Breast cancer is the second most common malignancy in women (after primary skin cancer) and is the second leading cause of cancer-related death in this population. In 2020, the American Cancer Society reported an estimated 276,480 new breast cancer diagnoses and 42,170 breast cancer–related deaths.¹ Despite the fact that routine screening with mammography and sonography is standard, the incidence of advanced breast cancer at the time of diagnosis has remained stable over time, suggesting that life-threatening breast cancers are not being caught at an earlier stage. The number of breast cancers with distant metastases at the time of diagnosis also has not decreased.² Therefore, although screening tests are valuable, they are imperfect and not without limitations.

Cutaneous metastasis is defined as the spread of malignant cells from an internal neoplasm to the skin, which can occur either by contiguous invasion or by distant metastasis through hematogenous or lymphatic routes.³ The diagnosis of cutaneous metastasis requires a high index of suspicion on the part of the clinician.⁴ Of the various internal malignancies in women, breast cancer most frequently results in metastasis to the skin,⁵ with up to 24% of patients with metastatic breast cancer developing cutaneous lesions.⁶

In recent years, there have been multiple reports of skin lesions prompting the diagnosis of a previously unknown breast cancer. In a study by Lookingbill et al,⁶ 6.3% of patients with breast cancer presented with cutaneous involvement at the time of diagnosis, with 3.5% having skin symptoms as the presenting sign. Although there have been studies analyzing cutaneous metastasis from various internal malignancies, none thus far have focused on cutaneous metastasis as a presenting sign of breast cancer. This systematic review aimed to highlight the diverse clinical presentations of cutaneous metastatic breast cancer and their clinical implications.

Methods

Study Selection
This study utilized the PRISMA guidelines for systematic reviews.⁷ A review of the literature was conducted using the following databases: MEDLINE/PubMed, EMBASE, Cochrane library, CINAHL, and EBSCO.

Search Strategy and Analysis
We completed our search of each of the databases on December 16, 2017, using the phrases cutaneous metastasis and breast cancer to find relevant case reports and retrospective studies. Three authors (C.J., S.R., and M.A.) manually reviewed the resulting abstracts. If an abstract did not include enough information to determine inclusion, the full-text version was reviewed by 2 of the authors (C.J. and S.R.). Two of the authors (C.J. and M.A.) also assessed each source for relevancy and included the articles deemed eligible (Figure 1).

For a retrospective review to be included, it must have specified the number of breast cancer cases and the number of cutaneous metastases presenting initially or simultaneously to the breast cancer diagnosis. Bansal et al⁸ defined a simultaneous diagnosis as a skin lesion presenting with other concerns associated with the primary malignancy.

Results

The initial search of MEDLINE/PubMed, EMBASE, Cochrane library, CINAHL, and EBSCO yielded a total of 722 articles. Seven other articles found separately while undergoing our initial research were added to this total. Abstracts were manually screened, with 657 articles discarded after failing to meet the predetermined inclusion criteria. After removal of 25 duplicate articles, the full text of the remaining 47 articles were reviewed, leading to the elimination of an additional 11 articles that did not meet the necessary criteria. This resulted in 36 articles (Figure 1), including 27 individual case reports (Table 1) and 9 retrospective reviews (Table 2). Approximately 13.7% of patients in the 9 retrospective reviews presented with a skin lesion before or simultaneous to the diagnosis of breast cancer (Figure 2).

Forty-one percent (17/41) of the patients with cutaneous metastasis as a presenting feature of their breast cancer fell outside the age range for breast cancer screening recommended by the US Preventive Services Task Force,⁴² with 24% of the patients younger than 50 years and 17% older than 74 years (Figure 3).

Comment

Our systematic review demonstrated that cutaneous lesions may be the first clinical manifestation of an undetected primary malignancy.⁴⁰ These lesions often occur on the chest but may involve the face, abdomen, or extremities. Although asymptomatic erythematous nodules and plaques are the most common clinical presentations, lesions may be tender or pruritic or may even resemble benign skin conditions, including dermatitis, cellulitis, urticaria, and papulovesicular eruptions, causing them to go unrecognized.

Nevertheless, cutaneous metastasis of a visceral malignancy generally is observed late in the disease course, often following the diagnosis of a primary malignancy.¹⁴ Breast cancer is the most common internal malignancy to feature cutaneous spread, with the largest case series revealing a 23.9% rate of cutaneous metastases in females with breast carcinoma.⁶ Because of its proximity, the chest wall is the most common location for cutaneous lesions of metastatic breast cancer.

Malignant cells from a primary breast tumor may spread to the skin via lymphatic, hematogenous, or contiguous tissue dissemination, as well as iatrogenically through direct implantation during surgical procedures.³ The mechanism of neoplasm spread may likewise influence the clinical appearance of the resulting lesions. The localized lymphedema with a peau d’orange appearance of inflammatory metastatic breast carcinoma or the erythematous plaques of carcinoma erysipeloides are caused by embolized tumor cells obstructing dermal lymphatic vessels.^3,11 On the other hand, the indurated erythematous plaques of carcinoma en cuirasse are caused by diffuse cutaneous and subcutaneous infiltration of tumor cells that also may be associated with marked reduction in breast volume.³

A primary breast cancer is classically diagnosed with a combination of clinical breast examination, radiologic imaging (ultrasound, mammogram, breast magnetic resonance imaging, or computed tomography), and fine-needle aspiration or lesional biopsy with histopathology.⁹ Given that in 20% of metastasized breast cancers the primary tumor may not be identified, a negative breast examination and imaging do not rule out breast cancer, especially if cutaneous biopsy reveals a primary malignancy.⁴³ Histopathology and immunohistochemistry can thereby confirm the presence of metastatic cutaneous lesions and help characterize the breast cancer type involved, with adenocarcinomas being most commonly implicated.²⁸ Although both ductal and lobular adenocarcinomas stain positive for cytokeratin 7, estrogen receptor, progesterone receptor, gross cystic disease fluid protein 15, carcinoembryonic antigen, and mammaglobin, only the former shows positivity for e-cadherin markers.³ Conversely, inflammatory carcinoma stains positive for CD31 and podoplanin, telangiectatic carcinoma stains positive for CD31, and mammary Paget disease stains positive for cytokeratin 7 and mucin 1, cell surface associated.³ Apart from cutaneous biopsy, fine-needle aspiration cytology can likewise provide a simple and rapid method of diagnosis with high sensitivity and specificity.¹⁴

Conclusion

Although cutaneous metastasis as the presenting sign of a breast malignancy is rare, a high index of suspicion should be exercised when encountering rapid-onset, out-of-place nodules or plaques in female patients, particularly nodules or plaques presenting on the chest.

Breast cancer is the second most common malignancy in women (after primary skin cancer) and is the second leading cause of cancer-related death in this population. In 2020, the American Cancer Society reported an estimated 276,480 new breast cancer diagnoses and 42,170 breast cancer–related deaths.¹ Despite the fact that routine screening with mammography and sonography is standard, the incidence of advanced breast cancer at the time of diagnosis has remained stable over time, suggesting that life-threatening breast cancers are not being caught at an earlier stage. The number of breast cancers with distant metastases at the time of diagnosis also has not decreased.² Therefore, although screening tests are valuable, they are imperfect and not without limitations.

Cutaneous metastasis is defined as the spread of malignant cells from an internal neoplasm to the skin, which can occur either by contiguous invasion or by distant metastasis through hematogenous or lymphatic routes.³ The diagnosis of cutaneous metastasis requires a high index of suspicion on the part of the clinician.⁴ Of the various internal malignancies in women, breast cancer most frequently results in metastasis to the skin,⁵ with up to 24% of patients with metastatic breast cancer developing cutaneous lesions.⁶

In recent years, there have been multiple reports of skin lesions prompting the diagnosis of a previously unknown breast cancer. In a study by Lookingbill et al,⁶ 6.3% of patients with breast cancer presented with cutaneous involvement at the time of diagnosis, with 3.5% having skin symptoms as the presenting sign. Although there have been studies analyzing cutaneous metastasis from various internal malignancies, none thus far have focused on cutaneous metastasis as a presenting sign of breast cancer. This systematic review aimed to highlight the diverse clinical presentations of cutaneous metastatic breast cancer and their clinical implications.

Methods

Study Selection
This study utilized the PRISMA guidelines for systematic reviews.⁷ A review of the literature was conducted using the following databases: MEDLINE/PubMed, EMBASE, Cochrane library, CINAHL, and EBSCO.

Search Strategy and Analysis
We completed our search of each of the databases on December 16, 2017, using the phrases cutaneous metastasis and breast cancer to find relevant case reports and retrospective studies. Three authors (C.J., S.R., and M.A.) manually reviewed the resulting abstracts. If an abstract did not include enough information to determine inclusion, the full-text version was reviewed by 2 of the authors (C.J. and S.R.). Two of the authors (C.J. and M.A.) also assessed each source for relevancy and included the articles deemed eligible (Figure 1).

For a retrospective review to be included, it must have specified the number of breast cancer cases and the number of cutaneous metastases presenting initially or simultaneously to the breast cancer diagnosis. Bansal et al⁸ defined a simultaneous diagnosis as a skin lesion presenting with other concerns associated with the primary malignancy.

Results

The initial search of MEDLINE/PubMed, EMBASE, Cochrane library, CINAHL, and EBSCO yielded a total of 722 articles. Seven other articles found separately while undergoing our initial research were added to this total. Abstracts were manually screened, with 657 articles discarded after failing to meet the predetermined inclusion criteria. After removal of 25 duplicate articles, the full text of the remaining 47 articles were reviewed, leading to the elimination of an additional 11 articles that did not meet the necessary criteria. This resulted in 36 articles (Figure 1), including 27 individual case reports (Table 1) and 9 retrospective reviews (Table 2). Approximately 13.7% of patients in the 9 retrospective reviews presented with a skin lesion before or simultaneous to the diagnosis of breast cancer (Figure 2).

Forty-one percent (17/41) of the patients with cutaneous metastasis as a presenting feature of their breast cancer fell outside the age range for breast cancer screening recommended by the US Preventive Services Task Force,⁴² with 24% of the patients younger than 50 years and 17% older than 74 years (Figure 3).

