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Guidance for Practicing Primary Care: Updated Clinical Guidelines Regarding Dry Eye Syndrome
On February 11, 2024, the American Academy of Ophthalmology (AAO) issued new guidelines regarding dry eye syndrome or keratoconjunctivitis sicca. According to the National Eye Institute, dry eye affects approximately 16 million Americans. Dry eye is a multifactorial disease with causes including excessive screen time and refractive surgery. While it may seem that dry eye is a nuisance disease, it can actually damage the cornea if not treated appropriately.
The guidelines state that dry eye can affect the quality of life as well as the outcomes of ocular surgeries such as cataract surgery. It is imperative that we discuss this potential complication before our patients undergo these procedures. As primary care physicians, we have seen that patients may not be well educated on their health conditions by other doctors. We may not be the one performing the surgery but it is likely the patient will seek our advice if any complication arises.
The guidelines say that clinical examination is the gold standard for diagnosing this disease. We need to be proficient at doing eye exams and refer to a specialist when appropriate. The treatment can likely be undertaken in the primary care office unless there are other symptoms such as loss of visual acuity. The guidelines suggest several diagnostic tests, such as the Schirmer test and tear osmolarity test, which may be outside the scope of the primary care setting. Often, clinical history will guide the diagnosis.
Treatments include several Food and Drug Administration–approved eye drops. We need to know what they are and when to prescribe them. We know they will not cure the disease but can keep it under control and improve the patient’s quality of life.
Dry eye may seem a trivial complaint in the sea of diseases we treat on a daily basis. However, it is not trivial to the patient. It can affect their vision and make their life miserable. We need to pay attention when our patients bring this to our attention. We are not just making them comfortable but protecting their corneas. This can be done in conjunction with routine ophthalmologic visits.
According to the authors of these guidelines, approximately 10% of patients with significantly dry eyes and mouth will have Sj
These guidelines also suggest a classification for dry eye including mild, moderate, and severe. Since the treatment varies depending on classification, we need to learn this classification system. They also stress follow-up visits. It is not enough just to diagnose the disease and start treatment, we need to see the patients back for follow-up.
Currently, most people work and play on electronic devices. Dry eye syndrome can make this more difficult and vice versa. While it is typically not a vision-threatening disease, it can be a life-altering one. Ocular symptoms are something we see frequently in our practices, from allergic conjunctivitis to glaucoma. Often, the patient starts seeking help in our office.
Yes, our patients may have more life-threatening diseases. Our job is not just to save lives but to help our patients live healthy lives. If their lives are being affected by any disease, we must step in and do something. Dry eye is not just an inconvenience but something that causes great suffering. Eventually we may end up referring the patient to the ophthalmologist, but if we can do something to ease their discomfort while they are waiting, we would be changing their lives. We must educate ourselves on this disease and appropriate treatments to be prescribed depending on the classification of disease.
Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, NJ. She has no conflicts of interest.
On February 11, 2024, the American Academy of Ophthalmology (AAO) issued new guidelines regarding dry eye syndrome or keratoconjunctivitis sicca. According to the National Eye Institute, dry eye affects approximately 16 million Americans. Dry eye is a multifactorial disease with causes including excessive screen time and refractive surgery. While it may seem that dry eye is a nuisance disease, it can actually damage the cornea if not treated appropriately.
The guidelines state that dry eye can affect the quality of life as well as the outcomes of ocular surgeries such as cataract surgery. It is imperative that we discuss this potential complication before our patients undergo these procedures. As primary care physicians, we have seen that patients may not be well educated on their health conditions by other doctors. We may not be the one performing the surgery but it is likely the patient will seek our advice if any complication arises.
The guidelines say that clinical examination is the gold standard for diagnosing this disease. We need to be proficient at doing eye exams and refer to a specialist when appropriate. The treatment can likely be undertaken in the primary care office unless there are other symptoms such as loss of visual acuity. The guidelines suggest several diagnostic tests, such as the Schirmer test and tear osmolarity test, which may be outside the scope of the primary care setting. Often, clinical history will guide the diagnosis.
Treatments include several Food and Drug Administration–approved eye drops. We need to know what they are and when to prescribe them. We know they will not cure the disease but can keep it under control and improve the patient’s quality of life.
Dry eye may seem a trivial complaint in the sea of diseases we treat on a daily basis. However, it is not trivial to the patient. It can affect their vision and make their life miserable. We need to pay attention when our patients bring this to our attention. We are not just making them comfortable but protecting their corneas. This can be done in conjunction with routine ophthalmologic visits.
According to the authors of these guidelines, approximately 10% of patients with significantly dry eyes and mouth will have Sj
These guidelines also suggest a classification for dry eye including mild, moderate, and severe. Since the treatment varies depending on classification, we need to learn this classification system. They also stress follow-up visits. It is not enough just to diagnose the disease and start treatment, we need to see the patients back for follow-up.
Currently, most people work and play on electronic devices. Dry eye syndrome can make this more difficult and vice versa. While it is typically not a vision-threatening disease, it can be a life-altering one. Ocular symptoms are something we see frequently in our practices, from allergic conjunctivitis to glaucoma. Often, the patient starts seeking help in our office.
Yes, our patients may have more life-threatening diseases. Our job is not just to save lives but to help our patients live healthy lives. If their lives are being affected by any disease, we must step in and do something. Dry eye is not just an inconvenience but something that causes great suffering. Eventually we may end up referring the patient to the ophthalmologist, but if we can do something to ease their discomfort while they are waiting, we would be changing their lives. We must educate ourselves on this disease and appropriate treatments to be prescribed depending on the classification of disease.
Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, NJ. She has no conflicts of interest.
On February 11, 2024, the American Academy of Ophthalmology (AAO) issued new guidelines regarding dry eye syndrome or keratoconjunctivitis sicca. According to the National Eye Institute, dry eye affects approximately 16 million Americans. Dry eye is a multifactorial disease with causes including excessive screen time and refractive surgery. While it may seem that dry eye is a nuisance disease, it can actually damage the cornea if not treated appropriately.
The guidelines state that dry eye can affect the quality of life as well as the outcomes of ocular surgeries such as cataract surgery. It is imperative that we discuss this potential complication before our patients undergo these procedures. As primary care physicians, we have seen that patients may not be well educated on their health conditions by other doctors. We may not be the one performing the surgery but it is likely the patient will seek our advice if any complication arises.
The guidelines say that clinical examination is the gold standard for diagnosing this disease. We need to be proficient at doing eye exams and refer to a specialist when appropriate. The treatment can likely be undertaken in the primary care office unless there are other symptoms such as loss of visual acuity. The guidelines suggest several diagnostic tests, such as the Schirmer test and tear osmolarity test, which may be outside the scope of the primary care setting. Often, clinical history will guide the diagnosis.
Treatments include several Food and Drug Administration–approved eye drops. We need to know what they are and when to prescribe them. We know they will not cure the disease but can keep it under control and improve the patient’s quality of life.
Dry eye may seem a trivial complaint in the sea of diseases we treat on a daily basis. However, it is not trivial to the patient. It can affect their vision and make their life miserable. We need to pay attention when our patients bring this to our attention. We are not just making them comfortable but protecting their corneas. This can be done in conjunction with routine ophthalmologic visits.
According to the authors of these guidelines, approximately 10% of patients with significantly dry eyes and mouth will have Sj
These guidelines also suggest a classification for dry eye including mild, moderate, and severe. Since the treatment varies depending on classification, we need to learn this classification system. They also stress follow-up visits. It is not enough just to diagnose the disease and start treatment, we need to see the patients back for follow-up.
Currently, most people work and play on electronic devices. Dry eye syndrome can make this more difficult and vice versa. While it is typically not a vision-threatening disease, it can be a life-altering one. Ocular symptoms are something we see frequently in our practices, from allergic conjunctivitis to glaucoma. Often, the patient starts seeking help in our office.
Yes, our patients may have more life-threatening diseases. Our job is not just to save lives but to help our patients live healthy lives. If their lives are being affected by any disease, we must step in and do something. Dry eye is not just an inconvenience but something that causes great suffering. Eventually we may end up referring the patient to the ophthalmologist, but if we can do something to ease their discomfort while they are waiting, we would be changing their lives. We must educate ourselves on this disease and appropriate treatments to be prescribed depending on the classification of disease.
Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, NJ. She has no conflicts of interest.
Macadamia and Sapucaia Extracts and the Skin
Macadamia (Macadamia tetraphylla) is endemic to Australia and is now commercially cultivated worldwide.1 It is closely related genetically to the other macadamia plants, including the other main one, M. integrifolia, cultivated for macadamia nuts. Known in Brazil as sapucaia or castanha-de-sapucaia, Lecythis pisonis (also referred to as “cream nut” or “monkey pot”) is a large, deciduous tropical tree and member of the Brazil nut family, Lecythidaceae.2 Various parts of both of these plants have been associated with medicinal properties, including the potential for dermatologic activity. Notably, the leaves of L. pisonis have been used in traditional medicine to treat pruritus.2.
Macadamia
Extraction to Harness Antioxidant Activity
In 2015, Dailey and Vuong developed an aqueous extraction process to recover the phenolic content and antioxidant functionality from the skin waste of M. tetraphylla using response surface methodology. As an environmentally suitable solvent that is also cheap and safe, water was chosen to maximize the extraction scenario. They identified the proper conditions (90° C, a time of 20 min, and a sample-to-solvent ratio of 5 g/100 mL) to obtain sufficient phenolic compounds, proanthocyanidins, and flavonoids to render robust antioxidant function.1
Early in 2023, Somwongin et al. investigated various green extraction methods for viability in harnessing the cosmetic/cosmeceutical ingredients of M. integrifolia pericarps. Extracts were assessed for total phenolic content as well as antioxidant and anti–skin aging functions. They found that among the green extraction methods (ultrasound, micellar, microwave, and pulsed electric field extraction with water used as a clean solvent), the ultrasound-assisted extraction method netted the greatest yield and total phenolic content. It was also associated with the most robust antioxidant and anti–skin aging activities. Indeed, the researchers reported that its antioxidant activities were comparable to ascorbic acid and Trolox and its anti–skin aging potency on a par with epigallocatechin-3-gallate and oleanolic acid. The ultrasound-assisted extract was also deemed safe as it did not provoke irritation. The authors concluded that this environmentally suitable extraction method for M. integrifolia is appropriate for obtaining effective macadamia extracts for use in cosmetics and cosmeceuticals.3
Anti-Aging Activity
In 2017, Addy et al. set out to characterize skin surface lipid composition and differences in an age- and sex-controlled population as a foundation for developing a botanically derived skin surface lipid mimetic agent. They noted that fatty acids, triglycerides, cholesterol, steryl esters, wax esters, and squalene are the main constituents of skin surface lipids. The investigators obtained skin surface lipid samples from the foreheads of 59 healthy 22-year-old women, analyzed them, and used the raw components of M. integrifolia, Simmondsia chinensis, and Olea europaea to engineer a mimetic product. They reported that the esterification reactions of jojoba, macadamia, and tall oils, combined with squalene derived from O. europaea, yielded an appropriate skin surface lipid mimetic, which, when applied to delipidized skin, assisted in recovering barrier function, enhancing skin hydration, and improving elasticity as well as firmness in aged skin. The researchers concluded that this skin surface lipid mimetic could serve as an effective supplement to human skin surface lipids in aged skin and for conditions in which the stratum corneum is impaired.4
Two years later, Hanum et al. compared the effects of macadamia nut oil nanocream and conventional cream for treating cutaneous aging over a 4-week period. The macadamia nut oil nanocream, which contained macadamia nut oil 10%, tween 80, propylene glycol, cetyl alcohol, methylparaben, propylparaben, and distilled water, was compared with the conventional cream based on effects on moisture, evenness, pore size, melanin, and wrinkling. The macadamia nut oil was found to yield superior anti-aging activity along each parameter as compared with the conventional cream. The researchers concluded that the macadamia nut oil in nanocream can be an effective formulation for providing benefits in addressing cutaneous aging.5
Macadamia nut oil has also been used in an anti-aging emulsion that was evaluated in a small study with 11 volunteers in 2008. Akhtar et al. prepared multiple emulsions of vitamin C and wheat protein using macadamia oil for its abundant supply of palmitoleic acid. Over 4 weeks, the emulsion was found to increase skin moisture without affecting other skin parameters, such as elasticity, erythema, melanin, pH, or sebum levels.6
Sapucaia (L. pisonis), an ornamental tree that is used for timber, produces edible, nutritious nuts that are rich in tocopherols, polyphenols, and fatty acids.7,8 In 2018, Demoliner et al. identified and characterized the phenolic substances present in sapucaia nut extract and its shell. Antioxidant activity conferred by the extract was attributed to the copious supply of catechin, epicatechin, and myricetin, as well as ellagic and ferulic acids, among the 14 phenolic constituents. The shell included 22 phenolic substances along with a significant level of condensed tannins and marked antioxidant function. The authors correlated the substantial activity imparted by the shell with its higher phenolic content, and suggested this robust source of natural antioxidants could be well suited to use in cosmetic products.9
Antifungal Activity
In 2015, Vieira et al. characterized 12 fractions enriched in peptides derived from L. pisonis seeds to determine inhibitory activity against Candida albicans. The fraction that exerted the strongest activity at 10 μg/mL, suppressing C. albicans growth by 38.5% and inducing a 69.3% loss of viability, was identified as similar to plant defensins and thus dubbed “L. pisonis defensin 1 (Lp-Def1).” The investigators concluded that Lp-Def1 acts on C. albicans by slightly elevating the induction of reactive oxygen species and causing a significant reduction in mitochondrial activity. They suggested that their findings support the use of plant defensins, particularly Lp-Def1, in the formulation of antifungal products, especially to address C. albicans.10
Pruritus
In 2012, Silva et al. studied the antipruritic impact of L. pisonis leaf extracts in mice and rats. Pretreatment with the various fractions of L. pisonis as well as constituent mixed triterpenes (ursolic and oleanolic acids) significantly blocked scratching behavior provoked by compound 48/80. The degranulation of rat peritoneal mast cells caused by compound 48/80 was also substantially decreased from pretreatment with the ethanol extract of L. pisonis, ether-L. pisonis fraction, and mixed triterpenes. The L. pisonis ether fraction suppressed edema induced by carrageenan administration and the ethanol extract displayed no toxicity up to an oral dose of 2g/kg. The investigators concluded that their results strongly support the antipruritic effects of L. pisonis leaves as well as the traditional use of the plant to treat pruritus.2
Stability for Cosmetic Creams
In 2020, Rampazzo et al. assessed the stability and cytotoxicity of a cosmetic cream containing sapucaia nut oil. All three tested concentrations (1%, 5%, and 10%) of the cream were found to be stable, with an effective preservative system, and deemed safe for use on human skin. To maintain a pH appropriate for a body cream, the formulation requires a stabilizing agent. The cream with 5% nut oil was identified as the most stable and satisfying for use on the skin.7
More recently, Hertel Pereira et al. investigated the benefits of using L. pisonis pericarp extract, known to exhibit abundant antioxidants, in an all-natural skin cream. They found that formulation instability increased proportionally with the concentration of the extract, but the use of the outer pericarp of L. pisonis was well suited for the cream formulation, with physical-chemical and organoleptic qualities unchanged after the stability test.11
Conclusion
The available literature on the medical applications of macadamia and sapucaia plants is sparse. Some recent findings are promising regarding possible uses in skin health. However, much more research is necessary before considering macadamia and sapucaia as viable sources of botanical agents capable of delivering significant cutaneous benefits.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. 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., an SaaS company used to generate skin care routines in office and as an e-commerce solution. Write to her at dermnews@mdedge.com.
