
MC is a complication of MG characterized by worsening muscle weakness that results in respiratory failure and necessitates mechanical ventilation.
MC is often the result of respiratory muscle weakness but can also be due to bulbar weakness with upper airway collapse. MC can occur in 15%-20% of patients within the first 2-3 years of the disease; however, it can also be the first presentation of MG in 18%-28% of cases.
MC can be triggered by multiple causes, including emotional or physical stress. The most common precipitant is infection; other precipitants include surgery, pregnancy, perimenstrual state, certain medications, tapering of immune-modulating medications, exposure to temperature extremes, pain, and sleep deprivation. Approximately one third to one half of patients with MC may have no obvious cause.
4. High levels of anti-AChR antibodies strongly indicate MG, but normal levels do not rule it out.
All patients with a clinical history suggestive of MG should be tested for antibodies for confirmation. Most patients have anti-AChR antibodies (~85%), and those without have anti–muscle-specific kinase (MuSK antibodies) (6%) and anti–lipoprotein receptor-related protein 4 (LRP4) antibodies (2%).
The sensitivity of anti-AChR antibodies varies depending on whether the antibody is binding, modulating, or blocking the AChR. Binding antibody is the most common, and when combined with blocking antibodies, has a high sensitivity (99.6%) and is typically tested first. Higher AChR antibody titers are more specific for the diagnosis of MG than are low titers, but they do not correlate with disease severity.
For patients who do not have anti-AChR antibodies but do have clinical features of MG, anti-MuSK antibodies and anti-LRP4 antibodies are measured to increase diagnostic sensitivity. For symptomatic patients who do not have any autoantibodies (seronegative), electrodiagnostic testing that shows evidence of impaired signal transmission at the neuromuscular junction is used to confirm the diagnosis of MG.
5. Studies suggest that over 75% of seropositive MG patients show distinct thymus abnormalities.
More than 75% of patients with AChR antibody–positive MG have abnormalities in their thymus, and up to 40% of patients with a thymoma have MG. Among those with thymic pathology, thymic hyperplasia is the most common type (85%), but other thymic tumors (mainly thymoma) can be present in up to 15% of cases. Thymomas are typically noninvasive and cortical, but in some rare cases, invasive thymic carcinoma can occur.
Given this overlap in presentation, it is recommended that patients with seronegative and seropositive MG undergo chest CT or MRI for evaluation of their anterior mediastinal anatomy and to detect the presence of a thymoma. For patients with MG and a thymoma, as well as selected (nonthymomatous) patients with seropositive or seronegative MG, therapeutic thymectomy is recommended.
Myasthenia gravis (MG) is a rare autoimmune neurologic disorder that occurs when the transmission between nerves and muscles is disrupted. It is caused by autoantibodies against acetylcholine receptors (AChRs), which results in muscle weakness that is often fatigable and affects various muscles in the body, including those that move the eyes, eyelids, and limbs. Ocular MG affects only the muscles that move the eyes and eyelids, whereas generalized MG (gMG) affects muscles throughout the body. When MG occurs with a thymoma, it is called thymoma-associated MG and is considered a paraneoplastic disease. In severe cases of MG, patients can experience a myasthenic crisis (MC), during which respiratory muscles weaken and necessitate mechanical ventilation. Diagnosis of MG is based on clinical examination, and laboratory tests are used to confirm the diagnosis. Treatment options include cholinesterase enzyme inhibitors and immunosuppressive agents, which aim to either reduce symptoms or cause nonspecific immunosuppression, respectively, but do not target the pathogenetic autoantibodies that characterize the disease.
1. The most common age at onset of gMG is the second and third decades in women and the seventh and eighth decades in men.
MG has an annual incidence of approximately four to 30 new cases per million population. Prevalence rates range from 150 to 200 cases per million population, and they have steadily increased over the past 50 years. This increase in prevalence is probably the result of better disease recognition, aging of the population, and an increased life span in patients.
MG can occur at any age; however, onset is more common in females in the second and third decades and is more common in males in the seventh to eighth decades. Before age 40 years, the female-to-male ratio is 3:1, and after age 50 years, the female-to-male ratio is 3:2.
2. gMG commonly weakens muscles responsible for eye movement, facial expressions, and functions such as chewing, swallowing, and speaking.
gMG typically manifests as muscle weakness that worsens with repeated use. Patients often report that their function is best in the morning, with more pronounced weakness at the end of the day. Permanent muscle damage is rare, however, and maximal muscle strength is often good.
Extraocular muscles are more commonly affected, as twitch fibers in these muscles develop tension faster, have a higher frequency of synaptic firing than limb muscles, and have fewer AChRs, making them more susceptible to fatigue. Patients present asymmetrically; intermittent drooping of the upper eyelid (ptosis) and double vision (diplopia) are the most common symptoms.
Muscles innervated by the cranial nerves (bulbar muscles) are involved in 60% of patients with gMG and can lead to fatigable chewing, reduced facial expression, speech difficulties (dysarthria), and weakness of swallowing (dysphagia). Up to 15% of patients initially present with bulbar muscle involvement, including dysarthria and painless dysphagia.
3. Emotional stress can trigger an MC.
MC is a complication of MG characterized by worsening muscle weakness that results in respiratory failure and necessitates mechanical ventilation.
MC is often the result of respiratory muscle weakness but can also be due to bulbar weakness with upper airway collapse. MC can occur in 15%-20% of patients within the first 2-3 years of the disease; however, it can also be the first presentation of MG in 18%-28% of cases.
MC can be triggered by multiple causes, including emotional or physical stress. The most common precipitant is infection; other precipitants include surgery, pregnancy, perimenstrual state, certain medications, tapering of immune-modulating medications, exposure to temperature extremes, pain, and sleep deprivation. Approximately one third to one half of patients with MC may have no obvious cause.
4. High levels of anti-AChR antibodies strongly indicate MG, but normal levels do not rule it out.
All patients with a clinical history suggestive of MG should be tested for antibodies for confirmation. Most patients have anti-AChR antibodies (~85%), and those without have anti–muscle-specific kinase (MuSK antibodies) (6%) and anti–lipoprotein receptor-related protein 4 (LRP4) antibodies (2%).