Comment

Our systematic review demonstrated that cutaneous lesions may be the first clinical manifestation of an undetected primary malignancy.⁴⁰ These lesions often occur on the chest but may involve the face, abdomen, or extremities. Although asymptomatic erythematous nodules and plaques are the most common clinical presentations, lesions may be tender or pruritic or may even resemble benign skin conditions, including dermatitis, cellulitis, urticaria, and papulovesicular eruptions, causing them to go unrecognized.

Nevertheless, cutaneous metastasis of a visceral malignancy generally is observed late in the disease course, often following the diagnosis of a primary malignancy.¹⁴ Breast cancer is the most common internal malignancy to feature cutaneous spread, with the largest case series revealing a 23.9% rate of cutaneous metastases in females with breast carcinoma.⁶ Because of its proximity, the chest wall is the most common location for cutaneous lesions of metastatic breast cancer.

Malignant cells from a primary breast tumor may spread to the skin via lymphatic, hematogenous, or contiguous tissue dissemination, as well as iatrogenically through direct implantation during surgical procedures.³ The mechanism of neoplasm spread may likewise influence the clinical appearance of the resulting lesions. The localized lymphedema with a peau d’orange appearance of inflammatory metastatic breast carcinoma or the erythematous plaques of carcinoma erysipeloides are caused by embolized tumor cells obstructing dermal lymphatic vessels.^3,11 On the other hand, the indurated erythematous plaques of carcinoma en cuirasse are caused by diffuse cutaneous and subcutaneous infiltration of tumor cells that also may be associated with marked reduction in breast volume.³

A primary breast cancer is classically diagnosed with a combination of clinical breast examination, radiologic imaging (ultrasound, mammogram, breast magnetic resonance imaging, or computed tomography), and fine-needle aspiration or lesional biopsy with histopathology.⁹ Given that in 20% of metastasized breast cancers the primary tumor may not be identified, a negative breast examination and imaging do not rule out breast cancer, especially if cutaneous biopsy reveals a primary malignancy.⁴³ Histopathology and immunohistochemistry can thereby confirm the presence of metastatic cutaneous lesions and help characterize the breast cancer type involved, with adenocarcinomas being most commonly implicated.²⁸ Although both ductal and lobular adenocarcinomas stain positive for cytokeratin 7, estrogen receptor, progesterone receptor, gross cystic disease fluid protein 15, carcinoembryonic antigen, and mammaglobin, only the former shows positivity for e-cadherin markers.³ Conversely, inflammatory carcinoma stains positive for CD31 and podoplanin, telangiectatic carcinoma stains positive for CD31, and mammary Paget disease stains positive for cytokeratin 7 and mucin 1, cell surface associated.³ Apart from cutaneous biopsy, fine-needle aspiration cytology can likewise provide a simple and rapid method of diagnosis with high sensitivity and specificity.¹⁴

Conclusion

Although cutaneous metastasis as the presenting sign of a breast malignancy is rare, a high index of suspicion should be exercised when encountering rapid-onset, out-of-place nodules or plaques in female patients, particularly nodules or plaques presenting on the chest.

Breast cancer is the second most common malignancy in women (after primary skin cancer) and is the second leading cause of cancer-related death in this population. In 2020, the American Cancer Society reported an estimated 276,480 new breast cancer diagnoses and 42,170 breast cancer–related deaths.¹ Despite the fact that routine screening with mammography and sonography is standard, the incidence of advanced breast cancer at the time of diagnosis has remained stable over time, suggesting that life-threatening breast cancers are not being caught at an earlier stage. The number of breast cancers with distant metastases at the time of diagnosis also has not decreased.² Therefore, although screening tests are valuable, they are imperfect and not without limitations.

Cutaneous metastasis is defined as the spread of malignant cells from an internal neoplasm to the skin, which can occur either by contiguous invasion or by distant metastasis through hematogenous or lymphatic routes.³ The diagnosis of cutaneous metastasis requires a high index of suspicion on the part of the clinician.⁴ Of the various internal malignancies in women, breast cancer most frequently results in metastasis to the skin,⁵ with up to 24% of patients with metastatic breast cancer developing cutaneous lesions.⁶

In recent years, there have been multiple reports of skin lesions prompting the diagnosis of a previously unknown breast cancer. In a study by Lookingbill et al,⁶ 6.3% of patients with breast cancer presented with cutaneous involvement at the time of diagnosis, with 3.5% having skin symptoms as the presenting sign. Although there have been studies analyzing cutaneous metastasis from various internal malignancies, none thus far have focused on cutaneous metastasis as a presenting sign of breast cancer. This systematic review aimed to highlight the diverse clinical presentations of cutaneous metastatic breast cancer and their clinical implications.

Methods

Study Selection
This study utilized the PRISMA guidelines for systematic reviews.⁷ A review of the literature was conducted using the following databases: MEDLINE/PubMed, EMBASE, Cochrane library, CINAHL, and EBSCO.

Search Strategy and Analysis
We completed our search of each of the databases on December 16, 2017, using the phrases cutaneous metastasis and breast cancer to find relevant case reports and retrospective studies. Three authors (C.J., S.R., and M.A.) manually reviewed the resulting abstracts. If an abstract did not include enough information to determine inclusion, the full-text version was reviewed by 2 of the authors (C.J. and S.R.). Two of the authors (C.J. and M.A.) also assessed each source for relevancy and included the articles deemed eligible (Figure 1).

For a retrospective review to be included, it must have specified the number of breast cancer cases and the number of cutaneous metastases presenting initially or simultaneously to the breast cancer diagnosis. Bansal et al⁸ defined a simultaneous diagnosis as a skin lesion presenting with other concerns associated with the primary malignancy.

Results

The initial search of MEDLINE/PubMed, EMBASE, Cochrane library, CINAHL, and EBSCO yielded a total of 722 articles. Seven other articles found separately while undergoing our initial research were added to this total. Abstracts were manually screened, with 657 articles discarded after failing to meet the predetermined inclusion criteria. After removal of 25 duplicate articles, the full text of the remaining 47 articles were reviewed, leading to the elimination of an additional 11 articles that did not meet the necessary criteria. This resulted in 36 articles (Figure 1), including 27 individual case reports (Table 1) and 9 retrospective reviews (Table 2). Approximately 13.7% of patients in the 9 retrospective reviews presented with a skin lesion before or simultaneous to the diagnosis of breast cancer (Figure 2).

Forty-one percent (17/41) of the patients with cutaneous metastasis as a presenting feature of their breast cancer fell outside the age range for breast cancer screening recommended by the US Preventive Services Task Force,⁴² with 24% of the patients younger than 50 years and 17% older than 74 years (Figure 3).

Comment

Our systematic review demonstrated that cutaneous lesions may be the first clinical manifestation of an undetected primary malignancy.⁴⁰ These lesions often occur on the chest but may involve the face, abdomen, or extremities. Although asymptomatic erythematous nodules and plaques are the most common clinical presentations, lesions may be tender or pruritic or may even resemble benign skin conditions, including dermatitis, cellulitis, urticaria, and papulovesicular eruptions, causing them to go unrecognized.

Nevertheless, cutaneous metastasis of a visceral malignancy generally is observed late in the disease course, often following the diagnosis of a primary malignancy.¹⁴ Breast cancer is the most common internal malignancy to feature cutaneous spread, with the largest case series revealing a 23.9% rate of cutaneous metastases in females with breast carcinoma.⁶ Because of its proximity, the chest wall is the most common location for cutaneous lesions of metastatic breast cancer.

Malignant cells from a primary breast tumor may spread to the skin via lymphatic, hematogenous, or contiguous tissue dissemination, as well as iatrogenically through direct implantation during surgical procedures.³ The mechanism of neoplasm spread may likewise influence the clinical appearance of the resulting lesions. The localized lymphedema with a peau d’orange appearance of inflammatory metastatic breast carcinoma or the erythematous plaques of carcinoma erysipeloides are caused by embolized tumor cells obstructing dermal lymphatic vessels.^3,11 On the other hand, the indurated erythematous plaques of carcinoma en cuirasse are caused by diffuse cutaneous and subcutaneous infiltration of tumor cells that also may be associated with marked reduction in breast volume.³

A primary breast cancer is classically diagnosed with a combination of clinical breast examination, radiologic imaging (ultrasound, mammogram, breast magnetic resonance imaging, or computed tomography), and fine-needle aspiration or lesional biopsy with histopathology.⁹ Given that in 20% of metastasized breast cancers the primary tumor may not be identified, a negative breast examination and imaging do not rule out breast cancer, especially if cutaneous biopsy reveals a primary malignancy.⁴³ Histopathology and immunohistochemistry can thereby confirm the presence of metastatic cutaneous lesions and help characterize the breast cancer type involved, with adenocarcinomas being most commonly implicated.²⁸ Although both ductal and lobular adenocarcinomas stain positive for cytokeratin 7, estrogen receptor, progesterone receptor, gross cystic disease fluid protein 15, carcinoembryonic antigen, and mammaglobin, only the former shows positivity for e-cadherin markers.³ Conversely, inflammatory carcinoma stains positive for CD31 and podoplanin, telangiectatic carcinoma stains positive for CD31, and mammary Paget disease stains positive for cytokeratin 7 and mucin 1, cell surface associated.³ Apart from cutaneous biopsy, fine-needle aspiration cytology can likewise provide a simple and rapid method of diagnosis with high sensitivity and specificity.¹⁴

Conclusion

Although cutaneous metastasis as the presenting sign of a breast malignancy is rare, a high index of suspicion should be exercised when encountering rapid-onset, out-of-place nodules or plaques in female patients, particularly nodules or plaques presenting on the chest.

Physicians are active on social media with contact dermatitis content, but they can take more advantage of this opportunity to educate patients, according to a review of posts on YouTube, Facebook, Instagram, Google, Twitter, and Reddit.

Data on social media use suggest that approximately 65% of U.S. adults regularly use social media, and 40% of individuals use it in making medical decisions, Morgan Nguyen, a medical student at Northwestern University, Chicago, said at the annual meeting of the American Contact Dermatitis Society, held virtually this year.