References
1. Dailey A and Vuong QV. Antioxidants (Basel). 2015 Nov 12;4(4):699-718.
2. Silva LL et al. J Ethnopharmacol. 2012 Jan 6;139(1):90-97.
3. Somwongin S et al. Ultrason Sonochem. 2023 Jan;92:106266.
4. Addy J et al. J Cosmet Sci. 2017 Jan/Feb;68(1):59-67.
5. Hanum TI et al. Open Access Maced J Med Sci. 2019 Nov 14;7(22):3917-3920.
6. Akhtar N and Yazan Y. Pak J Pharm Sci. 2008 Jan;21(1):45-50.
7. Rampazzo APS et al. J Cosmet Sci. 2020 Sep/Oct;71(5):239-250.
8. Rosa TLM et al. Food Res Int. 2020 Nov;137:109383.
9. Demoliner F et al. Food Res Int. 2018 Oct;112:434-442.
10. Vieira ME et al. Acta Biochim Biophys Sin (Shanghai). 2015 Sep;47(9):716-729.
11. Hertel Pereira AC et al. J Cosmet Sci. 2021 Mar-Apr;72(2):155-162.
Macadamia (Macadamia tetraphylla) is endemic to Australia and is now commercially cultivated worldwide.1 It is closely related genetically to the other macadamia plants, including the other main one, M. integrifolia, cultivated for macadamia nuts. Known in Brazil as sapucaia or castanha-de-sapucaia, Lecythis pisonis (also referred to as “cream nut” or “monkey pot”) is a large, deciduous tropical tree and member of the Brazil nut family, Lecythidaceae.2 Various parts of both of these plants have been associated with medicinal properties, including the potential for dermatologic activity. Notably, the leaves of L. pisonis have been used in traditional medicine to treat pruritus.2.
Macadamia
Extraction to Harness Antioxidant Activity
In 2015, Dailey and Vuong developed an aqueous extraction process to recover the phenolic content and antioxidant functionality from the skin waste of M. tetraphylla using response surface methodology. As an environmentally suitable solvent that is also cheap and safe, water was chosen to maximize the extraction scenario. They identified the proper conditions (90° C, a time of 20 min, and a sample-to-solvent ratio of 5 g/100 mL) to obtain sufficient phenolic compounds, proanthocyanidins, and flavonoids to render robust antioxidant function.1
Early in 2023, Somwongin et al. investigated various green extraction methods for viability in harnessing the cosmetic/cosmeceutical ingredients of M. integrifolia pericarps. Extracts were assessed for total phenolic content as well as antioxidant and anti–skin aging functions. They found that among the green extraction methods (ultrasound, micellar, microwave, and pulsed electric field extraction with water used as a clean solvent), the ultrasound-assisted extraction method netted the greatest yield and total phenolic content. It was also associated with the most robust antioxidant and anti–skin aging activities. Indeed, the researchers reported that its antioxidant activities were comparable to ascorbic acid and Trolox and its anti–skin aging potency on a par with epigallocatechin-3-gallate and oleanolic acid. The ultrasound-assisted extract was also deemed safe as it did not provoke irritation. The authors concluded that this environmentally suitable extraction method for M. integrifolia is appropriate for obtaining effective macadamia extracts for use in cosmetics and cosmeceuticals.3
Anti-Aging Activity
In 2017, Addy et al. set out to characterize skin surface lipid composition and differences in an age- and sex-controlled population as a foundation for developing a botanically derived skin surface lipid mimetic agent. They noted that fatty acids, triglycerides, cholesterol, steryl esters, wax esters, and squalene are the main constituents of skin surface lipids. The investigators obtained skin surface lipid samples from the foreheads of 59 healthy 22-year-old women, analyzed them, and used the raw components of M. integrifolia, Simmondsia chinensis, and Olea europaea to engineer a mimetic product. They reported that the esterification reactions of jojoba, macadamia, and tall oils, combined with squalene derived from O. europaea, yielded an appropriate skin surface lipid mimetic, which, when applied to delipidized skin, assisted in recovering barrier function, enhancing skin hydration, and improving elasticity as well as firmness in aged skin. The researchers concluded that this skin surface lipid mimetic could serve as an effective supplement to human skin surface lipids in aged skin and for conditions in which the stratum corneum is impaired.4
Two years later, Hanum et al. compared the effects of macadamia nut oil nanocream and conventional cream for treating cutaneous aging over a 4-week period. The macadamia nut oil nanocream, which contained macadamia nut oil 10%, tween 80, propylene glycol, cetyl alcohol, methylparaben, propylparaben, and distilled water, was compared with the conventional cream based on effects on moisture, evenness, pore size, melanin, and wrinkling. The macadamia nut oil was found to yield superior anti-aging activity along each parameter as compared with the conventional cream. The researchers concluded that the macadamia nut oil in nanocream can be an effective formulation for providing benefits in addressing cutaneous aging.5
Macadamia nut oil has also been used in an anti-aging emulsion that was evaluated in a small study with 11 volunteers in 2008. Akhtar et al. prepared multiple emulsions of vitamin C and wheat protein using macadamia oil for its abundant supply of palmitoleic acid. Over 4 weeks, the emulsion was found to increase skin moisture without affecting other skin parameters, such as elasticity, erythema, melanin, pH, or sebum levels.6
Sapucaia (L. pisonis), an ornamental tree that is used for timber, produces edible, nutritious nuts that are rich in tocopherols, polyphenols, and fatty acids.7,8 In 2018, Demoliner et al. identified and characterized the phenolic substances present in sapucaia nut extract and its shell. Antioxidant activity conferred by the extract was attributed to the copious supply of catechin, epicatechin, and myricetin, as well as ellagic and ferulic acids, among the 14 phenolic constituents. The shell included 22 phenolic substances along with a significant level of condensed tannins and marked antioxidant function. The authors correlated the substantial activity imparted by the shell with its higher phenolic content, and suggested this robust source of natural antioxidants could be well suited to use in cosmetic products.9
Antifungal Activity
In 2015, Vieira et al. characterized 12 fractions enriched in peptides derived from L. pisonis seeds to determine inhibitory activity against Candida albicans. The fraction that exerted the strongest activity at 10 μg/mL, suppressing C. albicans growth by 38.5% and inducing a 69.3% loss of viability, was identified as similar to plant defensins and thus dubbed “L. pisonis defensin 1 (Lp-Def1).” The investigators concluded that Lp-Def1 acts on C. albicans by slightly elevating the induction of reactive oxygen species and causing a significant reduction in mitochondrial activity. They suggested that their findings support the use of plant defensins, particularly Lp-Def1, in the formulation of antifungal products, especially to address C. albicans.10
Pruritus
In 2012, Silva et al. studied the antipruritic impact of L. pisonis leaf extracts in mice and rats. Pretreatment with the various fractions of L. pisonis as well as constituent mixed triterpenes (ursolic and oleanolic acids) significantly blocked scratching behavior provoked by compound 48/80. The degranulation of rat peritoneal mast cells caused by compound 48/80 was also substantially decreased from pretreatment with the ethanol extract of L. pisonis, ether-L. pisonis fraction, and mixed triterpenes. The L. pisonis ether fraction suppressed edema induced by carrageenan administration and the ethanol extract displayed no toxicity up to an oral dose of 2g/kg. The investigators concluded that their results strongly support the antipruritic effects of L. pisonis leaves as well as the traditional use of the plant to treat pruritus.2
Stability for Cosmetic Creams
In 2020, Rampazzo et al. assessed the stability and cytotoxicity of a cosmetic cream containing sapucaia nut oil. All three tested concentrations (1%, 5%, and 10%) of the cream were found to be stable, with an effective preservative system, and deemed safe for use on human skin. To maintain a pH appropriate for a body cream, the formulation requires a stabilizing agent. The cream with 5% nut oil was identified as the most stable and satisfying for use on the skin.7
More recently, Hertel Pereira et al. investigated the benefits of using L. pisonis pericarp extract, known to exhibit abundant antioxidants, in an all-natural skin cream. They found that formulation instability increased proportionally with the concentration of the extract, but the use of the outer pericarp of L. pisonis was well suited for the cream formulation, with physical-chemical and organoleptic qualities unchanged after the stability test.11
Conclusion
The available literature on the medical applications of macadamia and sapucaia plants is sparse. Some recent findings are promising regarding possible uses in skin health. However, much more research is necessary before considering macadamia and sapucaia as viable sources of botanical agents capable of delivering significant cutaneous benefits.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. 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., an SaaS company used to generate skin care routines in office and as an e-commerce solution. Write to her at dermnews@mdedge.com.
References
1. Dailey A and Vuong QV. Antioxidants (Basel). 2015 Nov 12;4(4):699-718.
2. Silva LL et al. J Ethnopharmacol. 2012 Jan 6;139(1):90-97.
3. Somwongin S et al. Ultrason Sonochem. 2023 Jan;92:106266.
4. Addy J et al. J Cosmet Sci. 2017 Jan/Feb;68(1):59-67.
5. Hanum TI et al. Open Access Maced J Med Sci. 2019 Nov 14;7(22):3917-3920.
6. Akhtar N and Yazan Y. Pak J Pharm Sci. 2008 Jan;21(1):45-50.
7. Rampazzo APS et al. J Cosmet Sci. 2020 Sep/Oct;71(5):239-250.
8. Rosa TLM et al. Food Res Int. 2020 Nov;137:109383.
9. Demoliner F et al. Food Res Int. 2018 Oct;112:434-442.
10. Vieira ME et al. Acta Biochim Biophys Sin (Shanghai). 2015 Sep;47(9):716-729.
11. Hertel Pereira AC et al. J Cosmet Sci. 2021 Mar-Apr;72(2):155-162.
Macadamia (Macadamia tetraphylla) is endemic to Australia and is now commercially cultivated worldwide.1 It is closely related genetically to the other macadamia plants, including the other main one, M. integrifolia, cultivated for macadamia nuts. Known in Brazil as sapucaia or castanha-de-sapucaia, Lecythis pisonis (also referred to as “cream nut” or “monkey pot”) is a large, deciduous tropical tree and member of the Brazil nut family, Lecythidaceae.2 Various parts of both of these plants have been associated with medicinal properties, including the potential for dermatologic activity. Notably, the leaves of L. pisonis have been used in traditional medicine to treat pruritus.2.
Macadamia
Extraction to Harness Antioxidant Activity
In 2015, Dailey and Vuong developed an aqueous extraction process to recover the phenolic content and antioxidant functionality from the skin waste of M. tetraphylla using response surface methodology. As an environmentally suitable solvent that is also cheap and safe, water was chosen to maximize the extraction scenario. They identified the proper conditions (90° C, a time of 20 min, and a sample-to-solvent ratio of 5 g/100 mL) to obtain sufficient phenolic compounds, proanthocyanidins, and flavonoids to render robust antioxidant function.1
Early in 2023, Somwongin et al. investigated various green extraction methods for viability in harnessing the cosmetic/cosmeceutical ingredients of M. integrifolia pericarps. Extracts were assessed for total phenolic content as well as antioxidant and anti–skin aging functions. They found that among the green extraction methods (ultrasound, micellar, microwave, and pulsed electric field extraction with water used as a clean solvent), the ultrasound-assisted extraction method netted the greatest yield and total phenolic content. It was also associated with the most robust antioxidant and anti–skin aging activities. Indeed, the researchers reported that its antioxidant activities were comparable to ascorbic acid and Trolox and its anti–skin aging potency on a par with epigallocatechin-3-gallate and oleanolic acid. The ultrasound-assisted extract was also deemed safe as it did not provoke irritation. The authors concluded that this environmentally suitable extraction method for M. integrifolia is appropriate for obtaining effective macadamia extracts for use in cosmetics and cosmeceuticals.3
Anti-Aging Activity
In 2017, Addy et al. set out to characterize skin surface lipid composition and differences in an age- and sex-controlled population as a foundation for developing a botanically derived skin surface lipid mimetic agent. They noted that fatty acids, triglycerides, cholesterol, steryl esters, wax esters, and squalene are the main constituents of skin surface lipids. The investigators obtained skin surface lipid samples from the foreheads of 59 healthy 22-year-old women, analyzed them, and used the raw components of M. integrifolia, Simmondsia chinensis, and Olea europaea to engineer a mimetic product. They reported that the esterification reactions of jojoba, macadamia, and tall oils, combined with squalene derived from O. europaea, yielded an appropriate skin surface lipid mimetic, which, when applied to delipidized skin, assisted in recovering barrier function, enhancing skin hydration, and improving elasticity as well as firmness in aged skin. The researchers concluded that this skin surface lipid mimetic could serve as an effective supplement to human skin surface lipids in aged skin and for conditions in which the stratum corneum is impaired.4
Two years later, Hanum et al. compared the effects of macadamia nut oil nanocream and conventional cream for treating cutaneous aging over a 4-week period. The macadamia nut oil nanocream, which contained macadamia nut oil 10%, tween 80, propylene glycol, cetyl alcohol, methylparaben, propylparaben, and distilled water, was compared with the conventional cream based on effects on moisture, evenness, pore size, melanin, and wrinkling. The macadamia nut oil was found to yield superior anti-aging activity along each parameter as compared with the conventional cream. The researchers concluded that the macadamia nut oil in nanocream can be an effective formulation for providing benefits in addressing cutaneous aging.5
Macadamia nut oil has also been used in an anti-aging emulsion that was evaluated in a small study with 11 volunteers in 2008. Akhtar et al. prepared multiple emulsions of vitamin C and wheat protein using macadamia oil for its abundant supply of palmitoleic acid. Over 4 weeks, the emulsion was found to increase skin moisture without affecting other skin parameters, such as elasticity, erythema, melanin, pH, or sebum levels.6
Sapucaia (L. pisonis), an ornamental tree that is used for timber, produces edible, nutritious nuts that are rich in tocopherols, polyphenols, and fatty acids.7,8 In 2018, Demoliner et al. identified and characterized the phenolic substances present in sapucaia nut extract and its shell. Antioxidant activity conferred by the extract was attributed to the copious supply of catechin, epicatechin, and myricetin, as well as ellagic and ferulic acids, among the 14 phenolic constituents. The shell included 22 phenolic substances along with a significant level of condensed tannins and marked antioxidant function. The authors correlated the substantial activity imparted by the shell with its higher phenolic content, and suggested this robust source of natural antioxidants could be well suited to use in cosmetic products.9
Antifungal Activity
In 2015, Vieira et al. characterized 12 fractions enriched in peptides derived from L. pisonis seeds to determine inhibitory activity against Candida albicans. The fraction that exerted the strongest activity at 10 μg/mL, suppressing C. albicans growth by 38.5% and inducing a 69.3% loss of viability, was identified as similar to plant defensins and thus dubbed “L. pisonis defensin 1 (Lp-Def1).” The investigators concluded that Lp-Def1 acts on C. albicans by slightly elevating the induction of reactive oxygen species and causing a significant reduction in mitochondrial activity. They suggested that their findings support the use of plant defensins, particularly Lp-Def1, in the formulation of antifungal products, especially to address C. albicans.10
Pruritus
In 2012, Silva et al. studied the antipruritic impact of L. pisonis leaf extracts in mice and rats. Pretreatment with the various fractions of L. pisonis as well as constituent mixed triterpenes (ursolic and oleanolic acids) significantly blocked scratching behavior provoked by compound 48/80. The degranulation of rat peritoneal mast cells caused by compound 48/80 was also substantially decreased from pretreatment with the ethanol extract of L. pisonis, ether-L. pisonis fraction, and mixed triterpenes. The L. pisonis ether fraction suppressed edema induced by carrageenan administration and the ethanol extract displayed no toxicity up to an oral dose of 2g/kg. The investigators concluded that their results strongly support the antipruritic effects of L. pisonis leaves as well as the traditional use of the plant to treat pruritus.2
Stability for Cosmetic Creams
In 2020, Rampazzo et al. assessed the stability and cytotoxicity of a cosmetic cream containing sapucaia nut oil. All three tested concentrations (1%, 5%, and 10%) of the cream were found to be stable, with an effective preservative system, and deemed safe for use on human skin. To maintain a pH appropriate for a body cream, the formulation requires a stabilizing agent. The cream with 5% nut oil was identified as the most stable and satisfying for use on the skin.7
More recently, Hertel Pereira et al. investigated the benefits of using L. pisonis pericarp extract, known to exhibit abundant antioxidants, in an all-natural skin cream. They found that formulation instability increased proportionally with the concentration of the extract, but the use of the outer pericarp of L. pisonis was well suited for the cream formulation, with physical-chemical and organoleptic qualities unchanged after the stability test.11
Conclusion
The available literature on the medical applications of macadamia and sapucaia plants is sparse. Some recent findings are promising regarding possible uses in skin health. However, much more research is necessary before considering macadamia and sapucaia as viable sources of botanical agents capable of delivering significant cutaneous benefits.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. 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., an SaaS company used to generate skin care routines in office and as an e-commerce solution. Write to her at dermnews@mdedge.com.