The sensitivity of anti-AChR antibodies varies depending on whether the antibody is binding, modulating, or blocking the AChR. Binding antibody is the most common, and when combined with blocking antibodies, has a high sensitivity (99.6%) and is typically tested first. Higher AChR antibody titers are more specific for the diagnosis of MG than are low titers, but they do not correlate with disease severity.
For patients who do not have anti-AChR antibodies but do have clinical features of MG, anti-MuSK antibodies and anti-LRP4 antibodies are measured to increase diagnostic sensitivity. For symptomatic patients who do not have any autoantibodies (seronegative), electrodiagnostic testing that shows evidence of impaired signal transmission at the neuromuscular junction is used to confirm the diagnosis of MG.
5. Studies suggest that over 75% of seropositive MG patients show distinct thymus abnormalities.
More than 75% of patients with AChR antibody–positive MG have abnormalities in their thymus, and up to 40% of patients with a thymoma have MG. Among those with thymic pathology, thymic hyperplasia is the most common type (85%), but other thymic tumors (mainly thymoma) can be present in up to 15% of cases. Thymomas are typically noninvasive and cortical, but in some rare cases, invasive thymic carcinoma can occur.
Given this overlap in presentation, it is recommended that patients with seronegative and seropositive MG undergo chest CT or MRI for evaluation of their anterior mediastinal anatomy and to detect the presence of a thymoma. For patients with MG and a thymoma, as well as selected (nonthymomatous) patients with seropositive or seronegative MG, therapeutic thymectomy is recommended.
COVID-19 Is a Very Weird Virus
This transcript has been edited for clarity.
Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.
In the early days of the pandemic, before we really understood what COVID was, two specialties in the hospital had a foreboding sense that something was very strange about this virus. The first was the pulmonologists, who noticed the striking levels of hypoxemia — low oxygen in the blood — and the rapidity with which patients who had previously been stable would crash in the intensive care unit.
The second, and I mark myself among this group, were the nephrologists. The dialysis machines stopped working right. I remember rounding on patients in the hospital who were on dialysis for kidney failure in the setting of severe COVID infection and seeing clots forming on the dialysis filters. Some patients could barely get in a full treatment because the filters would clog so quickly.
We knew it was worse than flu because of the mortality rates, but these oddities made us realize that it was different too — not just a particularly nasty respiratory virus but one that had effects on the body that we hadn’t really seen before.
That’s why I’ve always been interested in studies that compare what happens to patients after COVID infection vs what happens to patients after other respiratory infections. This week, we’ll look at an intriguing study that suggests that COVID may lead to autoimmune diseases like rheumatoid arthritis, lupus, and vasculitis.
The study appears in the Annals of Internal Medicine and is made possible by the universal electronic health record systems of South Korea and Japan, who collaborated to create a truly staggering cohort of more than 20 million individuals living in those countries from 2020 to 2021.
The exposure of interest? COVID infection, experienced by just under 5% of that cohort over the study period. (Remember, there was a time when COVID infections were relatively controlled, particularly in some countries.)
The researchers wanted to compare the risk for autoimmune disease among COVID-infected individuals against two control groups. The first control group was the general population. This is interesting but a difficult analysis, because people who become infected with COVID might be very different from the general population. The second control group was people infected with influenza. I like this a lot better; the risk factors for COVID and influenza are quite similar, and the fact that this group was diagnosed with flu means at least that they are getting medical care and are sort of “in the system,” so to speak.
But it’s not enough to simply identify these folks and see who ends up with more autoimmune disease. The authors used propensity score matching to pair individuals infected with COVID with individuals from the control groups who were very similar to them. I’ve talked about this strategy before, but the basic idea is that you build a model predicting the likelihood of infection with COVID, based on a slew of factors — and the slew these authors used is pretty big, as shown below — and then stick people with similar risk for COVID together, with one member of the pair having had COVID and the other having eluded it (at least for the study period).
After this statistical balancing, the authors looked at the risk for a variety of autoimmune diseases.
Compared with those infected with flu, those infected with COVID were more likely to be diagnosed with any autoimmune condition, connective tissue disease, and, in Japan at least, inflammatory arthritis.
The authors acknowledge that being diagnosed with a disease might not be the same as actually having the disease, so in another analysis they looked only at people who received treatment for the autoimmune conditions, and the signals were even stronger in that group.
This risk seemed to be highest in the 6 months following the COVID infection, which makes sense biologically if we think that the infection is somehow screwing up the immune system.
And the risk was similar with both COVID variants circulating at the time of the study.
The only factor that reduced the risk? You guessed it: vaccination. This is a particularly interesting finding because the exposure cohort was defined by having been infected with COVID. Therefore, the mechanism of protection is not prevention of infection; it’s something else. Perhaps vaccination helps to get the immune system in a state to respond to COVID infection more… appropriately?
Yes, this study is observational. We can’t draw causal conclusions here. But it does reinforce my long-held belief that COVID is a weird virus, one with effects that are different from the respiratory viruses we are used to. I can’t say for certain whether COVID causes immune system dysfunction that puts someone at risk for autoimmunity — not from this study. But I can say it wouldn’t surprise me.
Dr. F. Perry Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.
In the early days of the pandemic, before we really understood what COVID was, two specialties in the hospital had a foreboding sense that something was very strange about this virus. The first was the pulmonologists, who noticed the striking levels of hypoxemia — low oxygen in the blood — and the rapidity with which patients who had previously been stable would crash in the intensive care unit.
The second, and I mark myself among this group, were the nephrologists. The dialysis machines stopped working right. I remember rounding on patients in the hospital who were on dialysis for kidney failure in the setting of severe COVID infection and seeing clots forming on the dialysis filters. Some patients could barely get in a full treatment because the filters would clog so quickly.
We knew it was worse than flu because of the mortality rates, but these oddities made us realize that it was different too — not just a particularly nasty respiratory virus but one that had effects on the body that we hadn’t really seen before.