“Dermatologists’ awareness of social media discussions can further their understanding of where patients go for information and what they might encounter,” she said. In particular, “contact dermatitis practitioners can tailor their counseling by knowing what their patients are seeing online.”

To characterize the social media landscape for content related to allergic contact dermatitis (ACD), Ms. Nguyen and colleagues assessed metrics on content and authorship on six different platforms.

For YouTube, the authors reviewed 15 videos related to ACD with views ranging from 24,262 to 232,300. Of these videos, two were produced as medical education, four were produced by patients, and nine were produced by physicians. The content of many videos was poor quality, with an average QUEST score of 7.4/28 overall and 8.7 for physician videos. Video quality was not associated with increased views. Video titles included “What to do if you have a rash on your face,” and “Contact dermatitis on lips!”

Overall, Instagram was more popular than Twitter, particularly among patients. The investigators searched using the hashtags #ContactDermatitis, #AllergicContactDermatitis, and #ContactDerm and reviewed the 100 most recent posts for authorship. The most recent 100 posts occurred over 16 days; physicians, patients, and companies each contributed approximately one-third of the content, but patient content was more focused on symptoms, treatment progress, and advice.

For Instagram, the hashtag search phrase made a notable difference in authorship, Ms. Nguyen said. Physicians were disproportionately more likely to use #AllergicContactDermatitis (43%) compared with patients (22%).

On Twitter, the most recent 100 posts were spread over 152 days, and professional organizations and companies generated approximately two-thirds of the posts. The #ContactDermatitis hashtag was the most common, and accounted for 94% of tweets.

Although patient support groups specific to ACD exist on Facebook, the researchers found none on Reddit. These two venues are designed for creating online communities, rather than simply providing information, and the researchers searched for support groups related to contact dermatitis. One of the main differences between the two is that Facebook allows for the creation of private groups, while Reddit is an open forum.

The largest contact dermatitis Facebook group, the “Eczema, Contact Dermatitis and Patch Testing Alliance,” had 4,665 members at the time of the study, and most groups were private. Although no support groups existed on Reddit, titles of Reddit forums discussing ACD included allergies, askdoctors, fragrance, haircarescience, legaladvice, skincareaddicts, beauty, dermatologyquestions, medical_advice, skincare_addiction, tretinoin, and vulvodynia.

For Google, the researchers used terms similar to “contact dermatitis” as generated by the Google Keyword Planner tool, and used Google Adwords data to estimate monthly searches. The top estimated term was “contact dermatitis,” with 8,322 searches, followed by “contact dermatitis pictures,” with 1,666 searches, and “contact dermatitis treatment” with 595 searches. By contrast, “allergic dermatitis” had an estimated 346 monthly searches, and “allergic contact dermatitis” had 194.

Overall, approximately 9,000 searches each month involve “contact dermatitis,” “allergic contact dermatitis,” or “allergic dermatitis,” said Ms. Nguyen. However, these estimated searches seemed comparatively low, given the high burden of ACD, she said. Although ACD ranks eighth among skin diseases based on health care costs, psoriasis (fourteenth based on health care costs) shows an estimated monthly Google search volume of 600,462, she pointed out.

The study findings were limited by several factors including the potential impact of the COVID-19 pandemic on social media use, and by the lack of specificity associated with the search term “contact dermatitis,” which is not unique to ACD, Ms. Nguyen said.

Although more research on quality assessment is needed, the results suggest that social media is a popular venue for ACD patients to seek and share information, Ms. Nguyen emphasized. There is an opportunity for patch testing physicians to create and disperse educational content for patients using these sites, she concluded.
 

Study highlights education opportunities

“Due to the pandemic, patients have been increasingly interacting with online resources in lieu of coming to a physician’s office,” corresponding author Walter J. Liszewski, MD, of the department of dermatology, Northwestern University, Chicago, said in an interview. “As social media is increasingly used by patients and physicians, it is important to get a sense of its footprint,” he said.

He and Ms. Nguyen were surprised by several of their findings: First, searches for ACD on Google were not particularly common given its relatively high prevalence and economic cost to society. In addition, they found that physicians often used different language than that of patients to describe ACD on Twitter and Instagram. They were also surprised at how often ACD appeared in Reddit posts, which they noted highlights that ACD impacts multiple sections of society.

The greatest challenge in studying social media and medicine is the quality of material available, Dr. Liszewski and Ms. Nguyen observed, emphasizing that while there are numerous videos on ACD on YouTube, the quality is highly variable, and there is a need for more patient-centered, educational materials. However, the results of their study highlight the opportunity for physicians and industry to create medically-accurate educational materials, they added.

Ms. Nguyen and Dr. Liszewski had no financial conflicts to disclose.

Physicians are active on social media with contact dermatitis content, but they can take more advantage of this opportunity to educate patients, according to a review of posts on YouTube, Facebook, Instagram, Google, Twitter, and Reddit.

Data on social media use suggest that approximately 65% of U.S. adults regularly use social media, and 40% of individuals use it in making medical decisions, Morgan Nguyen, a medical student at Northwestern University, Chicago, said at the annual meeting of the American Contact Dermatitis Society, held virtually this year.

“Dermatologists’ awareness of social media discussions can further their understanding of where patients go for information and what they might encounter,” she said. In particular, “contact dermatitis practitioners can tailor their counseling by knowing what their patients are seeing online.”

To characterize the social media landscape for content related to allergic contact dermatitis (ACD), Ms. Nguyen and colleagues assessed metrics on content and authorship on six different platforms.

For YouTube, the authors reviewed 15 videos related to ACD with views ranging from 24,262 to 232,300. Of these videos, two were produced as medical education, four were produced by patients, and nine were produced by physicians. The content of many videos was poor quality, with an average QUEST score of 7.4/28 overall and 8.7 for physician videos. Video quality was not associated with increased views. Video titles included “What to do if you have a rash on your face,” and “Contact dermatitis on lips!”

Overall, Instagram was more popular than Twitter, particularly among patients. The investigators searched using the hashtags #ContactDermatitis, #AllergicContactDermatitis, and #ContactDerm and reviewed the 100 most recent posts for authorship. The most recent 100 posts occurred over 16 days; physicians, patients, and companies each contributed approximately one-third of the content, but patient content was more focused on symptoms, treatment progress, and advice.

For Instagram, the hashtag search phrase made a notable difference in authorship, Ms. Nguyen said. Physicians were disproportionately more likely to use #AllergicContactDermatitis (43%) compared with patients (22%).

On Twitter, the most recent 100 posts were spread over 152 days, and professional organizations and companies generated approximately two-thirds of the posts. The #ContactDermatitis hashtag was the most common, and accounted for 94% of tweets.

Although patient support groups specific to ACD exist on Facebook, the researchers found none on Reddit. These two venues are designed for creating online communities, rather than simply providing information, and the researchers searched for support groups related to contact dermatitis. One of the main differences between the two is that Facebook allows for the creation of private groups, while Reddit is an open forum.

The largest contact dermatitis Facebook group, the “Eczema, Contact Dermatitis and Patch Testing Alliance,” had 4,665 members at the time of the study, and most groups were private. Although no support groups existed on Reddit, titles of Reddit forums discussing ACD included allergies, askdoctors, fragrance, haircarescience, legaladvice, skincareaddicts, beauty, dermatologyquestions, medical_advice, skincare_addiction, tretinoin, and vulvodynia.

For Google, the researchers used terms similar to “contact dermatitis” as generated by the Google Keyword Planner tool, and used Google Adwords data to estimate monthly searches. The top estimated term was “contact dermatitis,” with 8,322 searches, followed by “contact dermatitis pictures,” with 1,666 searches, and “contact dermatitis treatment” with 595 searches. By contrast, “allergic dermatitis” had an estimated 346 monthly searches, and “allergic contact dermatitis” had 194.

Overall, approximately 9,000 searches each month involve “contact dermatitis,” “allergic contact dermatitis,” or “allergic dermatitis,” said Ms. Nguyen. However, these estimated searches seemed comparatively low, given the high burden of ACD, she said. Although ACD ranks eighth among skin diseases based on health care costs, psoriasis (fourteenth based on health care costs) shows an estimated monthly Google search volume of 600,462, she pointed out.

The study findings were limited by several factors including the potential impact of the COVID-19 pandemic on social media use, and by the lack of specificity associated with the search term “contact dermatitis,” which is not unique to ACD, Ms. Nguyen said.

Although more research on quality assessment is needed, the results suggest that social media is a popular venue for ACD patients to seek and share information, Ms. Nguyen emphasized. There is an opportunity for patch testing physicians to create and disperse educational content for patients using these sites, she concluded.
 

Study highlights education opportunities

“Due to the pandemic, patients have been increasingly interacting with online resources in lieu of coming to a physician’s office,” corresponding author Walter J. Liszewski, MD, of the department of dermatology, Northwestern University, Chicago, said in an interview. “As social media is increasingly used by patients and physicians, it is important to get a sense of its footprint,” he said.

He and Ms. Nguyen were surprised by several of their findings: First, searches for ACD on Google were not particularly common given its relatively high prevalence and economic cost to society. In addition, they found that physicians often used different language than that of patients to describe ACD on Twitter and Instagram. They were also surprised at how often ACD appeared in Reddit posts, which they noted highlights that ACD impacts multiple sections of society.

The greatest challenge in studying social media and medicine is the quality of material available, Dr. Liszewski and Ms. Nguyen observed, emphasizing that while there are numerous videos on ACD on YouTube, the quality is highly variable, and there is a need for more patient-centered, educational materials. However, the results of their study highlight the opportunity for physicians and industry to create medically-accurate educational materials, they added.

Ms. Nguyen and Dr. Liszewski had no financial conflicts to disclose.

Physicians are active on social media with contact dermatitis content, but they can take more advantage of this opportunity to educate patients, according to a review of posts on YouTube, Facebook, Instagram, Google, Twitter, and Reddit.

Data on social media use suggest that approximately 65% of U.S. adults regularly use social media, and 40% of individuals use it in making medical decisions, Morgan Nguyen, a medical student at Northwestern University, Chicago, said at the annual meeting of the American Contact Dermatitis Society, held virtually this year.