References
1. Dailey A and Vuong QV. Antioxidants (Basel). 2015 Nov 12;4(4):699-718.
2. Silva LL et al. J Ethnopharmacol. 2012 Jan 6;139(1):90-97.
3. Somwongin S et al. Ultrason Sonochem. 2023 Jan;92:106266.
4. Addy J et al. J Cosmet Sci. 2017 Jan/Feb;68(1):59-67.
5. Hanum TI et al. Open Access Maced J Med Sci. 2019 Nov 14;7(22):3917-3920.
6. Akhtar N and Yazan Y. Pak J Pharm Sci. 2008 Jan;21(1):45-50.
7. Rampazzo APS et al. J Cosmet Sci. 2020 Sep/Oct;71(5):239-250.
8. Rosa TLM et al. Food Res Int. 2020 Nov;137:109383.
9. Demoliner F et al. Food Res Int. 2018 Oct;112:434-442.
10. Vieira ME et al. Acta Biochim Biophys Sin (Shanghai). 2015 Sep;47(9):716-729.
11. Hertel Pereira AC et al. J Cosmet Sci. 2021 Mar-Apr;72(2):155-162.
Little Less Talk and a Lot More Action
No matter where one looks for the statistics, no matter what words one chooses to describe it, this country has a child and adolescent mental health crisis. Almost 20% of young people in the 3-17 age bracket have a mental, emotional, developmental, or behavioral disorder. COVID-19 has certainly exacerbated the problem, but the downward trend in the mental health of this nation has been going on for decades.
The voices calling for more services to address the problem are getting more numerous and louder. But, what exactly should those services look like and who should be delivering them?
When considered together, two recent research papers suggest that we should be venturing well beyond the usual mental health strategies if we are going to be successful in addressing the current crisis.
The first paper is an analysis by two psychologists who contend that our efforts to raise the awareness of mental issues may be contributing to the increase in reported mental health problems. The authors agree that more attention paid to mental health conditions can result in “more accurate reporting of previous under-recognized symptoms” and would seem to be a positive. However, the investigators also observe that when exposed to this flood of information, some individuals who are only experiencing minor distress may report their symptoms as mental problems. The authors of the paper have coined the term for this phenomenon as “prevalence inflation.” Their preliminary investigation suggests it may be much more common than once believed and they present numerous situations in which prevalence inflation seems to have occurred.
A New York Times article about this hypothesis reports on a British study in which nearly 30,000 teenagers were instructed by their teachers to “direct their attentions to the present moment” and utilize other mindfulness strategies. The educators had hoped that after 8 years of this indoctrination, the students’ mental health would have improved. The bottom line was that this mindfulness-based program was of no help and may have actually made things worse for a subgroup of students who were at greatest risk for mental health challenges.
Dr. Jack Andrews, one of the authors, feels that mindfulness training may encourage what he calls “co-rumination,” which he describes as “the kind of long, unresolved group discussion that churns up problems without finding solutions.” One has to wonder if “prevalence inflation” and “co-rumination,” if they do exist, may be playing a role in the hotly debated phenomenon some have termed “late-onset gender dysphoria.”
Never having been a fan of mindfulness training as an effective strategy, I am relieved to learn that serious investigators are finding evidence that supports my gut reaction.
If raising awareness, “education,” and group discussion aren’t working, and in some cases are actually contributing to the crisis, or at least making the data difficult to interpret, what should we be doing to turn this foundering ship around?
A second paper, coming from Taiwan, may provide an answer. Huey-Ling Chiang and fellow investigators have reported on a study of nearly two million children and adolescents in which they found improved performance in a variety of physical fitness challenges “was linked with a lower risk of mental health disorder.” The dose-dependent effect resulted in less anxiety and depressive disorders as well as less attention-deficit/hyperactivity disorder when cardio-respiratory, muscle endurance, and power indices improved.
There have been other observers who have suggested a link between physical fitness and improved mental health, but this Taiwanese study is by far one of the largest. And, the discovery of a dose-dependent effect makes it particularly convincing.
As I reviewed these two papers, I became increasingly frustrated because this is another example in which one of the answers is staring us in the face and we continue to do nothing more than talk about it.
We already know that physically active people are healthier both physically and mentally, but we do little more than talk. It may be helpful for some people to become a bit more self-aware. However, it is becoming increasingly clear that you can’t talk yourself into being mentally healthy without a concurrent effort to actually do the things that can improve your overall health, such as being physically active and adopting healthy sleep habits. A political advisor once said, “It’s the economy, stupid.” As a community interested in the health of our children and the adults they will become, we need to remind ourselves again, “It’s the old Mind-Body Thing, Stupid.” Our children need a little less talk and a lot more action.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.
No matter where one looks for the statistics, no matter what words one chooses to describe it, this country has a child and adolescent mental health crisis. Almost 20% of young people in the 3-17 age bracket have a mental, emotional, developmental, or behavioral disorder. COVID-19 has certainly exacerbated the problem, but the downward trend in the mental health of this nation has been going on for decades.
The voices calling for more services to address the problem are getting more numerous and louder. But, what exactly should those services look like and who should be delivering them?
When considered together, two recent research papers suggest that we should be venturing well beyond the usual mental health strategies if we are going to be successful in addressing the current crisis.
The first paper is an analysis by two psychologists who contend that our efforts to raise the awareness of mental issues may be contributing to the increase in reported mental health problems. The authors agree that more attention paid to mental health conditions can result in “more accurate reporting of previous under-recognized symptoms” and would seem to be a positive. However, the investigators also observe that when exposed to this flood of information, some individuals who are only experiencing minor distress may report their symptoms as mental problems. The authors of the paper have coined the term for this phenomenon as “prevalence inflation.” Their preliminary investigation suggests it may be much more common than once believed and they present numerous situations in which prevalence inflation seems to have occurred.
A New York Times article about this hypothesis reports on a British study in which nearly 30,000 teenagers were instructed by their teachers to “direct their attentions to the present moment” and utilize other mindfulness strategies. The educators had hoped that after 8 years of this indoctrination, the students’ mental health would have improved. The bottom line was that this mindfulness-based program was of no help and may have actually made things worse for a subgroup of students who were at greatest risk for mental health challenges.
Dr. Jack Andrews, one of the authors, feels that mindfulness training may encourage what he calls “co-rumination,” which he describes as “the kind of long, unresolved group discussion that churns up problems without finding solutions.” One has to wonder if “prevalence inflation” and “co-rumination,” if they do exist, may be playing a role in the hotly debated phenomenon some have termed “late-onset gender dysphoria.”
Never having been a fan of mindfulness training as an effective strategy, I am relieved to learn that serious investigators are finding evidence that supports my gut reaction.
If raising awareness, “education,” and group discussion aren’t working, and in some cases are actually contributing to the crisis, or at least making the data difficult to interpret, what should we be doing to turn this foundering ship around?
A second paper, coming from Taiwan, may provide an answer. Huey-Ling Chiang and fellow investigators have reported on a study of nearly two million children and adolescents in which they found improved performance in a variety of physical fitness challenges “was linked with a lower risk of mental health disorder.” The dose-dependent effect resulted in less anxiety and depressive disorders as well as less attention-deficit/hyperactivity disorder when cardio-respiratory, muscle endurance, and power indices improved.
There have been other observers who have suggested a link between physical fitness and improved mental health, but this Taiwanese study is by far one of the largest. And, the discovery of a dose-dependent effect makes it particularly convincing.
As I reviewed these two papers, I became increasingly frustrated because this is another example in which one of the answers is staring us in the face and we continue to do nothing more than talk about it.
We already know that physically active people are healthier both physically and mentally, but we do little more than talk. It may be helpful for some people to become a bit more self-aware. However, it is becoming increasingly clear that you can’t talk yourself into being mentally healthy without a concurrent effort to actually do the things that can improve your overall health, such as being physically active and adopting healthy sleep habits. A political advisor once said, “It’s the economy, stupid.” As a community interested in the health of our children and the adults they will become, we need to remind ourselves again, “It’s the old Mind-Body Thing, Stupid.” Our children need a little less talk and a lot more action.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.
No matter where one looks for the statistics, no matter what words one chooses to describe it, this country has a child and adolescent mental health crisis. Almost 20% of young people in the 3-17 age bracket have a mental, emotional, developmental, or behavioral disorder. COVID-19 has certainly exacerbated the problem, but the downward trend in the mental health of this nation has been going on for decades.
The voices calling for more services to address the problem are getting more numerous and louder. But, what exactly should those services look like and who should be delivering them?
When considered together, two recent research papers suggest that we should be venturing well beyond the usual mental health strategies if we are going to be successful in addressing the current crisis.
The first paper is an analysis by two psychologists who contend that our efforts to raise the awareness of mental issues may be contributing to the increase in reported mental health problems. The authors agree that more attention paid to mental health conditions can result in “more accurate reporting of previous under-recognized symptoms” and would seem to be a positive. However, the investigators also observe that when exposed to this flood of information, some individuals who are only experiencing minor distress may report their symptoms as mental problems. The authors of the paper have coined the term for this phenomenon as “prevalence inflation.” Their preliminary investigation suggests it may be much more common than once believed and they present numerous situations in which prevalence inflation seems to have occurred.
A New York Times article about this hypothesis reports on a British study in which nearly 30,000 teenagers were instructed by their teachers to “direct their attentions to the present moment” and utilize other mindfulness strategies. The educators had hoped that after 8 years of this indoctrination, the students’ mental health would have improved. The bottom line was that this mindfulness-based program was of no help and may have actually made things worse for a subgroup of students who were at greatest risk for mental health challenges.
Dr. Jack Andrews, one of the authors, feels that mindfulness training may encourage what he calls “co-rumination,” which he describes as “the kind of long, unresolved group discussion that churns up problems without finding solutions.” One has to wonder if “prevalence inflation” and “co-rumination,” if they do exist, may be playing a role in the hotly debated phenomenon some have termed “late-onset gender dysphoria.”
Never having been a fan of mindfulness training as an effective strategy, I am relieved to learn that serious investigators are finding evidence that supports my gut reaction.
If raising awareness, “education,” and group discussion aren’t working, and in some cases are actually contributing to the crisis, or at least making the data difficult to interpret, what should we be doing to turn this foundering ship around?
A second paper, coming from Taiwan, may provide an answer. Huey-Ling Chiang and fellow investigators have reported on a study of nearly two million children and adolescents in which they found improved performance in a variety of physical fitness challenges “was linked with a lower risk of mental health disorder.” The dose-dependent effect resulted in less anxiety and depressive disorders as well as less attention-deficit/hyperactivity disorder when cardio-respiratory, muscle endurance, and power indices improved.
There have been other observers who have suggested a link between physical fitness and improved mental health, but this Taiwanese study is by far one of the largest. And, the discovery of a dose-dependent effect makes it particularly convincing.
As I reviewed these two papers, I became increasingly frustrated because this is another example in which one of the answers is staring us in the face and we continue to do nothing more than talk about it.
We already know that physically active people are healthier both physically and mentally, but we do little more than talk. It may be helpful for some people to become a bit more self-aware. However, it is becoming increasingly clear that you can’t talk yourself into being mentally healthy without a concurrent effort to actually do the things that can improve your overall health, such as being physically active and adopting healthy sleep habits. A political advisor once said, “It’s the economy, stupid.” As a community interested in the health of our children and the adults they will become, we need to remind ourselves again, “It’s the old Mind-Body Thing, Stupid.” Our children need a little less talk and a lot more action.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.
Alcohol to Blame: Weight Regain After Bariatric Surgery
A 50-year-old woman with a history of class 3 obesity, gastroesophageal reflux disease, prediabetes, metabolic dysfunction–associated steatotic liver disease, asthma, and depression returns to our weight management clinic with weight regain 4 years after Roux-en-Y gastric bypass.
Her initial body weight was 389 lb (176.8 kg; body mass index [BMI], 65), and her nadir weight after surgery was 183 lb (83.2 kg; BMI, 30.5), representing a total weight loss of 53%. During the initial 2 years after surgery, she experienced multiple life stressors and was treated with venlafaxine for mild depression. She regained 25 lb (11.4 kg). Over the next 2 years, she gained another 20 lb (9.1 kg), for a total of 45 lb (20.5 kg) above nadir.
The patient reported increased nighttime consumption of alcohol including vodka, wine, and beer of over 20 drinks per week for the past 2 years. Her laboratory profile showed an elevated fasting glucose level (106 mg/dL, formerly 98 mg/dL), an elevated gamma-glutamyl transferase (GGT) level, and iron deficiency anemia. She admitted to regularly missing doses of postbariatric vitamins and minerals.
Ask Patients About Alcohol Use
It’s important to ask patients with significant weight regain after metabolic and bariatric surgery (MBS) about alcohol intake, because patients who have MBS are at an increased risk of developing alcohol use disorder (AUD).
The American Society for Metabolic and Bariatric Surgery recommends screening for alcohol intake both before and after MBS. Underreporting of alcohol consumption is common, but an elevated GGT level or elevated liver enzyme levels can indicate alcohol use. Depression and anxiety exacerbated by life stressors often accompany excessive alcohol intake.
Some antiobesity medications that regulate appetite may also help limit excessive alcohol intake. Naltrexone is used both for the treatment of AUD and for weight management, often in combination with bupropion). In a patient with weight regain and AUD, naltrexone alone would be a reasonable treatment option, although weight loss would probably be modest. The addition of bupropion to naltrexone would probably produce more weight loss; average total body weight loss with bupropion-naltrexone in clinical trials was about 6%. One cautionary note on bupropion: A patient’s seizure history should be elicited, because people with AUD are at increased risk for seizures in the withdrawal stage and bupropion can make those seizures more likely.
Glucagon-like peptide 1 (GLP-1) receptor agonists (eg, liraglutide and semaglutide) and dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide receptor agonists) (eg, tirzepatide) are second-generation antiobesity medications that produce more weight loss than first-generation agents such as bupropion/naltrexone. Of note, prior bariatric surgery was an exclusion criterion in the clinical trials assessing the efficacy of these agents for weight loss. The use of GLP-1 receptor agonists after MBS in people with inadequate weight loss or weight regain has been an area of active research. The BARI-OPTIMISE randomized clinical trial published in 2023 assessed the safety and efficacy of liraglutide 3.0 mg daily in patients with inadequate weight loss after MBS. The mean body weight reduction was 8.82% in the liraglutide group vs 0.54% in the placebo group.
There is also emerging interest in the potential of GLP-1 receptor agonists in AUD. These medications act on the central nervous system to influence reward pathways. In rodents, studies have shown that GLP-1 receptor agonist administration reduces alcohol intake, although most studies have focused on short-term effects.
A series of experiments assessed the effects of semaglutide on alcohol intake in rodents. The authors found that semaglutide lowered the alcohol-induced release of dopamine and enhanced dopamine metabolism within the nucleus accumbens.
Evidence in humans is still limited, with only one published randomized controlled trial to date. In the 26-week study, weekly exenatide was not superior to placebo in reducing the number of heavy drinking days in patients with AUD who also received cognitive-behavioral therapy. An exploratory analysis in a subgroup of patients with obesity and AUD showed that exenatide reduced alcohol consumption. Of note, exenatide is rarely used in clinical practice because it does not produce substantial weight loss.
Liraglutide was chosen for this patient because of the established efficacy for this agent in patients with a history of MBS. In addition, patients often anecdotally report reduced desire for alcohol while taking a GLP-1 receptor agonist. Although GLP-1 receptor agonists have been shown to reduce alcohol intake in animal studies, their efficacy and safety in humans with AUD are not yet well established.
Back to Our Patient:
Given the patient’s weight regain, an upper gastrointestinal series was performed to rule out gastro-gastric fistula or other anatomic abnormalities. After fistula was ruled out, she was prescribed liraglutide for weight management, which was titrated from 0.6 mg/d to 3 mg/d per the prescribing guidelines.