That’s why I’ve always been interested in studies that compare what happens to patients after COVID infection vs what happens to patients after other respiratory infections. This week, we’ll look at an intriguing study that suggests that COVID may lead to autoimmune diseases like rheumatoid arthritis, lupus, and vasculitis.
The study appears in the Annals of Internal Medicine and is made possible by the universal electronic health record systems of South Korea and Japan, who collaborated to create a truly staggering cohort of more than 20 million individuals living in those countries from 2020 to 2021.
The exposure of interest? COVID infection, experienced by just under 5% of that cohort over the study period. (Remember, there was a time when COVID infections were relatively controlled, particularly in some countries.)
The researchers wanted to compare the risk for autoimmune disease among COVID-infected individuals against two control groups. The first control group was the general population. This is interesting but a difficult analysis, because people who become infected with COVID might be very different from the general population. The second control group was people infected with influenza. I like this a lot better; the risk factors for COVID and influenza are quite similar, and the fact that this group was diagnosed with flu means at least that they are getting medical care and are sort of “in the system,” so to speak.
But it’s not enough to simply identify these folks and see who ends up with more autoimmune disease. The authors used propensity score matching to pair individuals infected with COVID with individuals from the control groups who were very similar to them. I’ve talked about this strategy before, but the basic idea is that you build a model predicting the likelihood of infection with COVID, based on a slew of factors — and the slew these authors used is pretty big, as shown below — and then stick people with similar risk for COVID together, with one member of the pair having had COVID and the other having eluded it (at least for the study period).
After this statistical balancing, the authors looked at the risk for a variety of autoimmune diseases.
Compared with those infected with flu, those infected with COVID were more likely to be diagnosed with any autoimmune condition, connective tissue disease, and, in Japan at least, inflammatory arthritis.
The authors acknowledge that being diagnosed with a disease might not be the same as actually having the disease, so in another analysis they looked only at people who received treatment for the autoimmune conditions, and the signals were even stronger in that group.
This risk seemed to be highest in the 6 months following the COVID infection, which makes sense biologically if we think that the infection is somehow screwing up the immune system.
And the risk was similar with both COVID variants circulating at the time of the study.
The only factor that reduced the risk? You guessed it: vaccination. This is a particularly interesting finding because the exposure cohort was defined by having been infected with COVID. Therefore, the mechanism of protection is not prevention of infection; it’s something else. Perhaps vaccination helps to get the immune system in a state to respond to COVID infection more… appropriately?
Yes, this study is observational. We can’t draw causal conclusions here. But it does reinforce my long-held belief that COVID is a weird virus, one with effects that are different from the respiratory viruses we are used to. I can’t say for certain whether COVID causes immune system dysfunction that puts someone at risk for autoimmunity — not from this study. But I can say it wouldn’t surprise me.
Dr. F. Perry Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.
In the early days of the pandemic, before we really understood what COVID was, two specialties in the hospital had a foreboding sense that something was very strange about this virus. The first was the pulmonologists, who noticed the striking levels of hypoxemia — low oxygen in the blood — and the rapidity with which patients who had previously been stable would crash in the intensive care unit.
The second, and I mark myself among this group, were the nephrologists. The dialysis machines stopped working right. I remember rounding on patients in the hospital who were on dialysis for kidney failure in the setting of severe COVID infection and seeing clots forming on the dialysis filters. Some patients could barely get in a full treatment because the filters would clog so quickly.
We knew it was worse than flu because of the mortality rates, but these oddities made us realize that it was different too — not just a particularly nasty respiratory virus but one that had effects on the body that we hadn’t really seen before.
That’s why I’ve always been interested in studies that compare what happens to patients after COVID infection vs what happens to patients after other respiratory infections. This week, we’ll look at an intriguing study that suggests that COVID may lead to autoimmune diseases like rheumatoid arthritis, lupus, and vasculitis.
The study appears in the Annals of Internal Medicine and is made possible by the universal electronic health record systems of South Korea and Japan, who collaborated to create a truly staggering cohort of more than 20 million individuals living in those countries from 2020 to 2021.
The exposure of interest? COVID infection, experienced by just under 5% of that cohort over the study period. (Remember, there was a time when COVID infections were relatively controlled, particularly in some countries.)
The researchers wanted to compare the risk for autoimmune disease among COVID-infected individuals against two control groups. The first control group was the general population. This is interesting but a difficult analysis, because people who become infected with COVID might be very different from the general population. The second control group was people infected with influenza. I like this a lot better; the risk factors for COVID and influenza are quite similar, and the fact that this group was diagnosed with flu means at least that they are getting medical care and are sort of “in the system,” so to speak.
But it’s not enough to simply identify these folks and see who ends up with more autoimmune disease. The authors used propensity score matching to pair individuals infected with COVID with individuals from the control groups who were very similar to them. I’ve talked about this strategy before, but the basic idea is that you build a model predicting the likelihood of infection with COVID, based on a slew of factors — and the slew these authors used is pretty big, as shown below — and then stick people with similar risk for COVID together, with one member of the pair having had COVID and the other having eluded it (at least for the study period).
After this statistical balancing, the authors looked at the risk for a variety of autoimmune diseases.
Compared with those infected with flu, those infected with COVID were more likely to be diagnosed with any autoimmune condition, connective tissue disease, and, in Japan at least, inflammatory arthritis.
The authors acknowledge that being diagnosed with a disease might not be the same as actually having the disease, so in another analysis they looked only at people who received treatment for the autoimmune conditions, and the signals were even stronger in that group.
This risk seemed to be highest in the 6 months following the COVID infection, which makes sense biologically if we think that the infection is somehow screwing up the immune system.
And the risk was similar with both COVID variants circulating at the time of the study.
The only factor that reduced the risk? You guessed it: vaccination. This is a particularly interesting finding because the exposure cohort was defined by having been infected with COVID. Therefore, the mechanism of protection is not prevention of infection; it’s something else. Perhaps vaccination helps to get the immune system in a state to respond to COVID infection more… appropriately?
Yes, this study is observational. We can’t draw causal conclusions here. But it does reinforce my long-held belief that COVID is a weird virus, one with effects that are different from the respiratory viruses we are used to. I can’t say for certain whether COVID causes immune system dysfunction that puts someone at risk for autoimmunity — not from this study. But I can say it wouldn’t surprise me.