“Dermatologists’ awareness of social media discussions can further their understanding of where patients go for information and what they might encounter,” she said. In particular, “contact dermatitis practitioners can tailor their counseling by knowing what their patients are seeing online.”

To characterize the social media landscape for content related to allergic contact dermatitis (ACD), Ms. Nguyen and colleagues assessed metrics on content and authorship on six different platforms.

For YouTube, the authors reviewed 15 videos related to ACD with views ranging from 24,262 to 232,300. Of these videos, two were produced as medical education, four were produced by patients, and nine were produced by physicians. The content of many videos was poor quality, with an average QUEST score of 7.4/28 overall and 8.7 for physician videos. Video quality was not associated with increased views. Video titles included “What to do if you have a rash on your face,” and “Contact dermatitis on lips!”

Overall, Instagram was more popular than Twitter, particularly among patients. The investigators searched using the hashtags #ContactDermatitis, #AllergicContactDermatitis, and #ContactDerm and reviewed the 100 most recent posts for authorship. The most recent 100 posts occurred over 16 days; physicians, patients, and companies each contributed approximately one-third of the content, but patient content was more focused on symptoms, treatment progress, and advice.

For Instagram, the hashtag search phrase made a notable difference in authorship, Ms. Nguyen said. Physicians were disproportionately more likely to use #AllergicContactDermatitis (43%) compared with patients (22%).

On Twitter, the most recent 100 posts were spread over 152 days, and professional organizations and companies generated approximately two-thirds of the posts. The #ContactDermatitis hashtag was the most common, and accounted for 94% of tweets.

Although patient support groups specific to ACD exist on Facebook, the researchers found none on Reddit. These two venues are designed for creating online communities, rather than simply providing information, and the researchers searched for support groups related to contact dermatitis. One of the main differences between the two is that Facebook allows for the creation of private groups, while Reddit is an open forum.

The largest contact dermatitis Facebook group, the “Eczema, Contact Dermatitis and Patch Testing Alliance,” had 4,665 members at the time of the study, and most groups were private. Although no support groups existed on Reddit, titles of Reddit forums discussing ACD included allergies, askdoctors, fragrance, haircarescience, legaladvice, skincareaddicts, beauty, dermatologyquestions, medical_advice, skincare_addiction, tretinoin, and vulvodynia.

For Google, the researchers used terms similar to “contact dermatitis” as generated by the Google Keyword Planner tool, and used Google Adwords data to estimate monthly searches. The top estimated term was “contact dermatitis,” with 8,322 searches, followed by “contact dermatitis pictures,” with 1,666 searches, and “contact dermatitis treatment” with 595 searches. By contrast, “allergic dermatitis” had an estimated 346 monthly searches, and “allergic contact dermatitis” had 194.

Overall, approximately 9,000 searches each month involve “contact dermatitis,” “allergic contact dermatitis,” or “allergic dermatitis,” said Ms. Nguyen. However, these estimated searches seemed comparatively low, given the high burden of ACD, she said. Although ACD ranks eighth among skin diseases based on health care costs, psoriasis (fourteenth based on health care costs) shows an estimated monthly Google search volume of 600,462, she pointed out.

The study findings were limited by several factors including the potential impact of the COVID-19 pandemic on social media use, and by the lack of specificity associated with the search term “contact dermatitis,” which is not unique to ACD, Ms. Nguyen said.

Although more research on quality assessment is needed, the results suggest that social media is a popular venue for ACD patients to seek and share information, Ms. Nguyen emphasized. There is an opportunity for patch testing physicians to create and disperse educational content for patients using these sites, she concluded.
 

Study highlights education opportunities

“Due to the pandemic, patients have been increasingly interacting with online resources in lieu of coming to a physician’s office,” corresponding author Walter J. Liszewski, MD, of the department of dermatology, Northwestern University, Chicago, said in an interview. “As social media is increasingly used by patients and physicians, it is important to get a sense of its footprint,” he said.

He and Ms. Nguyen were surprised by several of their findings: First, searches for ACD on Google were not particularly common given its relatively high prevalence and economic cost to society. In addition, they found that physicians often used different language than that of patients to describe ACD on Twitter and Instagram. They were also surprised at how often ACD appeared in Reddit posts, which they noted highlights that ACD impacts multiple sections of society.

The greatest challenge in studying social media and medicine is the quality of material available, Dr. Liszewski and Ms. Nguyen observed, emphasizing that while there are numerous videos on ACD on YouTube, the quality is highly variable, and there is a need for more patient-centered, educational materials. However, the results of their study highlight the opportunity for physicians and industry to create medically-accurate educational materials, they added.

Ms. Nguyen and Dr. Liszewski had no financial conflicts to disclose.

The number of new COVID-19 cases in children increased for the second consecutive week in the United States, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

Just over 64,000 new cases were reported among children for the week of March 19-25 – up from 57,000 the week before, which, in turn, marked the end of an 8-week decline in new cases. That brings the number of children infected with the coronavirus to over 3.4 million since the beginning of the pandemic, or 13.4% of all reported cases, the AAP and CHA said in their weekly COVID-19 report.

For just the week of March 19-25, however, the proportion of all cases occurring in children was quite a bit higher, 19.1%. That’s higher than at any other point during the pandemic, passing the previous high of 18.7% set just a week earlier, based on the data collected by AAP/CHA from 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.

The national infection rate was 4,525 cases per 100,000 children for the week of March 19-25, compared with 4,440 per 100,000 the previous week. States falling the farthest from that national mark were Hawaii at 1,101 per 100,000 and North Dakota at 8,848, the AAP and CHA said.

There was double-digit increase, 11, in the number of child deaths, as the total went from 268 to 279 despite Virginia’s revising its mortality data downward. The mortality rate for children remains 0.01%, and children represent only 0.06% of all COVID-19–related deaths in the 43 states, along with New York City, Puerto Rico, and Guam, that are reporting deaths by age, the report shows.

The state/local-level data show that Texas has the highest number of child deaths (48), followed by Arizona (26), New York City (22), California (16), and Illinois (16), while nine states and the District of Columbia have not yet reported a death, the AAP and CHA said.

[email protected]

The number of new COVID-19 cases in children increased for the second consecutive week in the United States, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

Just over 64,000 new cases were reported among children for the week of March 19-25 – up from 57,000 the week before, which, in turn, marked the end of an 8-week decline in new cases. That brings the number of children infected with the coronavirus to over 3.4 million since the beginning of the pandemic, or 13.4% of all reported cases, the AAP and CHA said in their weekly COVID-19 report.

For just the week of March 19-25, however, the proportion of all cases occurring in children was quite a bit higher, 19.1%. That’s higher than at any other point during the pandemic, passing the previous high of 18.7% set just a week earlier, based on the data collected by AAP/CHA from 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.

The national infection rate was 4,525 cases per 100,000 children for the week of March 19-25, compared with 4,440 per 100,000 the previous week. States falling the farthest from that national mark were Hawaii at 1,101 per 100,000 and North Dakota at 8,848, the AAP and CHA said.

There was double-digit increase, 11, in the number of child deaths, as the total went from 268 to 279 despite Virginia’s revising its mortality data downward. The mortality rate for children remains 0.01%, and children represent only 0.06% of all COVID-19–related deaths in the 43 states, along with New York City, Puerto Rico, and Guam, that are reporting deaths by age, the report shows.

The state/local-level data show that Texas has the highest number of child deaths (48), followed by Arizona (26), New York City (22), California (16), and Illinois (16), while nine states and the District of Columbia have not yet reported a death, the AAP and CHA said.

[email protected]

The number of new COVID-19 cases in children increased for the second consecutive week in the United States, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association.

Just over 64,000 new cases were reported among children for the week of March 19-25 – up from 57,000 the week before, which, in turn, marked the end of an 8-week decline in new cases. That brings the number of children infected with the coronavirus to over 3.4 million since the beginning of the pandemic, or 13.4% of all reported cases, the AAP and CHA said in their weekly COVID-19 report.

For just the week of March 19-25, however, the proportion of all cases occurring in children was quite a bit higher, 19.1%. That’s higher than at any other point during the pandemic, passing the previous high of 18.7% set just a week earlier, based on the data collected by AAP/CHA from 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.

The national infection rate was 4,525 cases per 100,000 children for the week of March 19-25, compared with 4,440 per 100,000 the previous week. States falling the farthest from that national mark were Hawaii at 1,101 per 100,000 and North Dakota at 8,848, the AAP and CHA said.

There was double-digit increase, 11, in the number of child deaths, as the total went from 268 to 279 despite Virginia’s revising its mortality data downward. The mortality rate for children remains 0.01%, and children represent only 0.06% of all COVID-19–related deaths in the 43 states, along with New York City, Puerto Rico, and Guam, that are reporting deaths by age, the report shows.

The state/local-level data show that Texas has the highest number of child deaths (48), followed by Arizona (26), New York City (22), California (16), and Illinois (16), while nine states and the District of Columbia have not yet reported a death, the AAP and CHA said.

[email protected]

The combination of ixabepilone and bevacizumab demonstrated efficacy in patients with platinum-resistant or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer in a phase 2 trial.

The median progression-free survival (PFS) was 5.5 months for patients randomized to receive ixabepilone and bevacizumab, versus 2.2 months for patients assigned to ixabepilone alone (P < .001). The median overall survival (OS) was 10 months and 6 months, respectively (P = .006), although the trial was underpowered to detect OS differences.

These results were presented in a late-breaking abstract session at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 11570).

“Therapeutic options for platinum- and taxane-resistant ovarian cancer are limited, and, unfortunately, median overall survival in this population is only approximately 12 months. It’s obvious that additional treatment strategies are warranted,” Dana M. Roque, MD, of the University of Maryland in Baltimore, said when presenting the results.
 

Study rationale and details

Dr. Roque explained that ixabepilone is an epothilone B analog that may retain activity in patients with taxane-resistant disease. She and her colleagues previously found, in a retrospective study, that ixabepilone, with or without bevacizumab, showed “promising” activity with acceptable toxicity in patients with recurrent uterine or ovarian/primary peritoneal/fallopian tube cancers.

At SGO 2021, Dr. Roque reported results of a prospective, phase 2 trial of 76 patients randomized to ixabepilone alone or in combination with bevacizumab.