With the use of liraglutide over the next year, the patient maintained a stable weight of 200 lb (90.9 kg) and noted that along with reduced appetite, her cravings for alcohol had diminished and she no longer felt the urge to drink alcohol at night. Her fasting glucose and GGT levels normalized. She began to see a nutritionist regularly and was planning to rejoin a bariatric support group.
Dr. Schmitz is an instructor in the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine, New York. She has disclosed no relevant financial relationships. Dr. Kashyap is a assistant chief of clinical affairs, Division of Endocrinology, Diabetes and Metabolism, Weill Cornell New York Presbyterian, New York. She disclosed ties to GI Dynamics.
A version of this article appeared on Medscape.com.
A 50-year-old woman with a history of class 3 obesity, gastroesophageal reflux disease, prediabetes, metabolic dysfunction–associated steatotic liver disease, asthma, and depression returns to our weight management clinic with weight regain 4 years after Roux-en-Y gastric bypass.
Her initial body weight was 389 lb (176.8 kg; body mass index [BMI], 65), and her nadir weight after surgery was 183 lb (83.2 kg; BMI, 30.5), representing a total weight loss of 53%. During the initial 2 years after surgery, she experienced multiple life stressors and was treated with venlafaxine for mild depression. She regained 25 lb (11.4 kg). Over the next 2 years, she gained another 20 lb (9.1 kg), for a total of 45 lb (20.5 kg) above nadir.
The patient reported increased nighttime consumption of alcohol including vodka, wine, and beer of over 20 drinks per week for the past 2 years. Her laboratory profile showed an elevated fasting glucose level (106 mg/dL, formerly 98 mg/dL), an elevated gamma-glutamyl transferase (GGT) level, and iron deficiency anemia. She admitted to regularly missing doses of postbariatric vitamins and minerals.
Ask Patients About Alcohol Use
It’s important to ask patients with significant weight regain after metabolic and bariatric surgery (MBS) about alcohol intake, because patients who have MBS are at an increased risk of developing alcohol use disorder (AUD).
The American Society for Metabolic and Bariatric Surgery recommends screening for alcohol intake both before and after MBS. Underreporting of alcohol consumption is common, but an elevated GGT level or elevated liver enzyme levels can indicate alcohol use. Depression and anxiety exacerbated by life stressors often accompany excessive alcohol intake.
Some antiobesity medications that regulate appetite may also help limit excessive alcohol intake. Naltrexone is used both for the treatment of AUD and for weight management, often in combination with bupropion). In a patient with weight regain and AUD, naltrexone alone would be a reasonable treatment option, although weight loss would probably be modest. The addition of bupropion to naltrexone would probably produce more weight loss; average total body weight loss with bupropion-naltrexone in clinical trials was about 6%. One cautionary note on bupropion: A patient’s seizure history should be elicited, because people with AUD are at increased risk for seizures in the withdrawal stage and bupropion can make those seizures more likely.
Glucagon-like peptide 1 (GLP-1) receptor agonists (eg, liraglutide and semaglutide) and dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide receptor agonists) (eg, tirzepatide) are second-generation antiobesity medications that produce more weight loss than first-generation agents such as bupropion/naltrexone. Of note, prior bariatric surgery was an exclusion criterion in the clinical trials assessing the efficacy of these agents for weight loss. The use of GLP-1 receptor agonists after MBS in people with inadequate weight loss or weight regain has been an area of active research. The BARI-OPTIMISE randomized clinical trial published in 2023 assessed the safety and efficacy of liraglutide 3.0 mg daily in patients with inadequate weight loss after MBS. The mean body weight reduction was 8.82% in the liraglutide group vs 0.54% in the placebo group.
There is also emerging interest in the potential of GLP-1 receptor agonists in AUD. These medications act on the central nervous system to influence reward pathways. In rodents, studies have shown that GLP-1 receptor agonist administration reduces alcohol intake, although most studies have focused on short-term effects.
A series of experiments assessed the effects of semaglutide on alcohol intake in rodents. The authors found that semaglutide lowered the alcohol-induced release of dopamine and enhanced dopamine metabolism within the nucleus accumbens.
Evidence in humans is still limited, with only one published randomized controlled trial to date. In the 26-week study, weekly exenatide was not superior to placebo in reducing the number of heavy drinking days in patients with AUD who also received cognitive-behavioral therapy. An exploratory analysis in a subgroup of patients with obesity and AUD showed that exenatide reduced alcohol consumption. Of note, exenatide is rarely used in clinical practice because it does not produce substantial weight loss.
Liraglutide was chosen for this patient because of the established efficacy for this agent in patients with a history of MBS. In addition, patients often anecdotally report reduced desire for alcohol while taking a GLP-1 receptor agonist. Although GLP-1 receptor agonists have been shown to reduce alcohol intake in animal studies, their efficacy and safety in humans with AUD are not yet well established.
Back to Our Patient:
Given the patient’s weight regain, an upper gastrointestinal series was performed to rule out gastro-gastric fistula or other anatomic abnormalities. After fistula was ruled out, she was prescribed liraglutide for weight management, which was titrated from 0.6 mg/d to 3 mg/d per the prescribing guidelines.
With the use of liraglutide over the next year, the patient maintained a stable weight of 200 lb (90.9 kg) and noted that along with reduced appetite, her cravings for alcohol had diminished and she no longer felt the urge to drink alcohol at night. Her fasting glucose and GGT levels normalized. She began to see a nutritionist regularly and was planning to rejoin a bariatric support group.
Dr. Schmitz is an instructor in the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine, New York. She has disclosed no relevant financial relationships. Dr. Kashyap is a assistant chief of clinical affairs, Division of Endocrinology, Diabetes and Metabolism, Weill Cornell New York Presbyterian, New York. She disclosed ties to GI Dynamics.
A version of this article appeared on Medscape.com.
A 50-year-old woman with a history of class 3 obesity, gastroesophageal reflux disease, prediabetes, metabolic dysfunction–associated steatotic liver disease, asthma, and depression returns to our weight management clinic with weight regain 4 years after Roux-en-Y gastric bypass.
Her initial body weight was 389 lb (176.8 kg; body mass index [BMI], 65), and her nadir weight after surgery was 183 lb (83.2 kg; BMI, 30.5), representing a total weight loss of 53%. During the initial 2 years after surgery, she experienced multiple life stressors and was treated with venlafaxine for mild depression. She regained 25 lb (11.4 kg). Over the next 2 years, she gained another 20 lb (9.1 kg), for a total of 45 lb (20.5 kg) above nadir.
The patient reported increased nighttime consumption of alcohol including vodka, wine, and beer of over 20 drinks per week for the past 2 years. Her laboratory profile showed an elevated fasting glucose level (106 mg/dL, formerly 98 mg/dL), an elevated gamma-glutamyl transferase (GGT) level, and iron deficiency anemia. She admitted to regularly missing doses of postbariatric vitamins and minerals.
Ask Patients About Alcohol Use
It’s important to ask patients with significant weight regain after metabolic and bariatric surgery (MBS) about alcohol intake, because patients who have MBS are at an increased risk of developing alcohol use disorder (AUD).
The American Society for Metabolic and Bariatric Surgery recommends screening for alcohol intake both before and after MBS. Underreporting of alcohol consumption is common, but an elevated GGT level or elevated liver enzyme levels can indicate alcohol use. Depression and anxiety exacerbated by life stressors often accompany excessive alcohol intake.
Some antiobesity medications that regulate appetite may also help limit excessive alcohol intake. Naltrexone is used both for the treatment of AUD and for weight management, often in combination with bupropion). In a patient with weight regain and AUD, naltrexone alone would be a reasonable treatment option, although weight loss would probably be modest. The addition of bupropion to naltrexone would probably produce more weight loss; average total body weight loss with bupropion-naltrexone in clinical trials was about 6%. One cautionary note on bupropion: A patient’s seizure history should be elicited, because people with AUD are at increased risk for seizures in the withdrawal stage and bupropion can make those seizures more likely.
Glucagon-like peptide 1 (GLP-1) receptor agonists (eg, liraglutide and semaglutide) and dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide receptor agonists) (eg, tirzepatide) are second-generation antiobesity medications that produce more weight loss than first-generation agents such as bupropion/naltrexone. Of note, prior bariatric surgery was an exclusion criterion in the clinical trials assessing the efficacy of these agents for weight loss. The use of GLP-1 receptor agonists after MBS in people with inadequate weight loss or weight regain has been an area of active research. The BARI-OPTIMISE randomized clinical trial published in 2023 assessed the safety and efficacy of liraglutide 3.0 mg daily in patients with inadequate weight loss after MBS. The mean body weight reduction was 8.82% in the liraglutide group vs 0.54% in the placebo group.
There is also emerging interest in the potential of GLP-1 receptor agonists in AUD. These medications act on the central nervous system to influence reward pathways. In rodents, studies have shown that GLP-1 receptor agonist administration reduces alcohol intake, although most studies have focused on short-term effects.
A series of experiments assessed the effects of semaglutide on alcohol intake in rodents. The authors found that semaglutide lowered the alcohol-induced release of dopamine and enhanced dopamine metabolism within the nucleus accumbens.
Evidence in humans is still limited, with only one published randomized controlled trial to date. In the 26-week study, weekly exenatide was not superior to placebo in reducing the number of heavy drinking days in patients with AUD who also received cognitive-behavioral therapy. An exploratory analysis in a subgroup of patients with obesity and AUD showed that exenatide reduced alcohol consumption. Of note, exenatide is rarely used in clinical practice because it does not produce substantial weight loss.
Liraglutide was chosen for this patient because of the established efficacy for this agent in patients with a history of MBS. In addition, patients often anecdotally report reduced desire for alcohol while taking a GLP-1 receptor agonist. Although GLP-1 receptor agonists have been shown to reduce alcohol intake in animal studies, their efficacy and safety in humans with AUD are not yet well established.
Back to Our Patient:
Given the patient’s weight regain, an upper gastrointestinal series was performed to rule out gastro-gastric fistula or other anatomic abnormalities. After fistula was ruled out, she was prescribed liraglutide for weight management, which was titrated from 0.6 mg/d to 3 mg/d per the prescribing guidelines.
With the use of liraglutide over the next year, the patient maintained a stable weight of 200 lb (90.9 kg) and noted that along with reduced appetite, her cravings for alcohol had diminished and she no longer felt the urge to drink alcohol at night. Her fasting glucose and GGT levels normalized. She began to see a nutritionist regularly and was planning to rejoin a bariatric support group.
Dr. Schmitz is an instructor in the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine, New York. She has disclosed no relevant financial relationships. Dr. Kashyap is a assistant chief of clinical affairs, Division of Endocrinology, Diabetes and Metabolism, Weill Cornell New York Presbyterian, New York. She disclosed ties to GI Dynamics.
A version of this article appeared on Medscape.com.
Specialists Are ‘Underwater’ With Some Insurance-Preferred Biosimilars
Editor’s note: This article is adapted from an explanatory statement that Dr. Feldman wrote for the Coalition of State Rheumatology Organizations (CSRO).
According to the Guinness Book of World records, the longest time someone has held their breath underwater voluntarily is 24 minutes and 37.36 seconds. While certainly an amazing feat, UnitedHealthcare, many of the Blues, and other national “payers” are expecting rheumatologists and other specialists to live “underwater” in order to take care of their patients. In other words, these insurance companies are mandating that specialists use certain provider-administered biosimilars whose acquisition cost is higher than what the insurance company is willing to reimburse them. Essentially, the insurance companies expect the rheumatologists to pay them to take care of their patients. Because of the substantial and destabilizing financial losses incurred, many practices and free-standing infusion centers have been forced to cease offering these biosimilars. Most rheumatologists will provide patients with appropriate alternatives when available and permitted by the insurer; otherwise, they must refer patients to hospital-based infusion centers. That results in delayed care and increased costs for patients and the system, because hospital-based infusion typically costs more than twice what office-based infusion costs.
Quantifying the Problem
To help quantify the magnitude of this issue, the Coalition of State Rheumatology Organizations (CSRO) recently conducted a survey of its membership. A shocking 97% of respondents reported that their practice had been affected by reimbursement rates for some biosimilars being lower than acquisition costs, with 91% of respondents stating that this issue is more pronounced for certain biosimilars than others. Across the board, respondents most frequently identified Inflectra (infliximab-dyyb) and Avsola (infliximab-axxq) as being especially affected: Over 88% and over 85% of respondents identified these two products, respectively, as being underwater. These results support the ongoing anecdotal reports CSRO continues to receive from rheumatology practices.
However, the survey results indicated that this issue is by no means confined to those two biosimilars. Truxima (rituximab-abbs) — a biosimilar for Rituxan — was frequently mentioned as well. Notably, respondents almost uniformly identified biosimilars in the infliximab and rituximab families, which illustrates that this issue is no longer confined to one or two early-to-market biosimilars but has almost become a hallmark of this particular biosimilars market. Remarkably, one respondent commented that the brand products are now cheaper to acquire than the biosimilars. Furthermore, the survey included respondents from across the country, indicating that this issue is not confined to a particular region.
How Did This Happen?
Biosimilars held promise for increasing availability and decreasing biologic costs for patients but, thus far, no patients have seen their cost go down. It appears that the only biosimilars that have made it to “preferred” status on the formulary are the ones that have made more money for the middlemen in the drug supply chain, particularly those that construct formularies. Now, we have provider-administered biosimilars whose acquisition cost exceeds the reimbursement for these drugs. This disparity was ultimately created by biosimilar manufacturers “over-rebating” their drugs to health insurance companies to gain “fail-first” status on the formulary.
For example, the manufacturer of Inflectra offered substantial rebates to health insurers for preferred formulary placement. These rebates are factored into the sales price of the medication, which then results in a rapidly declining average sales price (ASP) for the biosimilar. Unfortunately, the acquisition cost for the drug does not experience commensurate reductions, resulting in physicians being reimbursed far less for the drug than it costs to acquire. The financial losses for physicians put them underwater as a result of the acquisition costs for the preferred drugs far surpassing the reimbursement from the health insurance company that constructed the formulary.
While various factors affect ASPs and acquisition costs, this particular consequence of formulary placement based on price concessions is a major driver of the underwater situation in which physicians have found themselves with many biosimilars. Not only does that lead to a lower uptake of biosimilars, but it also results in patients being referred to the hospital outpatient infusion sites to receive this care, as freestanding infusion centers cannot treat these patients either. Hospitals incur higher costs because of facility fees and elevated rates, and this makes private rheumatology in-office infusion centers a much lower-cost option. Similarly, home infusion services, while convenient, are marginally more expensive than private practices and, in cases of biologic infusions, it is important to note that physicians’ offices have a greater safety profile than home infusion of biologics. The overall result of these “fail-first underwater drugs” is delayed and more costly care for the patient and the “system,” particularly self-insured employers.
What Is Being Done to Correct This?
Since ASPs are updated quarterly, it is possible that acquisition costs and reimbursements might stabilize over time, making the drugs affordable again to practices. However, that does not appear to be happening in the near future, so that possibility does not offer immediate relief to struggling practices. It doesn’t promise a favorable outlook for future biosimilar entries of provider-administered medications if formularies continue to prefer the highest-rebated medication.
This dynamic between ASP and acquisition cost does not happen on the pharmacy side because the price concessions on specific drug rebates and fees are proprietary. There appears to be no equivalent to a publicly known ASP on the pharmacy side, which has led to myriad pricing definitions and manipulation on the pharmacy benefit side of medications. In any event, the savings from rebates and other manufacturer price concessions on pharmacy drugs do not influence ASPs of medical benefit drugs.
The Inflation Reduction Act provided a temporary increase in the add-on payment for biosimilars from ASP+6% to ASP+8%, but as long as the biosimilar’s ASP is lower than the reference brand’s ASP, that temporary increase does not appear to make up for the large differential between ASP and acquisition cost. It should be noted that any federal attempt to artificially lower the ASP of a provider-administered drug without a pathway assuring that the acquisition cost for the provider is less than the reimbursement is going to result in loss of access for patients to those medications and/or higher hospital site of care costs.