Dr. F. Perry Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
What’s Changed in Asthma Treatment? Quite a Bit
This transcript has been edited for clarity.
I’m Dr. Neil Skolnik, and today I am going to talk about the 2023 update to the Global Strategy for Asthma Management and Prevention. We treat a lot of asthma, and there are some important changes, particularly around the use of albuterol. There are two main guidelines when it comes to asthma, the Global Initiative for Asthma (GINA) guideline and the US National Heart, Lung, and Blood Institute Guidelines. While I had the privilege of serving on the expert working group for the US guidelines, what I like about the GINA guidelines is that they are updated annually, and so they really help us keep up with rapid changes in the field.
Today, I’m going to focus on assessment and treatment.
Four Questions to Assess Asthma Control
Because over half of patients with asthma are not well controlled, it is important to assess control at every asthma visit. Asthma control has two domains: symptom control and the risk for future exacerbations. It is not enough to simply ask, “How is your asthma?” because many patients overrate their control and live with ongoing symptoms. There are many assessment tools; the Asthma Control Test (ACT) focuses on symptoms, and the new Asthma Impairment and Risk Questionnaire (AIRQ) assesses both symptoms and risk for exacerbations. The GINA assessment is probably the easiest to implement, with just four questions relevant to the past 4 weeks:
- Have you had daytime symptoms more than twice in one week?
- Have you had any night waking due to asthma?
- Have you needed short-acting beta-agonist (SABA), such as albuterol, rescue more than twice in one week?
- Have you had any activity limitation due to asthma?
Well-controlled asthma is defined as a negative response to all four of these questions, partly controlled asthma is one or two “yes” answers, and uncontrolled asthma is three to four positive responses. You can’t modify a patient’s therapy if you don’t know whether their asthma is well or poorly controlled. You’ll notice that these questions focus on symptom control. It is important also to ask about risk factors for exacerbations, particularly previous exacerbations.
Asthma Treatment Changes
The goals of treatment are control of symptoms and avoidance of exacerbations. The GINA guidelines emphasize that even patients with mild asthma can have severe or fatal exacerbations.
GINA recommends two management tracks. The preferred track uses inhaled corticosteroid (ICS)-formoterol as both maintenance and reliever therapy (MART). Track 2, without the use of ICS-formoterol for MART, is also offered, recognizing that the use of ICS-formoterol for MART is not approved by the US Food and Drug Administration. There is an easy-to-follow stepped-care diagram that is worth looking at; it’s on page 66 of the GINA guideline PDF.
For patients who have symptoms less than twice a month, begin with Step 1 therapy:
- Track 1: as-needed low-dose ICS-formoterol.
- Track 2: treatment with albuterol; also use ICS whenever albuterol is used.
For patients with symptoms more than twice a month (but not most days of the week) treatment can start with Step 2 therapy:
- Track 1: as-needed low-dose ICS-formoterol
- Track 2: daily low-dose ICS plus as-needed SABA
An option for rescue therapy for Track 2 across all steps of therapy is to use an ICS whenever a SABA is used for rescue to reduce the likelihood of exacerbation.
For patients with more severe asthma symptoms most days of the week, or whose asthma is waking them from sleep one or more times weekly, then you can start with Step 3 therapy as follows:
- Track 1: low dose ICS-formoterol as MART
- Track 2: low-dose ICS with long-acting beta-agonist (LABA) for maintenance, plus as needed SABA or as needed ICS-SABA
That’s going to cover most of our patients. As we see people back, if escalation of therapy is needed, then Step 4 therapy is:
- Track 1: medium-dose ICS-formoterol as MART
- Track 2: medium-dose ICS-LABA plus as needed SABA or as-needed ICS-SABA
For patients who remain uncontrolled, it’s important to realize that Step 5 gives you the option to add a long-acting muscarinic antagonist (LAMA). In my experience this can be very helpful. We can also consider going to high-dose ICS-LABS for maintenance. At this step, the patient usually has pretty severe, uncontrolled asthma and we can think about checking eosinophil counts, ordering pulmonary function tests, and referring to our specialist colleagues for consideration of biologic therapy.
It is important to see patients back regularly, and to assess asthma control. If a patient is not well controlled or has had exacerbations, consider stepping up therapy, or changing from albuterol alone as rescue to albuterol plus ICS for rescue. If they have been well controlled for a long time, consider de-escalation of therapy among patients on one of the higher therapy steps.
Dr. Skolnik has disclosed the following relevant financial relationships: Serve(d) on the advisory board for AstraZeneca, Teva, Eli Lilly and Company, Boehringer Ingelheim, Sanofi, Sanofi Pasteur, GlaxoSmithKline, Merck; and Bayer; serve(d) as a speaker or a member of a speakers bureau for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, GlaxoSmithKline. Received research grant from Sanofi, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Bayer; and received income in an amount equal to or greater than $250 from AstraZeneca, Teva, Eli Lilly and Company, Boehringer Ingelheim, Sanofi, Sanofi Pasteur, GlaxoSmithKline, Merck, and Bayer.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
I’m Dr. Neil Skolnik, and today I am going to talk about the 2023 update to the Global Strategy for Asthma Management and Prevention. We treat a lot of asthma, and there are some important changes, particularly around the use of albuterol. There are two main guidelines when it comes to asthma, the Global Initiative for Asthma (GINA) guideline and the US National Heart, Lung, and Blood Institute Guidelines. While I had the privilege of serving on the expert working group for the US guidelines, what I like about the GINA guidelines is that they are updated annually, and so they really help us keep up with rapid changes in the field.
Today, I’m going to focus on assessment and treatment.
Four Questions to Assess Asthma Control
Because over half of patients with asthma are not well controlled, it is important to assess control at every asthma visit. Asthma control has two domains: symptom control and the risk for future exacerbations. It is not enough to simply ask, “How is your asthma?” because many patients overrate their control and live with ongoing symptoms. There are many assessment tools; the Asthma Control Test (ACT) focuses on symptoms, and the new Asthma Impairment and Risk Questionnaire (AIRQ) assesses both symptoms and risk for exacerbations. The GINA assessment is probably the easiest to implement, with just four questions relevant to the past 4 weeks:
- Have you had daytime symptoms more than twice in one week?