Patients with measurable recurrent or persistent platinum-resistant or refractory epithelial nonmucinous ovarian, fallopian tube, or primary peritoneal cancers were enrolled. The patients had to have received at least three prior cycles of paclitaxel, but there was no upper limit on prior lines of therapy, including bevacizumab.

After stratification by prior bevacizumab and study site, the patients were randomly assigned to either ixabepilone monotherapy at a dose of 20 mg/m² on days 1, 8, and 15 of every 28-day cycle (n = 37), or the same dose of ixabepilone plus bevacizumab at 10 mg/kg on days 1 and 15 every 28 days (n = 39).

Most patients in each arm – 78% in the monotherapy arm and 87% in the combination arm – had serous tumors, with the remaining patients having carcinosarcomas or other, unspecified histologies.
 

Efficacy and safety

The overall response rate was 33% with the combination and 8% with ixabepilone monotherapy. There were no correlations between TUBB3 staining and either responses or durable disease control.

As noted before, PFS and OS were significantly better with the combination. Neither PFS nor OS were influenced by prior bevacizumab use, heavy pretreatment, poor performance status, nonserous histology, or age.

Dose-limiting toxicities with the combination included peripheral neuropathy, neutropenia, and fatigue. There was one bowel perforation in a patient on the combination.

Patients assigned to the combination were significantly more likely to experience hypertension (36% vs. 8%, P = .005) and peripheral neuropathy (51% vs. 19%, P = .004). However, there were no differences in serious adverse events between the treatment arms.

Dr. Roque acknowledged that this study was limited by incomplete immunohistochemistry data, a lack of stratification by extent of prior taxane exposure in the recurrent setting, a lack of a bevacizumab control arm, and underpowering to detect OS differences.
 

Comparison with AURELIA

Dr. Roque and the invited discussant, Thomas J. Herzog, MD, of the University of Cincinnati Cancer Center in Ohio, both compared results of the current trial to results from the AURELIA trial, in which patients with platinum-resistant ovarian cancers were randomized to chemotherapy with or without bevacizumab.

According to AURELIA data published in 2014, the ORR with the bevacizumab-chemotherapy combination was 27%, compared with 33% with ixabepilone-bevacizumab in the current trial. The median PFS was 6.7 months and 5.5 months, respectively, and the median OS was 16.6 months and 10 months, respectively.

An analysis of AURELIA data published in 2015 suggested that outcomes were even better for patients who received paclitaxel plus bevacizumab. This group had an ORR of 53.3%, a median PFS of 10.4 months, and a median OS of 22.4 months.

Though the current study’s results don’t appear to measure up to results from AURELIA, Dr. Herzog called the current study “very exciting.”

“The efficacy looks very promising,” he said. “They even showed efficacy for OS that looked very interesting, even though that was underpowered.”

Dr. Herzog did note the lack of a companion diagnostic because the TUBB3 staining did not correlate with response. He also said the trial was limited by the lack of a bevacizumab control arm. Furthermore, because of the relatively small sample size in the combination group (n = 39), the lower bound of the confidence interval for ORR includes response rates typically seen with conventional therapies.

“I do think that the combination does make sense biologically, so I’d like to see more data on that,” he concluded.

The trial was sponsored by Yale University, with study drug supplied by R-Pharm-US. Dr. Roque reported no conflicts of interest. Dr. Herzog disclosed serving as a scientific advisor to several companies, including Genentech, maker of bevacizumab.

The combination of ixabepilone and bevacizumab demonstrated efficacy in patients with platinum-resistant or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer in a phase 2 trial.

The median progression-free survival (PFS) was 5.5 months for patients randomized to receive ixabepilone and bevacizumab, versus 2.2 months for patients assigned to ixabepilone alone (P < .001). The median overall survival (OS) was 10 months and 6 months, respectively (P = .006), although the trial was underpowered to detect OS differences.

These results were presented in a late-breaking abstract session at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 11570).

“Therapeutic options for platinum- and taxane-resistant ovarian cancer are limited, and, unfortunately, median overall survival in this population is only approximately 12 months. It’s obvious that additional treatment strategies are warranted,” Dana M. Roque, MD, of the University of Maryland in Baltimore, said when presenting the results.
 

Study rationale and details

Dr. Roque explained that ixabepilone is an epothilone B analog that may retain activity in patients with taxane-resistant disease. She and her colleagues previously found, in a retrospective study, that ixabepilone, with or without bevacizumab, showed “promising” activity with acceptable toxicity in patients with recurrent uterine or ovarian/primary peritoneal/fallopian tube cancers.

At SGO 2021, Dr. Roque reported results of a prospective, phase 2 trial of 76 patients randomized to ixabepilone alone or in combination with bevacizumab.

Patients with measurable recurrent or persistent platinum-resistant or refractory epithelial nonmucinous ovarian, fallopian tube, or primary peritoneal cancers were enrolled. The patients had to have received at least three prior cycles of paclitaxel, but there was no upper limit on prior lines of therapy, including bevacizumab.

After stratification by prior bevacizumab and study site, the patients were randomly assigned to either ixabepilone monotherapy at a dose of 20 mg/m² on days 1, 8, and 15 of every 28-day cycle (n = 37), or the same dose of ixabepilone plus bevacizumab at 10 mg/kg on days 1 and 15 every 28 days (n = 39).

Most patients in each arm – 78% in the monotherapy arm and 87% in the combination arm – had serous tumors, with the remaining patients having carcinosarcomas or other, unspecified histologies.
 

Efficacy and safety

The overall response rate was 33% with the combination and 8% with ixabepilone monotherapy. There were no correlations between TUBB3 staining and either responses or durable disease control.

As noted before, PFS and OS were significantly better with the combination. Neither PFS nor OS were influenced by prior bevacizumab use, heavy pretreatment, poor performance status, nonserous histology, or age.

Dose-limiting toxicities with the combination included peripheral neuropathy, neutropenia, and fatigue. There was one bowel perforation in a patient on the combination.

Patients assigned to the combination were significantly more likely to experience hypertension (36% vs. 8%, P = .005) and peripheral neuropathy (51% vs. 19%, P = .004). However, there were no differences in serious adverse events between the treatment arms.

Dr. Roque acknowledged that this study was limited by incomplete immunohistochemistry data, a lack of stratification by extent of prior taxane exposure in the recurrent setting, a lack of a bevacizumab control arm, and underpowering to detect OS differences.
 

Comparison with AURELIA

Dr. Roque and the invited discussant, Thomas J. Herzog, MD, of the University of Cincinnati Cancer Center in Ohio, both compared results of the current trial to results from the AURELIA trial, in which patients with platinum-resistant ovarian cancers were randomized to chemotherapy with or without bevacizumab.

According to AURELIA data published in 2014, the ORR with the bevacizumab-chemotherapy combination was 27%, compared with 33% with ixabepilone-bevacizumab in the current trial. The median PFS was 6.7 months and 5.5 months, respectively, and the median OS was 16.6 months and 10 months, respectively.

An analysis of AURELIA data published in 2015 suggested that outcomes were even better for patients who received paclitaxel plus bevacizumab. This group had an ORR of 53.3%, a median PFS of 10.4 months, and a median OS of 22.4 months.

Though the current study’s results don’t appear to measure up to results from AURELIA, Dr. Herzog called the current study “very exciting.”

“The efficacy looks very promising,” he said. “They even showed efficacy for OS that looked very interesting, even though that was underpowered.”

Dr. Herzog did note the lack of a companion diagnostic because the TUBB3 staining did not correlate with response. He also said the trial was limited by the lack of a bevacizumab control arm. Furthermore, because of the relatively small sample size in the combination group (n = 39), the lower bound of the confidence interval for ORR includes response rates typically seen with conventional therapies.

“I do think that the combination does make sense biologically, so I’d like to see more data on that,” he concluded.

The trial was sponsored by Yale University, with study drug supplied by R-Pharm-US. Dr. Roque reported no conflicts of interest. Dr. Herzog disclosed serving as a scientific advisor to several companies, including Genentech, maker of bevacizumab.

The combination of ixabepilone and bevacizumab demonstrated efficacy in patients with platinum-resistant or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer in a phase 2 trial.

The median progression-free survival (PFS) was 5.5 months for patients randomized to receive ixabepilone and bevacizumab, versus 2.2 months for patients assigned to ixabepilone alone (P < .001). The median overall survival (OS) was 10 months and 6 months, respectively (P = .006), although the trial was underpowered to detect OS differences.

These results were presented in a late-breaking abstract session at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 11570).

“Therapeutic options for platinum- and taxane-resistant ovarian cancer are limited, and, unfortunately, median overall survival in this population is only approximately 12 months. It’s obvious that additional treatment strategies are warranted,” Dana M. Roque, MD, of the University of Maryland in Baltimore, said when presenting the results.
 

Study rationale and details

Dr. Roque explained that ixabepilone is an epothilone B analog that may retain activity in patients with taxane-resistant disease. She and her colleagues previously found, in a retrospective study, that ixabepilone, with or without bevacizumab, showed “promising” activity with acceptable toxicity in patients with recurrent uterine or ovarian/primary peritoneal/fallopian tube cancers.

At SGO 2021, Dr. Roque reported results of a prospective, phase 2 trial of 76 patients randomized to ixabepilone alone or in combination with bevacizumab.

Patients with measurable recurrent or persistent platinum-resistant or refractory epithelial nonmucinous ovarian, fallopian tube, or primary peritoneal cancers were enrolled. The patients had to have received at least three prior cycles of paclitaxel, but there was no upper limit on prior lines of therapy, including bevacizumab.

After stratification by prior bevacizumab and study site, the patients were randomly assigned to either ixabepilone monotherapy at a dose of 20 mg/m² on days 1, 8, and 15 of every 28-day cycle (n = 37), or the same dose of ixabepilone plus bevacizumab at 10 mg/kg on days 1 and 15 every 28 days (n = 39).

Most patients in each arm – 78% in the monotherapy arm and 87% in the combination arm – had serous tumors, with the remaining patients having carcinosarcomas or other, unspecified histologies.
 