A Few Partial Fixes, But Most Complaints Go Ignored
Considering the higher costs of hospital-based infusion, insurers should be motivated to keep patients within private practices. Perhaps through insurers’ recognition of that fact, some practices have successfully negotiated exceptions for specific patients by discussing this situation with insurers. From the feedback that CSRO has received from rheumatology practices, it appears that most insurers have been ignoring the complaints from physicians. The few who have responded have resulted in only partial fixes, with some of the biosimilars still left underwater.
Ultimate Solution?
This issue is a direct result of the “rebate game,” whereby price concessions from drug manufacturers drive formulary placement. For provider-administered medications, this results in an artificially lowered ASP, not as a consequence of free-market incentives that benefit the patient, but as a result of misaligned incentives created by Safe Harbor–protected “kickbacks,” distorting the free market and paradoxically reducing access to these medications, delaying care, and increasing prices for patients and the healthcare system.
While federal and state governments are not likely to address this particular situation in the biosimilars market, CSRO is highlighting this issue as a prime example of why the current formulary construction system urgently requires federal reform. At this time, the biosimilars most affected are Inflectra and Avsola, but if nothing changes, more and more biosimilars will fall victim to the short-sighted pricing strategy of aggressive rebating to gain formulary position, with physician purchasers and patients left to navigate the aftermath. The existing system, which necessitates drug companies purchasing formulary access from pharmacy benefit managers, has led to delayed and even denied patient access to certain provider-administered drugs. Moreover, it now appears to be hindering the adoption of biosimilars.
To address this, a multifaceted approach is required. It not only involves reevaluating the rebate system and its impact on formulary construction and ASP, but also ensuring that acquisition costs for providers are aligned with reimbursement rates. Insurers must recognize the economic and clinical value of maintaining infusions within private practices and immediately update their policies to ensure that physician in-office infusion is financially feasible for these “fail-first” biosimilars.
Ultimately, the goal should be to create a sustainable model that promotes the use of affordable biosimilars, enhances patient access to affordable care, and supports the financial viability of medical practices. Concerted efforts to reform the current formulary construction system are required to achieve a healthcare environment that is both cost effective and patient centric.
Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of advocacy and government affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at rhnews@mdedge.com.
Editor’s note: This article is adapted from an explanatory statement that Dr. Feldman wrote for the Coalition of State Rheumatology Organizations (CSRO).
According to the Guinness Book of World records, the longest time someone has held their breath underwater voluntarily is 24 minutes and 37.36 seconds. While certainly an amazing feat, UnitedHealthcare, many of the Blues, and other national “payers” are expecting rheumatologists and other specialists to live “underwater” in order to take care of their patients. In other words, these insurance companies are mandating that specialists use certain provider-administered biosimilars whose acquisition cost is higher than what the insurance company is willing to reimburse them. Essentially, the insurance companies expect the rheumatologists to pay them to take care of their patients. Because of the substantial and destabilizing financial losses incurred, many practices and free-standing infusion centers have been forced to cease offering these biosimilars. Most rheumatologists will provide patients with appropriate alternatives when available and permitted by the insurer; otherwise, they must refer patients to hospital-based infusion centers. That results in delayed care and increased costs for patients and the system, because hospital-based infusion typically costs more than twice what office-based infusion costs.
Quantifying the Problem
To help quantify the magnitude of this issue, the Coalition of State Rheumatology Organizations (CSRO) recently conducted a survey of its membership. A shocking 97% of respondents reported that their practice had been affected by reimbursement rates for some biosimilars being lower than acquisition costs, with 91% of respondents stating that this issue is more pronounced for certain biosimilars than others. Across the board, respondents most frequently identified Inflectra (infliximab-dyyb) and Avsola (infliximab-axxq) as being especially affected: Over 88% and over 85% of respondents identified these two products, respectively, as being underwater. These results support the ongoing anecdotal reports CSRO continues to receive from rheumatology practices.
However, the survey results indicated that this issue is by no means confined to those two biosimilars. Truxima (rituximab-abbs) — a biosimilar for Rituxan — was frequently mentioned as well. Notably, respondents almost uniformly identified biosimilars in the infliximab and rituximab families, which illustrates that this issue is no longer confined to one or two early-to-market biosimilars but has almost become a hallmark of this particular biosimilars market. Remarkably, one respondent commented that the brand products are now cheaper to acquire than the biosimilars. Furthermore, the survey included respondents from across the country, indicating that this issue is not confined to a particular region.
How Did This Happen?
Biosimilars held promise for increasing availability and decreasing biologic costs for patients but, thus far, no patients have seen their cost go down. It appears that the only biosimilars that have made it to “preferred” status on the formulary are the ones that have made more money for the middlemen in the drug supply chain, particularly those that construct formularies. Now, we have provider-administered biosimilars whose acquisition cost exceeds the reimbursement for these drugs. This disparity was ultimately created by biosimilar manufacturers “over-rebating” their drugs to health insurance companies to gain “fail-first” status on the formulary.
For example, the manufacturer of Inflectra offered substantial rebates to health insurers for preferred formulary placement. These rebates are factored into the sales price of the medication, which then results in a rapidly declining average sales price (ASP) for the biosimilar. Unfortunately, the acquisition cost for the drug does not experience commensurate reductions, resulting in physicians being reimbursed far less for the drug than it costs to acquire. The financial losses for physicians put them underwater as a result of the acquisition costs for the preferred drugs far surpassing the reimbursement from the health insurance company that constructed the formulary.
While various factors affect ASPs and acquisition costs, this particular consequence of formulary placement based on price concessions is a major driver of the underwater situation in which physicians have found themselves with many biosimilars. Not only does that lead to a lower uptake of biosimilars, but it also results in patients being referred to the hospital outpatient infusion sites to receive this care, as freestanding infusion centers cannot treat these patients either. Hospitals incur higher costs because of facility fees and elevated rates, and this makes private rheumatology in-office infusion centers a much lower-cost option. Similarly, home infusion services, while convenient, are marginally more expensive than private practices and, in cases of biologic infusions, it is important to note that physicians’ offices have a greater safety profile than home infusion of biologics. The overall result of these “fail-first underwater drugs” is delayed and more costly care for the patient and the “system,” particularly self-insured employers.
What Is Being Done to Correct This?
Since ASPs are updated quarterly, it is possible that acquisition costs and reimbursements might stabilize over time, making the drugs affordable again to practices. However, that does not appear to be happening in the near future, so that possibility does not offer immediate relief to struggling practices. It doesn’t promise a favorable outlook for future biosimilar entries of provider-administered medications if formularies continue to prefer the highest-rebated medication.
This dynamic between ASP and acquisition cost does not happen on the pharmacy side because the price concessions on specific drug rebates and fees are proprietary. There appears to be no equivalent to a publicly known ASP on the pharmacy side, which has led to myriad pricing definitions and manipulation on the pharmacy benefit side of medications. In any event, the savings from rebates and other manufacturer price concessions on pharmacy drugs do not influence ASPs of medical benefit drugs.
The Inflation Reduction Act provided a temporary increase in the add-on payment for biosimilars from ASP+6% to ASP+8%, but as long as the biosimilar’s ASP is lower than the reference brand’s ASP, that temporary increase does not appear to make up for the large differential between ASP and acquisition cost. It should be noted that any federal attempt to artificially lower the ASP of a provider-administered drug without a pathway assuring that the acquisition cost for the provider is less than the reimbursement is going to result in loss of access for patients to those medications and/or higher hospital site of care costs.
A Few Partial Fixes, But Most Complaints Go Ignored
Considering the higher costs of hospital-based infusion, insurers should be motivated to keep patients within private practices. Perhaps through insurers’ recognition of that fact, some practices have successfully negotiated exceptions for specific patients by discussing this situation with insurers. From the feedback that CSRO has received from rheumatology practices, it appears that most insurers have been ignoring the complaints from physicians. The few who have responded have resulted in only partial fixes, with some of the biosimilars still left underwater.
Ultimate Solution?
This issue is a direct result of the “rebate game,” whereby price concessions from drug manufacturers drive formulary placement. For provider-administered medications, this results in an artificially lowered ASP, not as a consequence of free-market incentives that benefit the patient, but as a result of misaligned incentives created by Safe Harbor–protected “kickbacks,” distorting the free market and paradoxically reducing access to these medications, delaying care, and increasing prices for patients and the healthcare system.
While federal and state governments are not likely to address this particular situation in the biosimilars market, CSRO is highlighting this issue as a prime example of why the current formulary construction system urgently requires federal reform. At this time, the biosimilars most affected are Inflectra and Avsola, but if nothing changes, more and more biosimilars will fall victim to the short-sighted pricing strategy of aggressive rebating to gain formulary position, with physician purchasers and patients left to navigate the aftermath. The existing system, which necessitates drug companies purchasing formulary access from pharmacy benefit managers, has led to delayed and even denied patient access to certain provider-administered drugs. Moreover, it now appears to be hindering the adoption of biosimilars.
To address this, a multifaceted approach is required. It not only involves reevaluating the rebate system and its impact on formulary construction and ASP, but also ensuring that acquisition costs for providers are aligned with reimbursement rates. Insurers must recognize the economic and clinical value of maintaining infusions within private practices and immediately update their policies to ensure that physician in-office infusion is financially feasible for these “fail-first” biosimilars.
Ultimately, the goal should be to create a sustainable model that promotes the use of affordable biosimilars, enhances patient access to affordable care, and supports the financial viability of medical practices. Concerted efforts to reform the current formulary construction system are required to achieve a healthcare environment that is both cost effective and patient centric.
Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of advocacy and government affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at rhnews@mdedge.com.
Editor’s note: This article is adapted from an explanatory statement that Dr. Feldman wrote for the Coalition of State Rheumatology Organizations (CSRO).
According to the Guinness Book of World records, the longest time someone has held their breath underwater voluntarily is 24 minutes and 37.36 seconds. While certainly an amazing feat, UnitedHealthcare, many of the Blues, and other national “payers” are expecting rheumatologists and other specialists to live “underwater” in order to take care of their patients. In other words, these insurance companies are mandating that specialists use certain provider-administered biosimilars whose acquisition cost is higher than what the insurance company is willing to reimburse them. Essentially, the insurance companies expect the rheumatologists to pay them to take care of their patients. Because of the substantial and destabilizing financial losses incurred, many practices and free-standing infusion centers have been forced to cease offering these biosimilars. Most rheumatologists will provide patients with appropriate alternatives when available and permitted by the insurer; otherwise, they must refer patients to hospital-based infusion centers. That results in delayed care and increased costs for patients and the system, because hospital-based infusion typically costs more than twice what office-based infusion costs.
Quantifying the Problem
To help quantify the magnitude of this issue, the Coalition of State Rheumatology Organizations (CSRO) recently conducted a survey of its membership. A shocking 97% of respondents reported that their practice had been affected by reimbursement rates for some biosimilars being lower than acquisition costs, with 91% of respondents stating that this issue is more pronounced for certain biosimilars than others. Across the board, respondents most frequently identified Inflectra (infliximab-dyyb) and Avsola (infliximab-axxq) as being especially affected: Over 88% and over 85% of respondents identified these two products, respectively, as being underwater. These results support the ongoing anecdotal reports CSRO continues to receive from rheumatology practices.
However, the survey results indicated that this issue is by no means confined to those two biosimilars. Truxima (rituximab-abbs) — a biosimilar for Rituxan — was frequently mentioned as well. Notably, respondents almost uniformly identified biosimilars in the infliximab and rituximab families, which illustrates that this issue is no longer confined to one or two early-to-market biosimilars but has almost become a hallmark of this particular biosimilars market. Remarkably, one respondent commented that the brand products are now cheaper to acquire than the biosimilars. Furthermore, the survey included respondents from across the country, indicating that this issue is not confined to a particular region.
How Did This Happen?
Biosimilars held promise for increasing availability and decreasing biologic costs for patients but, thus far, no patients have seen their cost go down. It appears that the only biosimilars that have made it to “preferred” status on the formulary are the ones that have made more money for the middlemen in the drug supply chain, particularly those that construct formularies. Now, we have provider-administered biosimilars whose acquisition cost exceeds the reimbursement for these drugs. This disparity was ultimately created by biosimilar manufacturers “over-rebating” their drugs to health insurance companies to gain “fail-first” status on the formulary.
For example, the manufacturer of Inflectra offered substantial rebates to health insurers for preferred formulary placement. These rebates are factored into the sales price of the medication, which then results in a rapidly declining average sales price (ASP) for the biosimilar. Unfortunately, the acquisition cost for the drug does not experience commensurate reductions, resulting in physicians being reimbursed far less for the drug than it costs to acquire. The financial losses for physicians put them underwater as a result of the acquisition costs for the preferred drugs far surpassing the reimbursement from the health insurance company that constructed the formulary.
While various factors affect ASPs and acquisition costs, this particular consequence of formulary placement based on price concessions is a major driver of the underwater situation in which physicians have found themselves with many biosimilars. Not only does that lead to a lower uptake of biosimilars, but it also results in patients being referred to the hospital outpatient infusion sites to receive this care, as freestanding infusion centers cannot treat these patients either. Hospitals incur higher costs because of facility fees and elevated rates, and this makes private rheumatology in-office infusion centers a much lower-cost option. Similarly, home infusion services, while convenient, are marginally more expensive than private practices and, in cases of biologic infusions, it is important to note that physicians’ offices have a greater safety profile than home infusion of biologics. The overall result of these “fail-first underwater drugs” is delayed and more costly care for the patient and the “system,” particularly self-insured employers.
What Is Being Done to Correct This?
Since ASPs are updated quarterly, it is possible that acquisition costs and reimbursements might stabilize over time, making the drugs affordable again to practices. However, that does not appear to be happening in the near future, so that possibility does not offer immediate relief to struggling practices. It doesn’t promise a favorable outlook for future biosimilar entries of provider-administered medications if formularies continue to prefer the highest-rebated medication.
This dynamic between ASP and acquisition cost does not happen on the pharmacy side because the price concessions on specific drug rebates and fees are proprietary. There appears to be no equivalent to a publicly known ASP on the pharmacy side, which has led to myriad pricing definitions and manipulation on the pharmacy benefit side of medications. In any event, the savings from rebates and other manufacturer price concessions on pharmacy drugs do not influence ASPs of medical benefit drugs.
The Inflation Reduction Act provided a temporary increase in the add-on payment for biosimilars from ASP+6% to ASP+8%, but as long as the biosimilar’s ASP is lower than the reference brand’s ASP, that temporary increase does not appear to make up for the large differential between ASP and acquisition cost. It should be noted that any federal attempt to artificially lower the ASP of a provider-administered drug without a pathway assuring that the acquisition cost for the provider is less than the reimbursement is going to result in loss of access for patients to those medications and/or higher hospital site of care costs.
A Few Partial Fixes, But Most Complaints Go Ignored
Considering the higher costs of hospital-based infusion, insurers should be motivated to keep patients within private practices. Perhaps through insurers’ recognition of that fact, some practices have successfully negotiated exceptions for specific patients by discussing this situation with insurers. From the feedback that CSRO has received from rheumatology practices, it appears that most insurers have been ignoring the complaints from physicians. The few who have responded have resulted in only partial fixes, with some of the biosimilars still left underwater.
Ultimate Solution?
This issue is a direct result of the “rebate game,” whereby price concessions from drug manufacturers drive formulary placement. For provider-administered medications, this results in an artificially lowered ASP, not as a consequence of free-market incentives that benefit the patient, but as a result of misaligned incentives created by Safe Harbor–protected “kickbacks,” distorting the free market and paradoxically reducing access to these medications, delaying care, and increasing prices for patients and the healthcare system.
While federal and state governments are not likely to address this particular situation in the biosimilars market, CSRO is highlighting this issue as a prime example of why the current formulary construction system urgently requires federal reform. At this time, the biosimilars most affected are Inflectra and Avsola, but if nothing changes, more and more biosimilars will fall victim to the short-sighted pricing strategy of aggressive rebating to gain formulary position, with physician purchasers and patients left to navigate the aftermath. The existing system, which necessitates drug companies purchasing formulary access from pharmacy benefit managers, has led to delayed and even denied patient access to certain provider-administered drugs. Moreover, it now appears to be hindering the adoption of biosimilars.