- Have you had any night waking due to asthma?
- Have you needed short-acting beta-agonist (SABA), such as albuterol, rescue more than twice in one week?
- Have you had any activity limitation due to asthma?
Well-controlled asthma is defined as a negative response to all four of these questions, partly controlled asthma is one or two “yes” answers, and uncontrolled asthma is three to four positive responses. You can’t modify a patient’s therapy if you don’t know whether their asthma is well or poorly controlled. You’ll notice that these questions focus on symptom control. It is important also to ask about risk factors for exacerbations, particularly previous exacerbations.
Asthma Treatment Changes
The goals of treatment are control of symptoms and avoidance of exacerbations. The GINA guidelines emphasize that even patients with mild asthma can have severe or fatal exacerbations.
GINA recommends two management tracks. The preferred track uses inhaled corticosteroid (ICS)-formoterol as both maintenance and reliever therapy (MART). Track 2, without the use of ICS-formoterol for MART, is also offered, recognizing that the use of ICS-formoterol for MART is not approved by the US Food and Drug Administration. There is an easy-to-follow stepped-care diagram that is worth looking at; it’s on page 66 of the GINA guideline PDF.
For patients who have symptoms less than twice a month, begin with Step 1 therapy:
- Track 1: as-needed low-dose ICS-formoterol.
- Track 2: treatment with albuterol; also use ICS whenever albuterol is used.
For patients with symptoms more than twice a month (but not most days of the week) treatment can start with Step 2 therapy:
- Track 1: as-needed low-dose ICS-formoterol
- Track 2: daily low-dose ICS plus as-needed SABA
An option for rescue therapy for Track 2 across all steps of therapy is to use an ICS whenever a SABA is used for rescue to reduce the likelihood of exacerbation.
For patients with more severe asthma symptoms most days of the week, or whose asthma is waking them from sleep one or more times weekly, then you can start with Step 3 therapy as follows:
- Track 1: low dose ICS-formoterol as MART
- Track 2: low-dose ICS with long-acting beta-agonist (LABA) for maintenance, plus as needed SABA or as needed ICS-SABA
That’s going to cover most of our patients. As we see people back, if escalation of therapy is needed, then Step 4 therapy is:
- Track 1: medium-dose ICS-formoterol as MART
- Track 2: medium-dose ICS-LABA plus as needed SABA or as-needed ICS-SABA
For patients who remain uncontrolled, it’s important to realize that Step 5 gives you the option to add a long-acting muscarinic antagonist (LAMA). In my experience this can be very helpful. We can also consider going to high-dose ICS-LABS for maintenance. At this step, the patient usually has pretty severe, uncontrolled asthma and we can think about checking eosinophil counts, ordering pulmonary function tests, and referring to our specialist colleagues for consideration of biologic therapy.
It is important to see patients back regularly, and to assess asthma control. If a patient is not well controlled or has had exacerbations, consider stepping up therapy, or changing from albuterol alone as rescue to albuterol plus ICS for rescue. If they have been well controlled for a long time, consider de-escalation of therapy among patients on one of the higher therapy steps.
Dr. Skolnik has disclosed the following relevant financial relationships: Serve(d) on the advisory board for AstraZeneca, Teva, Eli Lilly and Company, Boehringer Ingelheim, Sanofi, Sanofi Pasteur, GlaxoSmithKline, Merck; and Bayer; serve(d) as a speaker or a member of a speakers bureau for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, GlaxoSmithKline. Received research grant from Sanofi, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Bayer; and received income in an amount equal to or greater than $250 from AstraZeneca, Teva, Eli Lilly and Company, Boehringer Ingelheim, Sanofi, Sanofi Pasteur, GlaxoSmithKline, Merck, and Bayer.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
I’m Dr. Neil Skolnik, and today I am going to talk about the 2023 update to the Global Strategy for Asthma Management and Prevention. We treat a lot of asthma, and there are some important changes, particularly around the use of albuterol. There are two main guidelines when it comes to asthma, the Global Initiative for Asthma (GINA) guideline and the US National Heart, Lung, and Blood Institute Guidelines. While I had the privilege of serving on the expert working group for the US guidelines, what I like about the GINA guidelines is that they are updated annually, and so they really help us keep up with rapid changes in the field.
Today, I’m going to focus on assessment and treatment.
Four Questions to Assess Asthma Control
Because over half of patients with asthma are not well controlled, it is important to assess control at every asthma visit. Asthma control has two domains: symptom control and the risk for future exacerbations. It is not enough to simply ask, “How is your asthma?” because many patients overrate their control and live with ongoing symptoms. There are many assessment tools; the Asthma Control Test (ACT) focuses on symptoms, and the new Asthma Impairment and Risk Questionnaire (AIRQ) assesses both symptoms and risk for exacerbations. The GINA assessment is probably the easiest to implement, with just four questions relevant to the past 4 weeks:
- Have you had daytime symptoms more than twice in one week?
- Have you had any night waking due to asthma?
- Have you needed short-acting beta-agonist (SABA), such as albuterol, rescue more than twice in one week?
- Have you had any activity limitation due to asthma?
Well-controlled asthma is defined as a negative response to all four of these questions, partly controlled asthma is one or two “yes” answers, and uncontrolled asthma is three to four positive responses. You can’t modify a patient’s therapy if you don’t know whether their asthma is well or poorly controlled. You’ll notice that these questions focus on symptom control. It is important also to ask about risk factors for exacerbations, particularly previous exacerbations.
Asthma Treatment Changes
The goals of treatment are control of symptoms and avoidance of exacerbations. The GINA guidelines emphasize that even patients with mild asthma can have severe or fatal exacerbations.
GINA recommends two management tracks. The preferred track uses inhaled corticosteroid (ICS)-formoterol as both maintenance and reliever therapy (MART). Track 2, without the use of ICS-formoterol for MART, is also offered, recognizing that the use of ICS-formoterol for MART is not approved by the US Food and Drug Administration. There is an easy-to-follow stepped-care diagram that is worth looking at; it’s on page 66 of the GINA guideline PDF.