Efficacy and safety

The overall response rate was 33% with the combination and 8% with ixabepilone monotherapy. There were no correlations between TUBB3 staining and either responses or durable disease control.

As noted before, PFS and OS were significantly better with the combination. Neither PFS nor OS were influenced by prior bevacizumab use, heavy pretreatment, poor performance status, nonserous histology, or age.

Dose-limiting toxicities with the combination included peripheral neuropathy, neutropenia, and fatigue. There was one bowel perforation in a patient on the combination.

Patients assigned to the combination were significantly more likely to experience hypertension (36% vs. 8%, P = .005) and peripheral neuropathy (51% vs. 19%, P = .004). However, there were no differences in serious adverse events between the treatment arms.

Dr. Roque acknowledged that this study was limited by incomplete immunohistochemistry data, a lack of stratification by extent of prior taxane exposure in the recurrent setting, a lack of a bevacizumab control arm, and underpowering to detect OS differences.
 

Comparison with AURELIA

Dr. Roque and the invited discussant, Thomas J. Herzog, MD, of the University of Cincinnati Cancer Center in Ohio, both compared results of the current trial to results from the AURELIA trial, in which patients with platinum-resistant ovarian cancers were randomized to chemotherapy with or without bevacizumab.

According to AURELIA data published in 2014, the ORR with the bevacizumab-chemotherapy combination was 27%, compared with 33% with ixabepilone-bevacizumab in the current trial. The median PFS was 6.7 months and 5.5 months, respectively, and the median OS was 16.6 months and 10 months, respectively.

An analysis of AURELIA data published in 2015 suggested that outcomes were even better for patients who received paclitaxel plus bevacizumab. This group had an ORR of 53.3%, a median PFS of 10.4 months, and a median OS of 22.4 months.

Though the current study’s results don’t appear to measure up to results from AURELIA, Dr. Herzog called the current study “very exciting.”

“The efficacy looks very promising,” he said. “They even showed efficacy for OS that looked very interesting, even though that was underpowered.”

Dr. Herzog did note the lack of a companion diagnostic because the TUBB3 staining did not correlate with response. He also said the trial was limited by the lack of a bevacizumab control arm. Furthermore, because of the relatively small sample size in the combination group (n = 39), the lower bound of the confidence interval for ORR includes response rates typically seen with conventional therapies.

“I do think that the combination does make sense biologically, so I’d like to see more data on that,” he concluded.

The trial was sponsored by Yale University, with study drug supplied by R-Pharm-US. Dr. Roque reported no conflicts of interest. Dr. Herzog disclosed serving as a scientific advisor to several companies, including Genentech, maker of bevacizumab.

Recommendations for prescribing exercise to control high blood pressure have been put forward by various medical organizations and expert panels, but finding the bandwidth to craft personalized exercise training for their patients poses a challenge for clinicians.

Now, European cardiology societies have issued a consensus statement that offers an algorithm of sorts for developing personalized exercise programs as part of overall management approach for patients with or at risk of high BP.

The statement, published in the European Journal of Preventive Cardiology and issued by the European Association of Preventive Cardiology and the European Society of Cardiology Council on Hypertension, claims to be the first document to focus on personalized exercise for BP.

The statement draws on a systematic review, including meta-analyses, to produce guidance on how to lower BP in three specific types of patients: Those with hypertension (>140/90 mm Hg), high-normal blood pressure (130-139/85-89 mm Hg), and normal blood pressure (<130/84 mm Hg).

By making recommendations for these three specific groups, along with providing guidance for combined exercise – that is, blending aerobic exercise with resistance training (RT) – the consensus statement goes one step further than recommendations other organizations have issued, Matthew W. Martinez, MD, said in an interview.

“What it adds is an algorithmic approach, if you will,” said Dr. Martinez, a sports medicine cardiologist at Morristown (N.J.) Medical Center. “There are some recommendations to help the clinicians to decide what they’re going to offer individuals, but what’s a challenge for us when seeing patients is finding the time to deliver the message and explain how valuable nutrition and exercise are.”

Guidelines, updates, and statements that include the role of exercise in BP control have been issued by the European Society of Cardiology, American Heart Association, and American College of Sports Medicine (Med Sci Sports Exercise. 2019;51:1314-23).

The European consensus statement includes the expected range of BP lowering for each activity. For example, aerobic exercise for patients with hypertension should lead to a reduction from –4.9 to –12 mm Hg systolic and –3.4 to –5.8 mm Hg diastolic.

The consensus statement recommends the following exercise priorities based on a patient’s blood pressure:

• Hypertension: Aerobic training (AT) as a first-line exercise therapy; and low- to moderate-intensity RT – equally using dynamic and isometric RT – as second-line therapy. In non-White patients, dynamic RT should be considered as a first-line therapy. RT can be combined with aerobic exercise on an individual basis if the clinician determines either form of RT would provide a metabolic benefit.
• High-to-normal BP: Dynamic RT as a first-line exercise, which the systematic review determined led to greater BP reduction than that of aerobic training. “Isometric RT is likely to elicit similar if not superior BP-lowering effects as [dynamic RT], but the level of evidence is low and the available data are scarce,” wrote first author Henner Hanssen, MD, of the University of Basel, Switzerland, and coauthors. Combining dynamic resistance training with aerobic training “may be preferable” to dynamic RT alone in patients with a combination of cardiovascular risk factors.
• Normal BP: Isometric RT may be indicated as a first-line intervention in individuals with a family or gestational history or obese or overweight people currently with normal BP. This advice includes a caveat: “The number of studies is limited and the 95% confidence intervals are large,” Dr. Hanssen and coauthors noted. AT is also an option in these patients, with more high-quality meta-analyses than the recommendation for isometric RT. “Hence, the BP-lowering effects of [isometric RT] as compared to AT may be overestimated and both exercise modalities may have similar BP-lowering effects in individuals with normotension,” wrote the consensus statement authors.

They note that more research is needed to validate the BP-lowering effects of combined exercise.

The statement acknowledges the difficulty clinicians face in managing patients with high blood pressure. “From a socioeconomic health perspective, it is a major challenge to develop, promote, and implement individually tailored exercise programs for patients with hypertension under consideration of sustainable costs,” wrote Dr. Hanssen and coauthors.

Dr. Martinez noted that one strength of the consensus statement is that it addresses the impact exercise can have on vascular health and metabolic function. And, it points out existing knowledge gaps.

“Are we going to see greater applicability of this as we use IT health technology?” he asked. “Are wearables and telehealth going to help deliver this message more easily, more frequently? Is there work to be done in terms of differences in gender? Do men and women respond differently, and is there a different exercise prescription based on that as well as ethnicity? We well know there’s a different treatment for African Americans compared to other ethnic groups.”

The statement also raises the stakes for using exercise as part of a multifaceted, integrated approach to hypertension management, he said.

“It’s not enough to talk just about exercise or nutrition, or to just give an antihypertension medicine,” Dr. Martinez said. “Perhaps the sweet spot is in integrating an approach that includes all three.”

Consensus statement coauthor Antonio Coca, MD, reported financial relationships with Abbott, Berlin-Chemie, Biolab, Boehringer-Ingelheim, Ferrer, Menarini, Merck, Novartis and Sanofi-Aventis. Coauthor Maria Simonenko, MD, reported financial relationships with Novartis and Sanofi-Aventis. Linda Pescatello, PhD, is lead author of the American College of Sports Medicine 2019 statement. Dr. Hanssen and all other authors have no disclosures. Dr. Martinez has no relevant relationships to disclose.

Recommendations for prescribing exercise to control high blood pressure have been put forward by various medical organizations and expert panels, but finding the bandwidth to craft personalized exercise training for their patients poses a challenge for clinicians.

Now, European cardiology societies have issued a consensus statement that offers an algorithm of sorts for developing personalized exercise programs as part of overall management approach for patients with or at risk of high BP.

The statement, published in the European Journal of Preventive Cardiology and issued by the European Association of Preventive Cardiology and the European Society of Cardiology Council on Hypertension, claims to be the first document to focus on personalized exercise for BP.

The statement draws on a systematic review, including meta-analyses, to produce guidance on how to lower BP in three specific types of patients: Those with hypertension (>140/90 mm Hg), high-normal blood pressure (130-139/85-89 mm Hg), and normal blood pressure (<130/84 mm Hg).

By making recommendations for these three specific groups, along with providing guidance for combined exercise – that is, blending aerobic exercise with resistance training (RT) – the consensus statement goes one step further than recommendations other organizations have issued, Matthew W. Martinez, MD, said in an interview.

“What it adds is an algorithmic approach, if you will,” said Dr. Martinez, a sports medicine cardiologist at Morristown (N.J.) Medical Center. “There are some recommendations to help the clinicians to decide what they’re going to offer individuals, but what’s a challenge for us when seeing patients is finding the time to deliver the message and explain how valuable nutrition and exercise are.”

Guidelines, updates, and statements that include the role of exercise in BP control have been issued by the European Society of Cardiology, American Heart Association, and American College of Sports Medicine (Med Sci Sports Exercise. 2019;51:1314-23).

The European consensus statement includes the expected range of BP lowering for each activity. For example, aerobic exercise for patients with hypertension should lead to a reduction from –4.9 to –12 mm Hg systolic and –3.4 to –5.8 mm Hg diastolic.

The consensus statement recommends the following exercise priorities based on a patient’s blood pressure:

• Hypertension: Aerobic training (AT) as a first-line exercise therapy; and low- to moderate-intensity RT – equally using dynamic and isometric RT – as second-line therapy. In non-White patients, dynamic RT should be considered as a first-line therapy. RT can be combined with aerobic exercise on an individual basis if the clinician determines either form of RT would provide a metabolic benefit.
• High-to-normal BP: Dynamic RT as a first-line exercise, which the systematic review determined led to greater BP reduction than that of aerobic training. “Isometric RT is likely to elicit similar if not superior BP-lowering effects as [dynamic RT], but the level of evidence is low and the available data are scarce,” wrote first author Henner Hanssen, MD, of the University of Basel, Switzerland, and coauthors. Combining dynamic resistance training with aerobic training “may be preferable” to dynamic RT alone in patients with a combination of cardiovascular risk factors.
• Normal BP: Isometric RT may be indicated as a first-line intervention in individuals with a family or gestational history or obese or overweight people currently with normal BP. This advice includes a caveat: “The number of studies is limited and the 95% confidence intervals are large,” Dr. Hanssen and coauthors noted. AT is also an option in these patients, with more high-quality meta-analyses than the recommendation for isometric RT. “Hence, the BP-lowering effects of [isometric RT] as compared to AT may be overestimated and both exercise modalities may have similar BP-lowering effects in individuals with normotension,” wrote the consensus statement authors.