To address this, a multifaceted approach is required. It not only involves reevaluating the rebate system and its impact on formulary construction and ASP, but also ensuring that acquisition costs for providers are aligned with reimbursement rates. Insurers must recognize the economic and clinical value of maintaining infusions within private practices and immediately update their policies to ensure that physician in-office infusion is financially feasible for these “fail-first” biosimilars.
Ultimately, the goal should be to create a sustainable model that promotes the use of affordable biosimilars, enhances patient access to affordable care, and supports the financial viability of medical practices. Concerted efforts to reform the current formulary construction system are required to achieve a healthcare environment that is both cost effective and patient centric.
Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of advocacy and government affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at rhnews@mdedge.com.
Unplanned Pregnancy With Weight Loss Drugs: Fact or Fiction?
Claudia* was a charming 27-year-old newlywed. She and her husband wanted to start a family — with one small catch. She had recently gained 30 pounds. During COVID, she and her husband spent 18 months camped out in her parents’ guest room in upstate New York and had eaten their emotions with abandon. They ate when they were happy and ate more when they were sad. They ate when they felt isolated and again when they felt anxious. It didn’t help that her mother was a Culinary Institute–trained amateur chef. They both worked from home and logged long hours on Zoom calls. Because there was no home gym, they replaced their usual fitness club workouts in the city with leisurely strolls around the local lake. When I met her, Claudia categorically refused to entertain the notion of pregnancy until she reached her pre-COVID weight.
At the time, this all seemed quite reasonable to me. We outlined a plan including semaglutide (Wegovy) until she reached her target weight and then a minimum of 2 months off Wegovy prior to conception. We also lined up sessions with a dietitian and trainer and renewed her birth control pill. There was one detail I failed to mention to her: Birth control pills are less effective while on incretin hormones like semaglutide. The reason for my omission is that the medical community at large wasn’t yet aware of this issue.
About 12 weeks into treatment, Claudia had lost 20 of the 30 pounds. She had canceled several appointments with the trainer and dietitian due to work conflicts. She messaged me over the weekend in a panic. Her period was late, and her pregnancy test was positive.
She had three pressing questions for me:
Q: How had this happened while she had taken the birth control pills faithfully?
A: I answered that the scientific reasons for the decrease in efficacy of birth control pills while on semaglutide medications are threefold:
- Weight loss can improve menstrual cycle irregularities and improve fertility. In fact, I have been using semaglutide-like medications to treat polycystic ovary syndrome for decades, well before these medications became mainstream.
- The delayed gastric emptying inherent to incretins leads to decreased absorption of birth control pills.
- Finally, while this did not apply to Claudia, no medicine is particularly efficacious if vomited up shortly after taking. Wegovy is known to cause nausea and vomiting in a sizable percentage of patients.
Q: Would she have a healthy pregnancy given the lingering effects of Wegovy?
A: The short answer is: most likely yes. A review of the package insert revealed something fascinating. It was not strictly contraindicated. It advised doctors to weigh the risks and benefits of the medication during pregnancy. Animal studies have shown that semaglutide increases the risk for fetal death, birth defects, and growth issues, but this is probably due to restrictive eating patterns rather than a direct effect of the medication. A recent study of health records of more than 50,000 women with diabetes who had been inadvertently taking these medications in early pregnancy showed no increase in birth defects when compared with women who took insulin.
Q: What would happen to her weight loss efforts?
A: To address her third concern, I tried to offset the risk for rebound weight gain by stopping Wegovy and giving her metformin in the second and third trimesters. Considered a safe medication in pregnancy, metformin is thought to support weight loss, but it proved to be ineffective against the rebound weight gain from stopping Wegovy. Claudia had not resumed regular exercise and quickly fell into the age-old eating-for-two trap. She gained nearly 50 pounds over the course of her pregnancy.
After a short and unfulfilling attempt at nursing, Claudia restarted Wegovy, this time in conjunction with a Mediterranean meal plan and regular sessions at a fitness club. After losing the pregnancy weight, she has been able to successfully maintain her ideal body weight for the past year, and her baby is perfectly healthy and beautiful.
*Patient’s name changed.
A version of this article appeared on Medscape.com.
Claudia* was a charming 27-year-old newlywed. She and her husband wanted to start a family — with one small catch. She had recently gained 30 pounds. During COVID, she and her husband spent 18 months camped out in her parents’ guest room in upstate New York and had eaten their emotions with abandon. They ate when they were happy and ate more when they were sad. They ate when they felt isolated and again when they felt anxious. It didn’t help that her mother was a Culinary Institute–trained amateur chef. They both worked from home and logged long hours on Zoom calls. Because there was no home gym, they replaced their usual fitness club workouts in the city with leisurely strolls around the local lake. When I met her, Claudia categorically refused to entertain the notion of pregnancy until she reached her pre-COVID weight.
At the time, this all seemed quite reasonable to me. We outlined a plan including semaglutide (Wegovy) until she reached her target weight and then a minimum of 2 months off Wegovy prior to conception. We also lined up sessions with a dietitian and trainer and renewed her birth control pill. There was one detail I failed to mention to her: Birth control pills are less effective while on incretin hormones like semaglutide. The reason for my omission is that the medical community at large wasn’t yet aware of this issue.
About 12 weeks into treatment, Claudia had lost 20 of the 30 pounds. She had canceled several appointments with the trainer and dietitian due to work conflicts. She messaged me over the weekend in a panic. Her period was late, and her pregnancy test was positive.
She had three pressing questions for me:
Q: How had this happened while she had taken the birth control pills faithfully?
A: I answered that the scientific reasons for the decrease in efficacy of birth control pills while on semaglutide medications are threefold:
- Weight loss can improve menstrual cycle irregularities and improve fertility. In fact, I have been using semaglutide-like medications to treat polycystic ovary syndrome for decades, well before these medications became mainstream.
- The delayed gastric emptying inherent to incretins leads to decreased absorption of birth control pills.
- Finally, while this did not apply to Claudia, no medicine is particularly efficacious if vomited up shortly after taking. Wegovy is known to cause nausea and vomiting in a sizable percentage of patients.
Q: Would she have a healthy pregnancy given the lingering effects of Wegovy?
A: The short answer is: most likely yes. A review of the package insert revealed something fascinating. It was not strictly contraindicated. It advised doctors to weigh the risks and benefits of the medication during pregnancy. Animal studies have shown that semaglutide increases the risk for fetal death, birth defects, and growth issues, but this is probably due to restrictive eating patterns rather than a direct effect of the medication. A recent study of health records of more than 50,000 women with diabetes who had been inadvertently taking these medications in early pregnancy showed no increase in birth defects when compared with women who took insulin.
Q: What would happen to her weight loss efforts?
A: To address her third concern, I tried to offset the risk for rebound weight gain by stopping Wegovy and giving her metformin in the second and third trimesters. Considered a safe medication in pregnancy, metformin is thought to support weight loss, but it proved to be ineffective against the rebound weight gain from stopping Wegovy. Claudia had not resumed regular exercise and quickly fell into the age-old eating-for-two trap. She gained nearly 50 pounds over the course of her pregnancy.
After a short and unfulfilling attempt at nursing, Claudia restarted Wegovy, this time in conjunction with a Mediterranean meal plan and regular sessions at a fitness club. After losing the pregnancy weight, she has been able to successfully maintain her ideal body weight for the past year, and her baby is perfectly healthy and beautiful.
*Patient’s name changed.
A version of this article appeared on Medscape.com.
Claudia* was a charming 27-year-old newlywed. She and her husband wanted to start a family — with one small catch. She had recently gained 30 pounds. During COVID, she and her husband spent 18 months camped out in her parents’ guest room in upstate New York and had eaten their emotions with abandon. They ate when they were happy and ate more when they were sad. They ate when they felt isolated and again when they felt anxious. It didn’t help that her mother was a Culinary Institute–trained amateur chef. They both worked from home and logged long hours on Zoom calls. Because there was no home gym, they replaced their usual fitness club workouts in the city with leisurely strolls around the local lake. When I met her, Claudia categorically refused to entertain the notion of pregnancy until she reached her pre-COVID weight.
At the time, this all seemed quite reasonable to me. We outlined a plan including semaglutide (Wegovy) until she reached her target weight and then a minimum of 2 months off Wegovy prior to conception. We also lined up sessions with a dietitian and trainer and renewed her birth control pill. There was one detail I failed to mention to her: Birth control pills are less effective while on incretin hormones like semaglutide. The reason for my omission is that the medical community at large wasn’t yet aware of this issue.
About 12 weeks into treatment, Claudia had lost 20 of the 30 pounds. She had canceled several appointments with the trainer and dietitian due to work conflicts. She messaged me over the weekend in a panic. Her period was late, and her pregnancy test was positive.
She had three pressing questions for me:
Q: How had this happened while she had taken the birth control pills faithfully?
A: I answered that the scientific reasons for the decrease in efficacy of birth control pills while on semaglutide medications are threefold:
- Weight loss can improve menstrual cycle irregularities and improve fertility. In fact, I have been using semaglutide-like medications to treat polycystic ovary syndrome for decades, well before these medications became mainstream.
- The delayed gastric emptying inherent to incretins leads to decreased absorption of birth control pills.
- Finally, while this did not apply to Claudia, no medicine is particularly efficacious if vomited up shortly after taking. Wegovy is known to cause nausea and vomiting in a sizable percentage of patients.
Q: Would she have a healthy pregnancy given the lingering effects of Wegovy?
A: The short answer is: most likely yes. A review of the package insert revealed something fascinating. It was not strictly contraindicated. It advised doctors to weigh the risks and benefits of the medication during pregnancy. Animal studies have shown that semaglutide increases the risk for fetal death, birth defects, and growth issues, but this is probably due to restrictive eating patterns rather than a direct effect of the medication. A recent study of health records of more than 50,000 women with diabetes who had been inadvertently taking these medications in early pregnancy showed no increase in birth defects when compared with women who took insulin.
Q: What would happen to her weight loss efforts?
A: To address her third concern, I tried to offset the risk for rebound weight gain by stopping Wegovy and giving her metformin in the second and third trimesters. Considered a safe medication in pregnancy, metformin is thought to support weight loss, but it proved to be ineffective against the rebound weight gain from stopping Wegovy. Claudia had not resumed regular exercise and quickly fell into the age-old eating-for-two trap. She gained nearly 50 pounds over the course of her pregnancy.
After a short and unfulfilling attempt at nursing, Claudia restarted Wegovy, this time in conjunction with a Mediterranean meal plan and regular sessions at a fitness club. After losing the pregnancy weight, she has been able to successfully maintain her ideal body weight for the past year, and her baby is perfectly healthy and beautiful.
*Patient’s name changed.
A version of this article appeared on Medscape.com.
When Medicine Isn’t the Last Stop
A distant friend and I were recently chatting by email. After years of trying, she’s become a successful author, and decided to leave medicine to focus on the new career.
She’s excited about this, as it’s really what she’s always dreamed of doing, but at the same time feels guilty about it. Leaving medicine for a new career isn’t quite the same as quitting your job as a waitress or insurance salesman. You’ve put a lot of time, and effort, and money, into becoming an attending physician.
I also once dreamed of being a successful writer (amongst other things) but have no complaints about where I landed. I like what I do. Besides, I don’t have her kind of imagination.
It’s a valid point, though. Becoming a doc in practice takes a minimum of 4 years of college and 4 years of medical school. Then you tack on a residency of 3 years (internal medicine) to 7 years (neurosurgery). On top of that many add another 1-2 years for fellowship training. So you’re talking a bare minimum of at least 11 years, ranging up to 17 years.
Then you think of how much money was spent on college and medical school — tuition, living expenses, loan interest, not to mention the emotional toll of the training.
You also have to think that somewhere in there you got a chance to become a doctor while someone else didn’t.
So, I can see why she feels guilty, but she shouldn’t. She’s paid back all her loans, so no one else is left carrying the financial bag. The argument about denying someone else a spot can be kind of flimsy when you don’t know how that person might have turned out (the medical school dropout rate is 15%-18%).
Life is unpredictable. We often don’t really know what we want until we get there, and those journeys are rarely a straight line. That doesn’t mean those years were a waste, they’re just part of the trip — stepping stones to get you to the right place and realize who you really are. They also make these things possible — the experiences add to the background, and give you time and support to make the change.
She joins a group of other physicians who found their calling elsewhere, such as Graham Chapman or Michael Crichton. A nonmedical example is the renowned British astrophysicist, Sir Brian May.
I have no plans to leave medicine for another career. This fall will be 35 years since I started at Creighton Medical School, and I have no regrets. But if others have found something they enjoy more and are successful at, they have nothing to feel guilty about.
Good luck, friend.
Dr. Block has a solo neurology practice in Scottsdale, Arizona.
A distant friend and I were recently chatting by email. After years of trying, she’s become a successful author, and decided to leave medicine to focus on the new career.
She’s excited about this, as it’s really what she’s always dreamed of doing, but at the same time feels guilty about it. Leaving medicine for a new career isn’t quite the same as quitting your job as a waitress or insurance salesman. You’ve put a lot of time, and effort, and money, into becoming an attending physician.
I also once dreamed of being a successful writer (amongst other things) but have no complaints about where I landed. I like what I do. Besides, I don’t have her kind of imagination.
It’s a valid point, though. Becoming a doc in practice takes a minimum of 4 years of college and 4 years of medical school. Then you tack on a residency of 3 years (internal medicine) to 7 years (neurosurgery). On top of that many add another 1-2 years for fellowship training. So you’re talking a bare minimum of at least 11 years, ranging up to 17 years.
Then you think of how much money was spent on college and medical school — tuition, living expenses, loan interest, not to mention the emotional toll of the training.
You also have to think that somewhere in there you got a chance to become a doctor while someone else didn’t.
So, I can see why she feels guilty, but she shouldn’t. She’s paid back all her loans, so no one else is left carrying the financial bag. The argument about denying someone else a spot can be kind of flimsy when you don’t know how that person might have turned out (the medical school dropout rate is 15%-18%).
Life is unpredictable. We often don’t really know what we want until we get there, and those journeys are rarely a straight line. That doesn’t mean those years were a waste, they’re just part of the trip — stepping stones to get you to the right place and realize who you really are. They also make these things possible — the experiences add to the background, and give you time and support to make the change.
She joins a group of other physicians who found their calling elsewhere, such as Graham Chapman or Michael Crichton. A nonmedical example is the renowned British astrophysicist, Sir Brian May.
I have no plans to leave medicine for another career. This fall will be 35 years since I started at Creighton Medical School, and I have no regrets. But if others have found something they enjoy more and are successful at, they have nothing to feel guilty about.
Good luck, friend.
Dr. Block has a solo neurology practice in Scottsdale, Arizona.
A distant friend and I were recently chatting by email. After years of trying, she’s become a successful author, and decided to leave medicine to focus on the new career.
She’s excited about this, as it’s really what she’s always dreamed of doing, but at the same time feels guilty about it. Leaving medicine for a new career isn’t quite the same as quitting your job as a waitress or insurance salesman. You’ve put a lot of time, and effort, and money, into becoming an attending physician.
I also once dreamed of being a successful writer (amongst other things) but have no complaints about where I landed. I like what I do. Besides, I don’t have her kind of imagination.
It’s a valid point, though. Becoming a doc in practice takes a minimum of 4 years of college and 4 years of medical school. Then you tack on a residency of 3 years (internal medicine) to 7 years (neurosurgery). On top of that many add another 1-2 years for fellowship training. So you’re talking a bare minimum of at least 11 years, ranging up to 17 years.
Then you think of how much money was spent on college and medical school — tuition, living expenses, loan interest, not to mention the emotional toll of the training.
You also have to think that somewhere in there you got a chance to become a doctor while someone else didn’t.
So, I can see why she feels guilty, but she shouldn’t. She’s paid back all her loans, so no one else is left carrying the financial bag. The argument about denying someone else a spot can be kind of flimsy when you don’t know how that person might have turned out (the medical school dropout rate is 15%-18%).
Life is unpredictable. We often don’t really know what we want until we get there, and those journeys are rarely a straight line. That doesn’t mean those years were a waste, they’re just part of the trip — stepping stones to get you to the right place and realize who you really are. They also make these things possible — the experiences add to the background, and give you time and support to make the change.