For patients who have symptoms less than twice a month, begin with Step 1 therapy:
- Track 1: as-needed low-dose ICS-formoterol.
- Track 2: treatment with albuterol; also use ICS whenever albuterol is used.
For patients with symptoms more than twice a month (but not most days of the week) treatment can start with Step 2 therapy:
- Track 1: as-needed low-dose ICS-formoterol
- Track 2: daily low-dose ICS plus as-needed SABA
An option for rescue therapy for Track 2 across all steps of therapy is to use an ICS whenever a SABA is used for rescue to reduce the likelihood of exacerbation.
For patients with more severe asthma symptoms most days of the week, or whose asthma is waking them from sleep one or more times weekly, then you can start with Step 3 therapy as follows:
- Track 1: low dose ICS-formoterol as MART
- Track 2: low-dose ICS with long-acting beta-agonist (LABA) for maintenance, plus as needed SABA or as needed ICS-SABA
That’s going to cover most of our patients. As we see people back, if escalation of therapy is needed, then Step 4 therapy is:
- Track 1: medium-dose ICS-formoterol as MART
- Track 2: medium-dose ICS-LABA plus as needed SABA or as-needed ICS-SABA
For patients who remain uncontrolled, it’s important to realize that Step 5 gives you the option to add a long-acting muscarinic antagonist (LAMA). In my experience this can be very helpful. We can also consider going to high-dose ICS-LABS for maintenance. At this step, the patient usually has pretty severe, uncontrolled asthma and we can think about checking eosinophil counts, ordering pulmonary function tests, and referring to our specialist colleagues for consideration of biologic therapy.
It is important to see patients back regularly, and to assess asthma control. If a patient is not well controlled or has had exacerbations, consider stepping up therapy, or changing from albuterol alone as rescue to albuterol plus ICS for rescue. If they have been well controlled for a long time, consider de-escalation of therapy among patients on one of the higher therapy steps.
Dr. Skolnik has disclosed the following relevant financial relationships: Serve(d) on the advisory board for AstraZeneca, Teva, Eli Lilly and Company, Boehringer Ingelheim, Sanofi, Sanofi Pasteur, GlaxoSmithKline, Merck; and Bayer; serve(d) as a speaker or a member of a speakers bureau for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, GlaxoSmithKline. Received research grant from Sanofi, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Bayer; and received income in an amount equal to or greater than $250 from AstraZeneca, Teva, Eli Lilly and Company, Boehringer Ingelheim, Sanofi, Sanofi Pasteur, GlaxoSmithKline, Merck, and Bayer.
A version of this article appeared on Medscape.com.
Bartonella henselae Infection May Occasionally Distract Immune Control of Latent Human Herpesviruses
To the Editor:
We read with interest the September 2023 Cutis article by Swink et al,1 “Cat Scratch Disease Presenting With Concurrent Pityriasis Rosea in a 10-Year-Old Girl.” The authors documented the possibility of Bartonella henselae infection as another causative agent for pityriasis rosea (PR) even though the association of PR with human herpesvirus (HHV) 6 and HHV-7 infection is based on several consistent observations and not on occasional findings. The association of PR with endogenous systemic reactivation of HHV-6 and HHV-7 has been identified with different investigations and laboratory techniques. Using polymerase chain reaction, real-time calibrated quantitative polymerase chain reaction, in situ hybridization, immunohistochemistry, and electron microscopy, HHV-6 and HHV-7 have been detected in plasma (a marker of active viral replication), peripheral blood mononuclear cells, and skin lesions from patients with PR.2 In addition, HHV-6 and HHV-7 messenger RNA expression and their specific antigens have been detected in PR skin lesions and herpesvirus virions in various stages of morphogenesis as well as in the supernatant of co-cultured peripheral blood mononuclear cells of patients with PR.2,3 Lastly, the increased levels of several particular cytokines and chemokinesin the sera of patients with PR support a viral role in its pathogenesis.4
Bartonella henselae is a gram-negative intracellular facultative bacterium that is commonly implicated in causing zoonotic infections worldwide. The incidence of cat-scratch disease (CSD) was reported to be 6.4 cases per 100,000 population in adults and 9.4 cases per 100,000 population in children aged 5 to 9 years globally.5 Approximately 24,000 cases of CSD are reported in the United States every year.6 Therefore, considering these data, if B henselae was a causative agent for PR, the eruption would be observed frequently in many patients with CSD, which is not the case. On the contrary, it is possible that B henselae infection may have reactivated HHV-6 and/or HHV-7 infection. It is well established that B henselae causes a robust cell-mediated immune response by activating natural killer and helper T cells (TH1) and enhancement of cytotoxic T lymphocytes.7 It could be assumed that by strongly stimulating the immune response and polarizing it to a specific antigen cell response, B henselae infection may temporarily distract the T cell-mediated control of the latent infections, such as HHV-6 and HHV-7, which may reactivate and cause PR.
It is important to point out that a case of concomitant B henselae and Epstein-Barr virus infection has been described.8 Even in that case, the B henselae infection may have reactivated Epstein-Barr virus as well as HHV-6 and HHV-7 in the case described by Swink et al.1 Epstein-Barr virus reactivation has been detected in one case8 through serologic testing—IgM, IgG, Epstein-Barr virus nuclear antigen IgG, and heterophile antibodies—as there were no dermatologic manifestations that may be related to Epstein-Barr virus reactivation from latency.9
In conclusion, a viral or bacterial infection such as Epstein-Barr virus or B henselae may have a transactivating function allowing another (latent) virus such as HHV-6 or HHV-7 to reactivate. Indeed, it has been described that SARS-CoV-2 may act as a transactivator agent triggering HHV-6/HHV-7 reactivation, thereby indirectly causing PR clinical manifestation.10
- Swink SM, Rhodes LP, Levin J. Cat scratch disease presenting with concurrent pityriasis rosea in a 10-year-old girl. Cutis. 2023;112:E24-E26. doi:10.12788/cutis.0861
- Broccolo F, Drago F, Careddu AM, et al. Additional evidence that pityriasis rosea is associated with reactivation of human herpesvirus-6 and -7. J Invest Dermatol. 2005;124:1234-1240.