They note that more research is needed to validate the BP-lowering effects of combined exercise.

The statement acknowledges the difficulty clinicians face in managing patients with high blood pressure. “From a socioeconomic health perspective, it is a major challenge to develop, promote, and implement individually tailored exercise programs for patients with hypertension under consideration of sustainable costs,” wrote Dr. Hanssen and coauthors.

Dr. Martinez noted that one strength of the consensus statement is that it addresses the impact exercise can have on vascular health and metabolic function. And, it points out existing knowledge gaps.

“Are we going to see greater applicability of this as we use IT health technology?” he asked. “Are wearables and telehealth going to help deliver this message more easily, more frequently? Is there work to be done in terms of differences in gender? Do men and women respond differently, and is there a different exercise prescription based on that as well as ethnicity? We well know there’s a different treatment for African Americans compared to other ethnic groups.”

The statement also raises the stakes for using exercise as part of a multifaceted, integrated approach to hypertension management, he said.

“It’s not enough to talk just about exercise or nutrition, or to just give an antihypertension medicine,” Dr. Martinez said. “Perhaps the sweet spot is in integrating an approach that includes all three.”

Consensus statement coauthor Antonio Coca, MD, reported financial relationships with Abbott, Berlin-Chemie, Biolab, Boehringer-Ingelheim, Ferrer, Menarini, Merck, Novartis and Sanofi-Aventis. Coauthor Maria Simonenko, MD, reported financial relationships with Novartis and Sanofi-Aventis. Linda Pescatello, PhD, is lead author of the American College of Sports Medicine 2019 statement. Dr. Hanssen and all other authors have no disclosures. Dr. Martinez has no relevant relationships to disclose.

Recommendations for prescribing exercise to control high blood pressure have been put forward by various medical organizations and expert panels, but finding the bandwidth to craft personalized exercise training for their patients poses a challenge for clinicians.

Now, European cardiology societies have issued a consensus statement that offers an algorithm of sorts for developing personalized exercise programs as part of overall management approach for patients with or at risk of high BP.

The statement, published in the European Journal of Preventive Cardiology and issued by the European Association of Preventive Cardiology and the European Society of Cardiology Council on Hypertension, claims to be the first document to focus on personalized exercise for BP.

The statement draws on a systematic review, including meta-analyses, to produce guidance on how to lower BP in three specific types of patients: Those with hypertension (>140/90 mm Hg), high-normal blood pressure (130-139/85-89 mm Hg), and normal blood pressure (<130/84 mm Hg).

By making recommendations for these three specific groups, along with providing guidance for combined exercise – that is, blending aerobic exercise with resistance training (RT) – the consensus statement goes one step further than recommendations other organizations have issued, Matthew W. Martinez, MD, said in an interview.

“What it adds is an algorithmic approach, if you will,” said Dr. Martinez, a sports medicine cardiologist at Morristown (N.J.) Medical Center. “There are some recommendations to help the clinicians to decide what they’re going to offer individuals, but what’s a challenge for us when seeing patients is finding the time to deliver the message and explain how valuable nutrition and exercise are.”

Guidelines, updates, and statements that include the role of exercise in BP control have been issued by the European Society of Cardiology, American Heart Association, and American College of Sports Medicine (Med Sci Sports Exercise. 2019;51:1314-23).

The European consensus statement includes the expected range of BP lowering for each activity. For example, aerobic exercise for patients with hypertension should lead to a reduction from –4.9 to –12 mm Hg systolic and –3.4 to –5.8 mm Hg diastolic.

The consensus statement recommends the following exercise priorities based on a patient’s blood pressure:

• Hypertension: Aerobic training (AT) as a first-line exercise therapy; and low- to moderate-intensity RT – equally using dynamic and isometric RT – as second-line therapy. In non-White patients, dynamic RT should be considered as a first-line therapy. RT can be combined with aerobic exercise on an individual basis if the clinician determines either form of RT would provide a metabolic benefit.
• High-to-normal BP: Dynamic RT as a first-line exercise, which the systematic review determined led to greater BP reduction than that of aerobic training. “Isometric RT is likely to elicit similar if not superior BP-lowering effects as [dynamic RT], but the level of evidence is low and the available data are scarce,” wrote first author Henner Hanssen, MD, of the University of Basel, Switzerland, and coauthors. Combining dynamic resistance training with aerobic training “may be preferable” to dynamic RT alone in patients with a combination of cardiovascular risk factors.
• Normal BP: Isometric RT may be indicated as a first-line intervention in individuals with a family or gestational history or obese or overweight people currently with normal BP. This advice includes a caveat: “The number of studies is limited and the 95% confidence intervals are large,” Dr. Hanssen and coauthors noted. AT is also an option in these patients, with more high-quality meta-analyses than the recommendation for isometric RT. “Hence, the BP-lowering effects of [isometric RT] as compared to AT may be overestimated and both exercise modalities may have similar BP-lowering effects in individuals with normotension,” wrote the consensus statement authors.

They note that more research is needed to validate the BP-lowering effects of combined exercise.

The statement acknowledges the difficulty clinicians face in managing patients with high blood pressure. “From a socioeconomic health perspective, it is a major challenge to develop, promote, and implement individually tailored exercise programs for patients with hypertension under consideration of sustainable costs,” wrote Dr. Hanssen and coauthors.

Dr. Martinez noted that one strength of the consensus statement is that it addresses the impact exercise can have on vascular health and metabolic function. And, it points out existing knowledge gaps.

“Are we going to see greater applicability of this as we use IT health technology?” he asked. “Are wearables and telehealth going to help deliver this message more easily, more frequently? Is there work to be done in terms of differences in gender? Do men and women respond differently, and is there a different exercise prescription based on that as well as ethnicity? We well know there’s a different treatment for African Americans compared to other ethnic groups.”

The statement also raises the stakes for using exercise as part of a multifaceted, integrated approach to hypertension management, he said.

“It’s not enough to talk just about exercise or nutrition, or to just give an antihypertension medicine,” Dr. Martinez said. “Perhaps the sweet spot is in integrating an approach that includes all three.”

Consensus statement coauthor Antonio Coca, MD, reported financial relationships with Abbott, Berlin-Chemie, Biolab, Boehringer-Ingelheim, Ferrer, Menarini, Merck, Novartis and Sanofi-Aventis. Coauthor Maria Simonenko, MD, reported financial relationships with Novartis and Sanofi-Aventis. Linda Pescatello, PhD, is lead author of the American College of Sports Medicine 2019 statement. Dr. Hanssen and all other authors have no disclosures. Dr. Martinez has no relevant relationships to disclose.

In a recent commentary published in Obstetrics & Gynecology, Katie L. Watson, JD, and Louise P. King, MD, JD, describe the issue of “double discrimination” in gynecologic surgery. The authors outlined how lower pay in a specialty where a majority of the surgeons and all of the patients are women may impact quality of care.

The commentary raises a number of concerns in gynecologic surgery that are important to discuss. Ob.gyn. as a whole is underpaid, as are many nonprocedural specialties such as family medicine and internal medicine. When ob.gyns. were predominantly men, the same situation existed – ob.gyns. were paid less than many other procedural specialties. While we’ve come a long way from the relative value unit (RVU) originally determined from the Harvard studies 30 years ago, there is room for additional improvement.

Several rationales were proposed by the authors to explain the disparities in pay between gynecologic surgery and those in urology: patient gender, surgeon gender, and length of training for gynecologic surgeons. The authors cited comparisons between urology and gynecology regarding “anatomically similar, sex-specific procedures” which require closer examination. Many of the code pairs selected were not actually comparable services. For example, management of Peyronie’s disease is a highly complex treatment performed by urologists that is not comparable with vaginectomy, yet this is an example of two codes used in the reference cited by the authors to conclude that surgeries on women are undervalued.

The overall RVUs for a procedure are also dependent upon the global period. The Centers for Medicare & Medicaid Services designated RVUs as the total amount of work before, during, and after a procedure. If a surgery has a 90-day global period, all the work for 90 days thereafter is bundled into the value, whereas if something is a zero-day global, only that day’s work is counted. A gynecologic surgeon who sees a patient back two or three times is coding and billing for those encounters in addition to that initial procedure.

Many of the code comparisons used in the analysis of gender in RVUs compared services with different global periods. Finally, some of the services that were compared had vastly different utilization. Some of the services and codes that were compared are performed extremely rarely and for that reason have not had their values reassessed over the years. There may be inequities in the RVUs for these services, but they will account for extremely little in overall compensation.

As a former chair of the American Medical Association’s RVS Update Committee (RUC), I spent years attempting to revalue ob.gyn. procedures. CMS assigns work RVUs based on physician work, practice expense, and professional liability insurance. The work is calculated using total physician time and intensity based on surveys completed by the specialty. The American College of Obstetrician and Gynecologist’s Committee on Health Economics and Coding, and the AMA RUC have worked diligently over many years to reassess potentially misvalued services. The ultimate RVUs assigned by CMS for gynecologic surgery are determined by the surveys completed by ACOG members. One issue we encountered with reexamining some procedures under RBRVS is that they have become so low volume that it has been difficult to justify the cost and effort to revalue them.

Lack of ob.gyn. training isn’t the full story

On average, ob.gyns. have between 18 and 24 months of surgical training, which is significantly less than other specialties. Lack of training in gynecologic surgery was proposed as another explanation for reduced compensation among female gynecologic surgeons. This is a complex issue not adequately explained by training time for gynecologic surgeons alone. While the number of trained ob.gyns. has increased in recent decades, the surgical volume has diminished and the workload of gynecologic surgery is far lower than it used to be. Surgical volume during and after training was much higher 35 years ago, prior to the advancements of procedures like endometrial ablation or tubal ligation. Women who had finished childbearing often underwent vaginal hysterectomies to manage contraception along with various other conditions.