She joins a group of other physicians who found their calling elsewhere, such as Graham Chapman or Michael Crichton. A nonmedical example is the renowned British astrophysicist, Sir Brian May.
I have no plans to leave medicine for another career. This fall will be 35 years since I started at Creighton Medical School, and I have no regrets. But if others have found something they enjoy more and are successful at, they have nothing to feel guilty about.
Good luck, friend.
Dr. Block has a solo neurology practice in Scottsdale, Arizona.
PCP Compensation, Part 4
I have already shared with you that healthcare systems value panel size and productivity when they are considering primary care physician compensation. Your employers also know that the market won’t bear a substantial price increase for the procedure-poor practice style typical of primary care. You know that the relative value unit (RVU) system for calculating complexity of service is time consuming and discourages the inclusion of customer-friendly short visits that could allow an efficient provider to see more patients. Unfortunately, there is little hope that RVUs will become more PCP-friendly in the near future.
However, before leaving the topic of value and moving on to a consideration of quality, I can’t resist sharing some thoughts about efficiency and time management.
First, it must be said that the inexpert development and the clumsy rollout of electronic medical records (EMRs) have struck the biggest blow to the compensation potential and mental health of even the most efficient PCPs. Until that chasm is filled, there will be little progress in improving the efficiency and, consequently, the fair compensation of PCPs.
However, there is a myth that there is a direct correlation between the time spent with the patient and the quality of care. Eighty-five percent of PCPs report they would like to spend more time to get to know their patients. On the other hand, in my experience, really getting to know a patient is a process best done over multiple visits — some long, many of them short. It is unrealistic and inefficient to gain an in-depth understanding of the patient in a single visit.
Yes, one often hears a patient complain “they only spent 5 minutes with me.” While the patient may be technically correct, I contend that the provider’s manner has a major influence on the patient’s perception of the time spent in the exam room.
Was the provider reasonably prompt? In other words did they value my time? Did they appear rushed? Were they aware of my relevant history and prepared to deal with the current situation? In other words, did they do their homework? Did they engage me visually and seem to know what they were talking about? But, most importantly, did they exude sympathy and seem to care? Was I treated in the same manner that they would like to have been treated? If the answer is YES to those questions, then likely the patient could care less about the time spent.
It may seem counterintuitive to some of you, but there is a simple strategy that a provider can employ that will give them more time with the patient and at the same time allow them to claim to the boss that they are lowering the overhead costs. Management consultants often lean heavily on delegation as a more efficient use of resources. However, when the provider takes the patient’s vital signs and gives the injections, this multitasking provides an excellent hands-on opportunity to take the history and get to know the patient better. And, by giving the immunizations the provider is making the clearest statement possible that these vaccines are so important that they administer them personally.
You may have been wondering why I haven’t included the quality of PCP care in a discussion of compensation. It is because I don’t believe anyone has figured out how to do it in a manner that makes sense and is fair. PCPs don’t do procedures on which their success rate can be measured. A PCP’s patient panel almost by definition is going to be a mix of ages with a broad variety of complaints. Do they see enough diabetics to use their panel’s hemoglobin A1cs as a metric, or enough asthmatics to use emergency department visits as a quality-of-care measurement? In pediatrics, the closest we can come to a valid measure may be the provider’s vaccine acceptance rate.
But, then how does one factor in the general health of the community? If I open a practice in an underserved community, can you measure the quality of my care based on how quickly I can improve the metrics when I have no control over the poverty and educational system?
Since we aren’t surgeons, outcomes can’t be used to judge our quality. I’m afraid the only way we can assure quality is to demand evidence of our efforts to keep abreast of the current knowledge in our field and hope that at some level CME credits accumulated translate to the care we provide. A recent study has demonstrated an association between board certification exam board scores and newly trained internists and the care they provide. The patients of the physicians with the top scores had a lower risk of being readmitted to the hospital and were less likely to die in the first seven days of hospitalization.
We now may have come full circle. The fact is that, like it or not, our value to the folks that pay us lies in the number of patients we can bring into the system. To keep our overhead down, we will always be encouraged to see as many patients as we can, or at least be efficient. Even if there were a way to quantify the quality of our care using outcome metrics, the patients will continue to select their providers based on availability, and the professional and consumer-friendly behavior of those providers. The patients’ perception of how good we are at making them feel better may be our strongest argument for better compensation.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.
I have already shared with you that healthcare systems value panel size and productivity when they are considering primary care physician compensation. Your employers also know that the market won’t bear a substantial price increase for the procedure-poor practice style typical of primary care. You know that the relative value unit (RVU) system for calculating complexity of service is time consuming and discourages the inclusion of customer-friendly short visits that could allow an efficient provider to see more patients. Unfortunately, there is little hope that RVUs will become more PCP-friendly in the near future.
However, before leaving the topic of value and moving on to a consideration of quality, I can’t resist sharing some thoughts about efficiency and time management.
First, it must be said that the inexpert development and the clumsy rollout of electronic medical records (EMRs) have struck the biggest blow to the compensation potential and mental health of even the most efficient PCPs. Until that chasm is filled, there will be little progress in improving the efficiency and, consequently, the fair compensation of PCPs.
However, there is a myth that there is a direct correlation between the time spent with the patient and the quality of care. Eighty-five percent of PCPs report they would like to spend more time to get to know their patients. On the other hand, in my experience, really getting to know a patient is a process best done over multiple visits — some long, many of them short. It is unrealistic and inefficient to gain an in-depth understanding of the patient in a single visit.
Yes, one often hears a patient complain “they only spent 5 minutes with me.” While the patient may be technically correct, I contend that the provider’s manner has a major influence on the patient’s perception of the time spent in the exam room.
Was the provider reasonably prompt? In other words did they value my time? Did they appear rushed? Were they aware of my relevant history and prepared to deal with the current situation? In other words, did they do their homework? Did they engage me visually and seem to know what they were talking about? But, most importantly, did they exude sympathy and seem to care? Was I treated in the same manner that they would like to have been treated? If the answer is YES to those questions, then likely the patient could care less about the time spent.
It may seem counterintuitive to some of you, but there is a simple strategy that a provider can employ that will give them more time with the patient and at the same time allow them to claim to the boss that they are lowering the overhead costs. Management consultants often lean heavily on delegation as a more efficient use of resources. However, when the provider takes the patient’s vital signs and gives the injections, this multitasking provides an excellent hands-on opportunity to take the history and get to know the patient better. And, by giving the immunizations the provider is making the clearest statement possible that these vaccines are so important that they administer them personally.
You may have been wondering why I haven’t included the quality of PCP care in a discussion of compensation. It is because I don’t believe anyone has figured out how to do it in a manner that makes sense and is fair. PCPs don’t do procedures on which their success rate can be measured. A PCP’s patient panel almost by definition is going to be a mix of ages with a broad variety of complaints. Do they see enough diabetics to use their panel’s hemoglobin A1cs as a metric, or enough asthmatics to use emergency department visits as a quality-of-care measurement? In pediatrics, the closest we can come to a valid measure may be the provider’s vaccine acceptance rate.
But, then how does one factor in the general health of the community? If I open a practice in an underserved community, can you measure the quality of my care based on how quickly I can improve the metrics when I have no control over the poverty and educational system?
Since we aren’t surgeons, outcomes can’t be used to judge our quality. I’m afraid the only way we can assure quality is to demand evidence of our efforts to keep abreast of the current knowledge in our field and hope that at some level CME credits accumulated translate to the care we provide. A recent study has demonstrated an association between board certification exam board scores and newly trained internists and the care they provide. The patients of the physicians with the top scores had a lower risk of being readmitted to the hospital and were less likely to die in the first seven days of hospitalization.
We now may have come full circle. The fact is that, like it or not, our value to the folks that pay us lies in the number of patients we can bring into the system. To keep our overhead down, we will always be encouraged to see as many patients as we can, or at least be efficient. Even if there were a way to quantify the quality of our care using outcome metrics, the patients will continue to select their providers based on availability, and the professional and consumer-friendly behavior of those providers. The patients’ perception of how good we are at making them feel better may be our strongest argument for better compensation.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.
I have already shared with you that healthcare systems value panel size and productivity when they are considering primary care physician compensation. Your employers also know that the market won’t bear a substantial price increase for the procedure-poor practice style typical of primary care. You know that the relative value unit (RVU) system for calculating complexity of service is time consuming and discourages the inclusion of customer-friendly short visits that could allow an efficient provider to see more patients. Unfortunately, there is little hope that RVUs will become more PCP-friendly in the near future.
However, before leaving the topic of value and moving on to a consideration of quality, I can’t resist sharing some thoughts about efficiency and time management.
First, it must be said that the inexpert development and the clumsy rollout of electronic medical records (EMRs) have struck the biggest blow to the compensation potential and mental health of even the most efficient PCPs. Until that chasm is filled, there will be little progress in improving the efficiency and, consequently, the fair compensation of PCPs.
However, there is a myth that there is a direct correlation between the time spent with the patient and the quality of care. Eighty-five percent of PCPs report they would like to spend more time to get to know their patients. On the other hand, in my experience, really getting to know a patient is a process best done over multiple visits — some long, many of them short. It is unrealistic and inefficient to gain an in-depth understanding of the patient in a single visit.
Yes, one often hears a patient complain “they only spent 5 minutes with me.” While the patient may be technically correct, I contend that the provider’s manner has a major influence on the patient’s perception of the time spent in the exam room.
Was the provider reasonably prompt? In other words did they value my time? Did they appear rushed? Were they aware of my relevant history and prepared to deal with the current situation? In other words, did they do their homework? Did they engage me visually and seem to know what they were talking about? But, most importantly, did they exude sympathy and seem to care? Was I treated in the same manner that they would like to have been treated? If the answer is YES to those questions, then likely the patient could care less about the time spent.
It may seem counterintuitive to some of you, but there is a simple strategy that a provider can employ that will give them more time with the patient and at the same time allow them to claim to the boss that they are lowering the overhead costs. Management consultants often lean heavily on delegation as a more efficient use of resources. However, when the provider takes the patient’s vital signs and gives the injections, this multitasking provides an excellent hands-on opportunity to take the history and get to know the patient better. And, by giving the immunizations the provider is making the clearest statement possible that these vaccines are so important that they administer them personally.
You may have been wondering why I haven’t included the quality of PCP care in a discussion of compensation. It is because I don’t believe anyone has figured out how to do it in a manner that makes sense and is fair. PCPs don’t do procedures on which their success rate can be measured. A PCP’s patient panel almost by definition is going to be a mix of ages with a broad variety of complaints. Do they see enough diabetics to use their panel’s hemoglobin A1cs as a metric, or enough asthmatics to use emergency department visits as a quality-of-care measurement? In pediatrics, the closest we can come to a valid measure may be the provider’s vaccine acceptance rate.
But, then how does one factor in the general health of the community? If I open a practice in an underserved community, can you measure the quality of my care based on how quickly I can improve the metrics when I have no control over the poverty and educational system?
Since we aren’t surgeons, outcomes can’t be used to judge our quality. I’m afraid the only way we can assure quality is to demand evidence of our efforts to keep abreast of the current knowledge in our field and hope that at some level CME credits accumulated translate to the care we provide. A recent study has demonstrated an association between board certification exam board scores and newly trained internists and the care they provide. The patients of the physicians with the top scores had a lower risk of being readmitted to the hospital and were less likely to die in the first seven days of hospitalization.
We now may have come full circle. The fact is that, like it or not, our value to the folks that pay us lies in the number of patients we can bring into the system. To keep our overhead down, we will always be encouraged to see as many patients as we can, or at least be efficient. Even if there were a way to quantify the quality of our care using outcome metrics, the patients will continue to select their providers based on availability, and the professional and consumer-friendly behavior of those providers. The patients’ perception of how good we are at making them feel better may be our strongest argument for better compensation.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.
Nocturnal Hot Flashes and Alzheimer’s Risk
In a recent article in the American Journal of Obstetrics & Gynecology, Rebecca C. Thurston, PhD, and Pauline Maki, PhD, leading scientists in the area of menopause’s impact on brain function, presented data from their assessment of 248 late perimenopausal and postmenopausal women who reported hot flashes, also known as vasomotor symptoms (VMS).
Hot flashes are known to be associated with changes in brain white matter, carotid atherosclerosis, brain function, and memory. Dr. Thurston and colleagues objectively measured VMS over 24 hours, using skin conductance monitoring. Plasma concentrations of Alzheimer’s disease biomarkers, including the amyloid beta 42–to–amyloid beta 40 ratio, were assessed. The mean age of study participants was 59 years, and they experienced a mean of five objective VMS daily.
A key finding was that VMS, particularly those occurring during sleep, were associated with a significantly lower amyloid beta 42–to–beta 40 ratio. This finding suggests that nighttime VMS may be a marker of risk for Alzheimer’s disease.
Previous research has found that menopausal hormone therapy is associated with favorable changes in Alzheimer’s disease biomarkers. Likewise, large observational studies have shown a lower incidence of Alzheimer’s disease among women who initiate hormone therapy in their late perimenopausal or early postmenopausal years and continue such therapy long term.
The findings of this important study by Thurston and colleagues provide further evidence to support the tantalizing possibility that agents that reduce nighttime hot flashes (including hormone therapy) may lower the subsequent incidence of Alzheimer’s disease in high-risk women.
Dr. Kaunitz is a tenured professor and associate chair in the department of obstetrics and gynecology at the University of Florida College of Medicine–Jacksonville, and medical director and director of menopause and gynecologic ultrasound services at the University of Florida Southside Women’s Health, Jacksonville. He disclosed ties to Sumitomo Pharma America, Mithra, Viatris, Bayer, Merck, Mylan (Viatris), and UpToDate.
A version of this article appeared on Medscape.com.
In a recent article in the American Journal of Obstetrics & Gynecology, Rebecca C. Thurston, PhD, and Pauline Maki, PhD, leading scientists in the area of menopause’s impact on brain function, presented data from their assessment of 248 late perimenopausal and postmenopausal women who reported hot flashes, also known as vasomotor symptoms (VMS).
Hot flashes are known to be associated with changes in brain white matter, carotid atherosclerosis, brain function, and memory. Dr. Thurston and colleagues objectively measured VMS over 24 hours, using skin conductance monitoring. Plasma concentrations of Alzheimer’s disease biomarkers, including the amyloid beta 42–to–amyloid beta 40 ratio, were assessed. The mean age of study participants was 59 years, and they experienced a mean of five objective VMS daily.
A key finding was that VMS, particularly those occurring during sleep, were associated with a significantly lower amyloid beta 42–to–beta 40 ratio. This finding suggests that nighttime VMS may be a marker of risk for Alzheimer’s disease.
Previous research has found that menopausal hormone therapy is associated with favorable changes in Alzheimer’s disease biomarkers. Likewise, large observational studies have shown a lower incidence of Alzheimer’s disease among women who initiate hormone therapy in their late perimenopausal or early postmenopausal years and continue such therapy long term.
The findings of this important study by Thurston and colleagues provide further evidence to support the tantalizing possibility that agents that reduce nighttime hot flashes (including hormone therapy) may lower the subsequent incidence of Alzheimer’s disease in high-risk women.
Dr. Kaunitz is a tenured professor and associate chair in the department of obstetrics and gynecology at the University of Florida College of Medicine–Jacksonville, and medical director and director of menopause and gynecologic ultrasound services at the University of Florida Southside Women’s Health, Jacksonville. He disclosed ties to Sumitomo Pharma America, Mithra, Viatris, Bayer, Merck, Mylan (Viatris), and UpToDate.
A version of this article appeared on Medscape.com.
In a recent article in the American Journal of Obstetrics & Gynecology, Rebecca C. Thurston, PhD, and Pauline Maki, PhD, leading scientists in the area of menopause’s impact on brain function, presented data from their assessment of 248 late perimenopausal and postmenopausal women who reported hot flashes, also known as vasomotor symptoms (VMS).
Hot flashes are known to be associated with changes in brain white matter, carotid atherosclerosis, brain function, and memory. Dr. Thurston and colleagues objectively measured VMS over 24 hours, using skin conductance monitoring. Plasma concentrations of Alzheimer’s disease biomarkers, including the amyloid beta 42–to–amyloid beta 40 ratio, were assessed. The mean age of study participants was 59 years, and they experienced a mean of five objective VMS daily.