- Rebora A, Ciccarese G, Herzum A, et al. Pityriasis rosea and other infectious eruptions during pregnancy: possible life-threatening health conditions for the fetus. Clin Dermatol. 2020;38:105-112.
- Drago F, Ciccarese G, Broccolo F, et al. The role of cytokines, chemokines, and growth factors in the pathogenesis of pityriasis rosea. Mediators Inflamm. 2015;2015:438963. doi:10.1155/2015/438963
- Nelson CA, Moore AR, Perea AE, et al. Cat scratch disease: U.S. clinicians’ experience and knowledge. Zoonoses Public Health. 2018;65:67-73.
- Ackson LA, Perkins BA, Wenger JD. Cat scratch disease in the United States: an analysis of three national databases. Am J Public Health. 1993;83:1707-1711.
- Resto-Ruiz S, Burgess A, Anderson BE. The role of the host immune response in pathogenesis of Bartonella henselae. DNA Cell Biol. 2003; 22:431-440.
- Aparicio-Casares H, Puente-Rico MH, Tomé-Nestal C, et al. A pediatric case of Bartonella henselae and Epstein Barr virus disease with bone and hepatosplenic involvement. Bol Med Hosp Infant Mex. 2021;78:467-473.
- Ciccarese G, Trave I, Herzum A, et al. Dermatological manifestations of Epstein-Barr virus systemic infection: a case report and literature review. Int J Dermatol. 2020;59:1202-1209.
- Drago F, Broccolo F, Ciccarese G. Pityriasis rosea, pityriasis rosea-like eruptions, and herpes zoster in the setting of COVID-19 and COVID-19 vaccination. Clin Dermatol. 2022;40:586-590.
To the Editor:
We read with interest the September 2023 Cutis article by Swink et al,1 “Cat Scratch Disease Presenting With Concurrent Pityriasis Rosea in a 10-Year-Old Girl.” The authors documented the possibility of Bartonella henselae infection as another causative agent for pityriasis rosea (PR) even though the association of PR with human herpesvirus (HHV) 6 and HHV-7 infection is based on several consistent observations and not on occasional findings. The association of PR with endogenous systemic reactivation of HHV-6 and HHV-7 has been identified with different investigations and laboratory techniques. Using polymerase chain reaction, real-time calibrated quantitative polymerase chain reaction, in situ hybridization, immunohistochemistry, and electron microscopy, HHV-6 and HHV-7 have been detected in plasma (a marker of active viral replication), peripheral blood mononuclear cells, and skin lesions from patients with PR.2 In addition, HHV-6 and HHV-7 messenger RNA expression and their specific antigens have been detected in PR skin lesions and herpesvirus virions in various stages of morphogenesis as well as in the supernatant of co-cultured peripheral blood mononuclear cells of patients with PR.2,3 Lastly, the increased levels of several particular cytokines and chemokinesin the sera of patients with PR support a viral role in its pathogenesis.4
Bartonella henselae is a gram-negative intracellular facultative bacterium that is commonly implicated in causing zoonotic infections worldwide. The incidence of cat-scratch disease (CSD) was reported to be 6.4 cases per 100,000 population in adults and 9.4 cases per 100,000 population in children aged 5 to 9 years globally.5 Approximately 24,000 cases of CSD are reported in the United States every year.6 Therefore, considering these data, if B henselae was a causative agent for PR, the eruption would be observed frequently in many patients with CSD, which is not the case. On the contrary, it is possible that B henselae infection may have reactivated HHV-6 and/or HHV-7 infection. It is well established that B henselae causes a robust cell-mediated immune response by activating natural killer and helper T cells (TH1) and enhancement of cytotoxic T lymphocytes.7 It could be assumed that by strongly stimulating the immune response and polarizing it to a specific antigen cell response, B henselae infection may temporarily distract the T cell-mediated control of the latent infections, such as HHV-6 and HHV-7, which may reactivate and cause PR.
It is important to point out that a case of concomitant B henselae and Epstein-Barr virus infection has been described.8 Even in that case, the B henselae infection may have reactivated Epstein-Barr virus as well as HHV-6 and HHV-7 in the case described by Swink et al.1 Epstein-Barr virus reactivation has been detected in one case8 through serologic testing—IgM, IgG, Epstein-Barr virus nuclear antigen IgG, and heterophile antibodies—as there were no dermatologic manifestations that may be related to Epstein-Barr virus reactivation from latency.9
In conclusion, a viral or bacterial infection such as Epstein-Barr virus or B henselae may have a transactivating function allowing another (latent) virus such as HHV-6 or HHV-7 to reactivate. Indeed, it has been described that SARS-CoV-2 may act as a transactivator agent triggering HHV-6/HHV-7 reactivation, thereby indirectly causing PR clinical manifestation.10
To the Editor:
We read with interest the September 2023 Cutis article by Swink et al,1 “Cat Scratch Disease Presenting With Concurrent Pityriasis Rosea in a 10-Year-Old Girl.” The authors documented the possibility of Bartonella henselae infection as another causative agent for pityriasis rosea (PR) even though the association of PR with human herpesvirus (HHV) 6 and HHV-7 infection is based on several consistent observations and not on occasional findings. The association of PR with endogenous systemic reactivation of HHV-6 and HHV-7 has been identified with different investigations and laboratory techniques. Using polymerase chain reaction, real-time calibrated quantitative polymerase chain reaction, in situ hybridization, immunohistochemistry, and electron microscopy, HHV-6 and HHV-7 have been detected in plasma (a marker of active viral replication), peripheral blood mononuclear cells, and skin lesions from patients with PR.2 In addition, HHV-6 and HHV-7 messenger RNA expression and their specific antigens have been detected in PR skin lesions and herpesvirus virions in various stages of morphogenesis as well as in the supernatant of co-cultured peripheral blood mononuclear cells of patients with PR.2,3 Lastly, the increased levels of several particular cytokines and chemokinesin the sera of patients with PR support a viral role in its pathogenesis.4
Bartonella henselae is a gram-negative intracellular facultative bacterium that is commonly implicated in causing zoonotic infections worldwide. The incidence of cat-scratch disease (CSD) was reported to be 6.4 cases per 100,000 population in adults and 9.4 cases per 100,000 population in children aged 5 to 9 years globally.5 Approximately 24,000 cases of CSD are reported in the United States every year.6 Therefore, considering these data, if B henselae was a causative agent for PR, the eruption would be observed frequently in many patients with CSD, which is not the case. On the contrary, it is possible that B henselae infection may have reactivated HHV-6 and/or HHV-7 infection. It is well established that B henselae causes a robust cell-mediated immune response by activating natural killer and helper T cells (TH1) and enhancement of cytotoxic T lymphocytes.7 It could be assumed that by strongly stimulating the immune response and polarizing it to a specific antigen cell response, B henselae infection may temporarily distract the T cell-mediated control of the latent infections, such as HHV-6 and HHV-7, which may reactivate and cause PR.
It is important to point out that a case of concomitant B henselae and Epstein-Barr virus infection has been described.8 Even in that case, the B henselae infection may have reactivated Epstein-Barr virus as well as HHV-6 and HHV-7 in the case described by Swink et al.1 Epstein-Barr virus reactivation has been detected in one case8 through serologic testing—IgM, IgG, Epstein-Barr virus nuclear antigen IgG, and heterophile antibodies—as there were no dermatologic manifestations that may be related to Epstein-Barr virus reactivation from latency.9
In conclusion, a viral or bacterial infection such as Epstein-Barr virus or B henselae may have a transactivating function allowing another (latent) virus such as HHV-6 or HHV-7 to reactivate. Indeed, it has been described that SARS-CoV-2 may act as a transactivator agent triggering HHV-6/HHV-7 reactivation, thereby indirectly causing PR clinical manifestation.10
- Swink SM, Rhodes LP, Levin J. Cat scratch disease presenting with concurrent pityriasis rosea in a 10-year-old girl. Cutis. 2023;112:E24-E26. doi:10.12788/cutis.0861
- Broccolo F, Drago F, Careddu AM, et al. Additional evidence that pityriasis rosea is associated with reactivation of human herpesvirus-6 and -7. J Invest Dermatol. 2005;124:1234-1240.
- Rebora A, Ciccarese G, Herzum A, et al. Pityriasis rosea and other infectious eruptions during pregnancy: possible life-threatening health conditions for the fetus. Clin Dermatol. 2020;38:105-112.
- Drago F, Ciccarese G, Broccolo F, et al. The role of cytokines, chemokines, and growth factors in the pathogenesis of pityriasis rosea. Mediators Inflamm. 2015;2015:438963. doi:10.1155/2015/438963
- Nelson CA, Moore AR, Perea AE, et al. Cat scratch disease: U.S. clinicians’ experience and knowledge. Zoonoses Public Health. 2018;65:67-73.
- Ackson LA, Perkins BA, Wenger JD. Cat scratch disease in the United States: an analysis of three national databases. Am J Public Health. 1993;83:1707-1711.
- Resto-Ruiz S, Burgess A, Anderson BE. The role of the host immune response in pathogenesis of Bartonella henselae. DNA Cell Biol. 2003; 22:431-440.
- Aparicio-Casares H, Puente-Rico MH, Tomé-Nestal C, et al. A pediatric case of Bartonella henselae and Epstein Barr virus disease with bone and hepatosplenic involvement. Bol Med Hosp Infant Mex. 2021;78:467-473.
- Ciccarese G, Trave I, Herzum A, et al. Dermatological manifestations of Epstein-Barr virus systemic infection: a case report and literature review. Int J Dermatol. 2020;59:1202-1209.
- Drago F, Broccolo F, Ciccarese G. Pityriasis rosea, pityriasis rosea-like eruptions, and herpes zoster in the setting of COVID-19 and COVID-19 vaccination. Clin Dermatol. 2022;40:586-590.
- Swink SM, Rhodes LP, Levin J. Cat scratch disease presenting with concurrent pityriasis rosea in a 10-year-old girl. Cutis. 2023;112:E24-E26. doi:10.12788/cutis.0861
- Broccolo F, Drago F, Careddu AM, et al. Additional evidence that pityriasis rosea is associated with reactivation of human herpesvirus-6 and -7. J Invest Dermatol. 2005;124:1234-1240.
- Rebora A, Ciccarese G, Herzum A, et al. Pityriasis rosea and other infectious eruptions during pregnancy: possible life-threatening health conditions for the fetus. Clin Dermatol. 2020;38:105-112.
- Drago F, Ciccarese G, Broccolo F, et al. The role of cytokines, chemokines, and growth factors in the pathogenesis of pityriasis rosea. Mediators Inflamm. 2015;2015:438963. doi:10.1155/2015/438963
- Nelson CA, Moore AR, Perea AE, et al. Cat scratch disease: U.S. clinicians’ experience and knowledge. Zoonoses Public Health. 2018;65:67-73.
- Ackson LA, Perkins BA, Wenger JD. Cat scratch disease in the United States: an analysis of three national databases. Am J Public Health. 1993;83:1707-1711.
- Resto-Ruiz S, Burgess A, Anderson BE. The role of the host immune response in pathogenesis of Bartonella henselae. DNA Cell Biol. 2003; 22:431-440.
- Aparicio-Casares H, Puente-Rico MH, Tomé-Nestal C, et al. A pediatric case of Bartonella henselae and Epstein Barr virus disease with bone and hepatosplenic involvement. Bol Med Hosp Infant Mex. 2021;78:467-473.
- Ciccarese G, Trave I, Herzum A, et al. Dermatological manifestations of Epstein-Barr virus systemic infection: a case report and literature review. Int J Dermatol. 2020;59:1202-1209.
- Drago F, Broccolo F, Ciccarese G. Pityriasis rosea, pityriasis rosea-like eruptions, and herpes zoster in the setting of COVID-19 and COVID-19 vaccination. Clin Dermatol. 2022;40:586-590.