A key finding was that VMS, particularly those occurring during sleep, were associated with a significantly lower amyloid beta 42–to–beta 40 ratio. This finding suggests that nighttime VMS may be a marker of risk for Alzheimer’s disease.
Previous research has found that menopausal hormone therapy is associated with favorable changes in Alzheimer’s disease biomarkers. Likewise, large observational studies have shown a lower incidence of Alzheimer’s disease among women who initiate hormone therapy in their late perimenopausal or early postmenopausal years and continue such therapy long term.
The findings of this important study by Thurston and colleagues provide further evidence to support the tantalizing possibility that agents that reduce nighttime hot flashes (including hormone therapy) may lower the subsequent incidence of Alzheimer’s disease in high-risk women.
Dr. Kaunitz is a tenured professor and associate chair in the department of obstetrics and gynecology at the University of Florida College of Medicine–Jacksonville, and medical director and director of menopause and gynecologic ultrasound services at the University of Florida Southside Women’s Health, Jacksonville. He disclosed ties to Sumitomo Pharma America, Mithra, Viatris, Bayer, Merck, Mylan (Viatris), and UpToDate.
A version of this article appeared on Medscape.com.
Molecular Classification of Endometrial Carcinomas
Historically, endometrial cancer has been classified as type I or type II. Type I endometrial cancers are typically estrogen driven, low grade, with endometrioid histology, and have a more favorable prognosis. In contrast, type II endometrial cancers are typically high grade, have more aggressive histologies (eg, serous or clear cell), and have a poorer prognosis.1
While this system provides a helpful schema for understanding endometrial cancers, it fails to represent the immense variation of biologic behavior and outcomes in endometrial cancers and oversimplifies what has come to be understood as a complex and molecularly diverse disease.
In 2013, The Cancer Genome Atlas (TCGA) performed genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas. They identified four categories with distinct genetic profiles corresponding to clinical outcomes: 1) DNA polymerase epsilon (POLE) mutated; 2) mismatch repair deficient; 3) copy number high/p53 abnormal; and 4) copy number low/no specific molecular profile.2 By providing both predictive and prognostic information, these molecular features may be incorporated into treatment planning decisions in the future.
The POLE-mutated subtype are endometrial cancers with recurrent mutations in the POLE gene, which is involved in DNA replication and repair. POLE mutations occur in about 5%-10% of endometrial cancers. Despite some more aggressive histopathologic findings (eg, higher grade, deeper myometrial invasion, positive lymphovascular space invasion), recurrences rarely occur, and patients with POLE mutations have the best prognosis of the four molecular subtypes, with a 5-year recurrence-free survival of 92%-100%.3
The mismatch repair–deficient (MMRd) subtype are endometrial cancers with abnormalities in any of the mismatch repair proteins (MLH1, PMS2, MSH2, MSH6). These alterations may result from hereditary or somatic mutations in any of the MMR genes or epigenetic changes in the MLH1 promoter. Germ-line mutations are associated with Lynch syndrome; thus, patients found to have a germ-line mutation in any of the MMR genes necessitate a genetics referral. The MMRd subtype accounts for about 20%-30% of endometrial cancers, and patients with MMRd tumors have an intermediate prognosis, with a 5-year recurrence-free survival of about 70%.3. These tumors are more responsive to the use of immunotherapy checkpoint inhibitors. Two recent landmark trials showed improved outcomes in patients with advanced MMRd endometrial cancer treated with immune checkpoint inhibitors in addition to standard chemotherapy.4,5
The worst prognosis belongs to the copy number high subgroup, which accounts for approximately 10% of endometrial cancers. Five-year recurrence-free survival is ~50%.3 These tumors often contain TP53 mutations and are composed of aggressive histologies, such as serous, clear cell, high-grade endometrioid, and carcinosarcomas. Recent data suggests that human epidermal growth factor receptor 2 (HER2) amplification may also be prevalent in this subgroup.6
Endometrial cancers that lack any of the above alterations fall into the no specific molecular profile (NSMP) or copy number low subgroup. Mutations in other genes, such as PTEN, PIK3CA, CTNNB1, KRAS, and ARID1A, are often present in these tumors. As the most common subtype, this heterogeneous group accounts for about 50% of all endometrial cancers. These tumors frequently comprise endometrioid histology with estrogen and progesterone receptor positivity, high rates of response to hormonal therapy, and an overall intermediate to favorable prognosis, with a 5-year recurrence-free survival of ~75%.3
The use of whole-genome sequencing in TCGA limits the clinical applicability of testing because of the cost and complex methodologies involved. Multiple algorithms have been developed in the interim that approximate TCGA subtypes using relatively less expensive and more widely available testing methods, such as immunohistochemistry and next-generation sequencing. In the ProMisE algorithm, immunohistochemistry for p53 and MMR proteins is used as a surrogate for copy number high and MMRd tumors, respectively, and targeted sequencing is used to identify POLE mutations.7
Full molecular classification of endometrial tumors provides important prognostic information and allows for incorporation into treatment planning. To this end, the new 2023 International Federation of Gynecology and Obstetrics (FIGO) endometrial cancer staging incorporates an option for the addition of molecular subtype, with the stance that it allows for better prognostic prediction.8 While complete molecular classification is not required, it is encouraged. Furthermore, several clinical trials are currently investigating different treatment regimens based on these distinct molecular profiles.
Dr. Haag is a gynecologic oncology fellow in the Department of Obstetrics and Gynecology, University of North Carolina Hospitals, Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. They have no conflicts of interest.
References
1. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecologic Oncology. 1983;15(1):10-17.
2. Kandoth C et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.
3. León-Castillo A et al. Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: Impact on prognosis and benefit from adjuvant therapy. J Clin Oncology. 2020;38(29):3388-3397.
4. Mirza MR et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023;388(23):2145-2158.
5. Eskander RN et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388(23):2159-2170.
6. Talia KL et al. The role of HER2 as a therapeutic biomarker in gynaecological malignancy: Potential for use beyond uterine serous carcinoma. Pathology. 2023;55(1):8-18.
7. Kommoss S et al. Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. Annals Oncology. 2018;29(5):1180-1188.
8. Berek JS et al. FIGO staging of endometrial cancer: 2023. Int J Gynaecol Obstet. 2023;162(2):383-394.
Historically, endometrial cancer has been classified as type I or type II. Type I endometrial cancers are typically estrogen driven, low grade, with endometrioid histology, and have a more favorable prognosis. In contrast, type II endometrial cancers are typically high grade, have more aggressive histologies (eg, serous or clear cell), and have a poorer prognosis.1
While this system provides a helpful schema for understanding endometrial cancers, it fails to represent the immense variation of biologic behavior and outcomes in endometrial cancers and oversimplifies what has come to be understood as a complex and molecularly diverse disease.
In 2013, The Cancer Genome Atlas (TCGA) performed genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas. They identified four categories with distinct genetic profiles corresponding to clinical outcomes: 1) DNA polymerase epsilon (POLE) mutated; 2) mismatch repair deficient; 3) copy number high/p53 abnormal; and 4) copy number low/no specific molecular profile.2 By providing both predictive and prognostic information, these molecular features may be incorporated into treatment planning decisions in the future.
The POLE-mutated subtype are endometrial cancers with recurrent mutations in the POLE gene, which is involved in DNA replication and repair. POLE mutations occur in about 5%-10% of endometrial cancers. Despite some more aggressive histopathologic findings (eg, higher grade, deeper myometrial invasion, positive lymphovascular space invasion), recurrences rarely occur, and patients with POLE mutations have the best prognosis of the four molecular subtypes, with a 5-year recurrence-free survival of 92%-100%.3
The mismatch repair–deficient (MMRd) subtype are endometrial cancers with abnormalities in any of the mismatch repair proteins (MLH1, PMS2, MSH2, MSH6). These alterations may result from hereditary or somatic mutations in any of the MMR genes or epigenetic changes in the MLH1 promoter. Germ-line mutations are associated with Lynch syndrome; thus, patients found to have a germ-line mutation in any of the MMR genes necessitate a genetics referral. The MMRd subtype accounts for about 20%-30% of endometrial cancers, and patients with MMRd tumors have an intermediate prognosis, with a 5-year recurrence-free survival of about 70%.3. These tumors are more responsive to the use of immunotherapy checkpoint inhibitors. Two recent landmark trials showed improved outcomes in patients with advanced MMRd endometrial cancer treated with immune checkpoint inhibitors in addition to standard chemotherapy.4,5
The worst prognosis belongs to the copy number high subgroup, which accounts for approximately 10% of endometrial cancers. Five-year recurrence-free survival is ~50%.3 These tumors often contain TP53 mutations and are composed of aggressive histologies, such as serous, clear cell, high-grade endometrioid, and carcinosarcomas. Recent data suggests that human epidermal growth factor receptor 2 (HER2) amplification may also be prevalent in this subgroup.6
Endometrial cancers that lack any of the above alterations fall into the no specific molecular profile (NSMP) or copy number low subgroup. Mutations in other genes, such as PTEN, PIK3CA, CTNNB1, KRAS, and ARID1A, are often present in these tumors. As the most common subtype, this heterogeneous group accounts for about 50% of all endometrial cancers. These tumors frequently comprise endometrioid histology with estrogen and progesterone receptor positivity, high rates of response to hormonal therapy, and an overall intermediate to favorable prognosis, with a 5-year recurrence-free survival of ~75%.3
The use of whole-genome sequencing in TCGA limits the clinical applicability of testing because of the cost and complex methodologies involved. Multiple algorithms have been developed in the interim that approximate TCGA subtypes using relatively less expensive and more widely available testing methods, such as immunohistochemistry and next-generation sequencing. In the ProMisE algorithm, immunohistochemistry for p53 and MMR proteins is used as a surrogate for copy number high and MMRd tumors, respectively, and targeted sequencing is used to identify POLE mutations.7
Full molecular classification of endometrial tumors provides important prognostic information and allows for incorporation into treatment planning. To this end, the new 2023 International Federation of Gynecology and Obstetrics (FIGO) endometrial cancer staging incorporates an option for the addition of molecular subtype, with the stance that it allows for better prognostic prediction.8 While complete molecular classification is not required, it is encouraged. Furthermore, several clinical trials are currently investigating different treatment regimens based on these distinct molecular profiles.
Dr. Haag is a gynecologic oncology fellow in the Department of Obstetrics and Gynecology, University of North Carolina Hospitals, Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. They have no conflicts of interest.
References
1. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecologic Oncology. 1983;15(1):10-17.
2. Kandoth C et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.
3. León-Castillo A et al. Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: Impact on prognosis and benefit from adjuvant therapy. J Clin Oncology. 2020;38(29):3388-3397.
4. Mirza MR et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023;388(23):2145-2158.
5. Eskander RN et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388(23):2159-2170.
6. Talia KL et al. The role of HER2 as a therapeutic biomarker in gynaecological malignancy: Potential for use beyond uterine serous carcinoma. Pathology. 2023;55(1):8-18.
7. Kommoss S et al. Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. Annals Oncology. 2018;29(5):1180-1188.
8. Berek JS et al. FIGO staging of endometrial cancer: 2023. Int J Gynaecol Obstet. 2023;162(2):383-394.
Historically, endometrial cancer has been classified as type I or type II. Type I endometrial cancers are typically estrogen driven, low grade, with endometrioid histology, and have a more favorable prognosis. In contrast, type II endometrial cancers are typically high grade, have more aggressive histologies (eg, serous or clear cell), and have a poorer prognosis.1
While this system provides a helpful schema for understanding endometrial cancers, it fails to represent the immense variation of biologic behavior and outcomes in endometrial cancers and oversimplifies what has come to be understood as a complex and molecularly diverse disease.
In 2013, The Cancer Genome Atlas (TCGA) performed genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas. They identified four categories with distinct genetic profiles corresponding to clinical outcomes: 1) DNA polymerase epsilon (POLE) mutated; 2) mismatch repair deficient; 3) copy number high/p53 abnormal; and 4) copy number low/no specific molecular profile.2 By providing both predictive and prognostic information, these molecular features may be incorporated into treatment planning decisions in the future.
The POLE-mutated subtype are endometrial cancers with recurrent mutations in the POLE gene, which is involved in DNA replication and repair. POLE mutations occur in about 5%-10% of endometrial cancers. Despite some more aggressive histopathologic findings (eg, higher grade, deeper myometrial invasion, positive lymphovascular space invasion), recurrences rarely occur, and patients with POLE mutations have the best prognosis of the four molecular subtypes, with a 5-year recurrence-free survival of 92%-100%.3
The mismatch repair–deficient (MMRd) subtype are endometrial cancers with abnormalities in any of the mismatch repair proteins (MLH1, PMS2, MSH2, MSH6). These alterations may result from hereditary or somatic mutations in any of the MMR genes or epigenetic changes in the MLH1 promoter. Germ-line mutations are associated with Lynch syndrome; thus, patients found to have a germ-line mutation in any of the MMR genes necessitate a genetics referral. The MMRd subtype accounts for about 20%-30% of endometrial cancers, and patients with MMRd tumors have an intermediate prognosis, with a 5-year recurrence-free survival of about 70%.3. These tumors are more responsive to the use of immunotherapy checkpoint inhibitors. Two recent landmark trials showed improved outcomes in patients with advanced MMRd endometrial cancer treated with immune checkpoint inhibitors in addition to standard chemotherapy.4,5
The worst prognosis belongs to the copy number high subgroup, which accounts for approximately 10% of endometrial cancers. Five-year recurrence-free survival is ~50%.3 These tumors often contain TP53 mutations and are composed of aggressive histologies, such as serous, clear cell, high-grade endometrioid, and carcinosarcomas. Recent data suggests that human epidermal growth factor receptor 2 (HER2) amplification may also be prevalent in this subgroup.6
Endometrial cancers that lack any of the above alterations fall into the no specific molecular profile (NSMP) or copy number low subgroup. Mutations in other genes, such as PTEN, PIK3CA, CTNNB1, KRAS, and ARID1A, are often present in these tumors. As the most common subtype, this heterogeneous group accounts for about 50% of all endometrial cancers. These tumors frequently comprise endometrioid histology with estrogen and progesterone receptor positivity, high rates of response to hormonal therapy, and an overall intermediate to favorable prognosis, with a 5-year recurrence-free survival of ~75%.3
The use of whole-genome sequencing in TCGA limits the clinical applicability of testing because of the cost and complex methodologies involved. Multiple algorithms have been developed in the interim that approximate TCGA subtypes using relatively less expensive and more widely available testing methods, such as immunohistochemistry and next-generation sequencing. In the ProMisE algorithm, immunohistochemistry for p53 and MMR proteins is used as a surrogate for copy number high and MMRd tumors, respectively, and targeted sequencing is used to identify POLE mutations.7
Full molecular classification of endometrial tumors provides important prognostic information and allows for incorporation into treatment planning. To this end, the new 2023 International Federation of Gynecology and Obstetrics (FIGO) endometrial cancer staging incorporates an option for the addition of molecular subtype, with the stance that it allows for better prognostic prediction.8 While complete molecular classification is not required, it is encouraged. Furthermore, several clinical trials are currently investigating different treatment regimens based on these distinct molecular profiles.
Dr. Haag is a gynecologic oncology fellow in the Department of Obstetrics and Gynecology, University of North Carolina Hospitals, Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. They have no conflicts of interest.
References
1. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecologic Oncology. 1983;15(1):10-17.
2. Kandoth C et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.
3. León-Castillo A et al. Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: Impact on prognosis and benefit from adjuvant therapy. J Clin Oncology. 2020;38(29):3388-3397.
4. Mirza MR et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023;388(23):2145-2158.
5. Eskander RN et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388(23):2159-2170.
6. Talia KL et al. The role of HER2 as a therapeutic biomarker in gynaecological malignancy: Potential for use beyond uterine serous carcinoma. Pathology. 2023;55(1):8-18.
7. Kommoss S et al. Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. Annals Oncology. 2018;29(5):1180-1188.
8. Berek JS et al. FIGO staging of endometrial cancer: 2023. Int J Gynaecol Obstet. 2023;162(2):383-394.