With the advent of minimally invasive surgery, laparoscopic sterilization became possible, which has reduced the number of hysterectomies performed. Endometrial ablation is an office-based, noninvasive procedure. The development of the levonorgestrel IUD has helped manage abnormal bleeding, further reducing the need for hysterectomy.

This reduction in surgical volume does have an impact on quality of care. The model of tracking surgical outcomes at Kaiser Health System, as mentioned by the authors, could work well in some, but not all centers. A more approachable solution to address surgical volume for the average ob.gyn. would be to implement a mentoring and coaching process whereby recently trained ob.gyns. assist their senior partner(s) in surgery. This was the model years ago: I was trained by an ob.gyn. who was trained as a general surgeon. It was through the experience of assisting on each one of his cases – and him assisting on each one of my cases – that I received incredibly thorough surgical training.

These changes in practice, however, do not impact reimbursement. Rather than discrimination based on the gender of the surgeon, lower salaries in ob.gyn. are more likely to be the result of these and other factors.

The wage and quality gap in ob.gyn.

As a predominantly female surgical specialty, some of the disparity between gynecology and urology could be explained by how each specialty values its work. Here, gender plays a role in that when ob.gyns. are surveyed during the RUC process they may undervalue their work by reporting they can perform a procedure (and the before and after care) faster than what a urologist reports. The survey results may then result in lower RVUs.

Ob.gyn. is an overpopulated specialty for the number of surgeons needed to manage the volume of gynecologic surgery. When a health system wants to hire a general ob.gyn., it doesn’t have trouble finding one, while urologists are more challenging to recruit. This is not because of the structure of resource-based relative value scale (RBRVS) – despite the overall RVUs for gynecologic surgery, gynecologic oncologists are often paid well because health systems need them – but rather to the market economy of hiring physicians in specialty areas where there is demand.

Women are also chronically undervalued for the hours that we spend with patients. Data show that we spend more time with patients, which does not generate as many RVUs, but it generates better outcomes for patients. Evidence shows that women doctors in internal medicine and family medicine have better outcomes than doctors who are men.

On Jan. 1, 2021, Medicare and other payers implemented a new structure to reporting the level of office visit based on either medical decision-making or time spent on the date of encounter. Time spent with patients will now be rewarded – increased RVUs for increased time.

Part of the solution is value-based medicine and moving away from counting RVUs. This is also an opportunity to look at where time is spent in general ob.gyn. training and redistribute it, focusing on what trainees need for their education and not what hospitals need to service labor and delivery. We should step back and look creatively at optimizing the education and the training of ob.gyns., and where possible utilize other health care professionals such as nurse practitioners and midwives to address the uncomplicated obstetric needs of the hospital which could free up ob.gyn. trainees to obtain further surgical education.

To be clear, gender discrimination in compensation is prevalent and a persistent problem in medicine – ob.gyn. is no exception. Many ob.gyns. are employed by large health systems with payment structures and incentives that don’t align with those of the physician or the patient. There is definite misalignment in the way salaries are determined. Transparency on salaries is a critical component of addressing the pay gap that exists between women and men in medicine and in other industries.

The pay gap as it relates to reimbursement for gynecologic surgery, however, is a more complex matter that relates to how the RBRVS system was developed nearly 30 years ago when gynecologic surgery was not predominantly performed by women.

Dr. Levy is a voluntary clinical professor in the department of obstetrics, gynecology, and reproductive sciences at University of California San Diego Health, the former vice president of health policy at ACOG, past chair of the AMA/RUC, and current voting member of the AMA CPT editorial panel. She reported no relevant financial disclosures.

In a recent commentary published in Obstetrics & Gynecology, Katie L. Watson, JD, and Louise P. King, MD, JD, describe the issue of “double discrimination” in gynecologic surgery. The authors outlined how lower pay in a specialty where a majority of the surgeons and all of the patients are women may impact quality of care.

The commentary raises a number of concerns in gynecologic surgery that are important to discuss. Ob.gyn. as a whole is underpaid, as are many nonprocedural specialties such as family medicine and internal medicine. When ob.gyns. were predominantly men, the same situation existed – ob.gyns. were paid less than many other procedural specialties. While we’ve come a long way from the relative value unit (RVU) originally determined from the Harvard studies 30 years ago, there is room for additional improvement.

Several rationales were proposed by the authors to explain the disparities in pay between gynecologic surgery and those in urology: patient gender, surgeon gender, and length of training for gynecologic surgeons. The authors cited comparisons between urology and gynecology regarding “anatomically similar, sex-specific procedures” which require closer examination. Many of the code pairs selected were not actually comparable services. For example, management of Peyronie’s disease is a highly complex treatment performed by urologists that is not comparable with vaginectomy, yet this is an example of two codes used in the reference cited by the authors to conclude that surgeries on women are undervalued.

The overall RVUs for a procedure are also dependent upon the global period. The Centers for Medicare & Medicaid Services designated RVUs as the total amount of work before, during, and after a procedure. If a surgery has a 90-day global period, all the work for 90 days thereafter is bundled into the value, whereas if something is a zero-day global, only that day’s work is counted. A gynecologic surgeon who sees a patient back two or three times is coding and billing for those encounters in addition to that initial procedure.

Many of the code comparisons used in the analysis of gender in RVUs compared services with different global periods. Finally, some of the services that were compared had vastly different utilization. Some of the services and codes that were compared are performed extremely rarely and for that reason have not had their values reassessed over the years. There may be inequities in the RVUs for these services, but they will account for extremely little in overall compensation.

As a former chair of the American Medical Association’s RVS Update Committee (RUC), I spent years attempting to revalue ob.gyn. procedures. CMS assigns work RVUs based on physician work, practice expense, and professional liability insurance. The work is calculated using total physician time and intensity based on surveys completed by the specialty. The American College of Obstetrician and Gynecologist’s Committee on Health Economics and Coding, and the AMA RUC have worked diligently over many years to reassess potentially misvalued services. The ultimate RVUs assigned by CMS for gynecologic surgery are determined by the surveys completed by ACOG members. One issue we encountered with reexamining some procedures under RBRVS is that they have become so low volume that it has been difficult to justify the cost and effort to revalue them.

Lack of ob.gyn. training isn’t the full story

On average, ob.gyns. have between 18 and 24 months of surgical training, which is significantly less than other specialties. Lack of training in gynecologic surgery was proposed as another explanation for reduced compensation among female gynecologic surgeons. This is a complex issue not adequately explained by training time for gynecologic surgeons alone. While the number of trained ob.gyns. has increased in recent decades, the surgical volume has diminished and the workload of gynecologic surgery is far lower than it used to be. Surgical volume during and after training was much higher 35 years ago, prior to the advancements of procedures like endometrial ablation or tubal ligation. Women who had finished childbearing often underwent vaginal hysterectomies to manage contraception along with various other conditions.

With the advent of minimally invasive surgery, laparoscopic sterilization became possible, which has reduced the number of hysterectomies performed. Endometrial ablation is an office-based, noninvasive procedure. The development of the levonorgestrel IUD has helped manage abnormal bleeding, further reducing the need for hysterectomy.

This reduction in surgical volume does have an impact on quality of care. The model of tracking surgical outcomes at Kaiser Health System, as mentioned by the authors, could work well in some, but not all centers. A more approachable solution to address surgical volume for the average ob.gyn. would be to implement a mentoring and coaching process whereby recently trained ob.gyns. assist their senior partner(s) in surgery. This was the model years ago: I was trained by an ob.gyn. who was trained as a general surgeon. It was through the experience of assisting on each one of his cases – and him assisting on each one of my cases – that I received incredibly thorough surgical training.

These changes in practice, however, do not impact reimbursement. Rather than discrimination based on the gender of the surgeon, lower salaries in ob.gyn. are more likely to be the result of these and other factors.

The wage and quality gap in ob.gyn.

As a predominantly female surgical specialty, some of the disparity between gynecology and urology could be explained by how each specialty values its work. Here, gender plays a role in that when ob.gyns. are surveyed during the RUC process they may undervalue their work by reporting they can perform a procedure (and the before and after care) faster than what a urologist reports. The survey results may then result in lower RVUs.

Ob.gyn. is an overpopulated specialty for the number of surgeons needed to manage the volume of gynecologic surgery. When a health system wants to hire a general ob.gyn., it doesn’t have trouble finding one, while urologists are more challenging to recruit. This is not because of the structure of resource-based relative value scale (RBRVS) – despite the overall RVUs for gynecologic surgery, gynecologic oncologists are often paid well because health systems need them – but rather to the market economy of hiring physicians in specialty areas where there is demand.

Women are also chronically undervalued for the hours that we spend with patients. Data show that we spend more time with patients, which does not generate as many RVUs, but it generates better outcomes for patients. Evidence shows that women doctors in internal medicine and family medicine have better outcomes than doctors who are men.

On Jan. 1, 2021, Medicare and other payers implemented a new structure to reporting the level of office visit based on either medical decision-making or time spent on the date of encounter. Time spent with patients will now be rewarded – increased RVUs for increased time.

Part of the solution is value-based medicine and moving away from counting RVUs. This is also an opportunity to look at where time is spent in general ob.gyn. training and redistribute it, focusing on what trainees need for their education and not what hospitals need to service labor and delivery. We should step back and look creatively at optimizing the education and the training of ob.gyns., and where possible utilize other health care professionals such as nurse practitioners and midwives to address the uncomplicated obstetric needs of the hospital which could free up ob.gyn. trainees to obtain further surgical education.

To be clear, gender discrimination in compensation is prevalent and a persistent problem in medicine – ob.gyn. is no exception. Many ob.gyns. are employed by large health systems with payment structures and incentives that don’t align with those of the physician or the patient. There is definite misalignment in the way salaries are determined. Transparency on salaries is a critical component of addressing the pay gap that exists between women and men in medicine and in other industries.

The pay gap as it relates to reimbursement for gynecologic surgery, however, is a more complex matter that relates to how the RBRVS system was developed nearly 30 years ago when gynecologic surgery was not predominantly performed by women.

Dr. Levy is a voluntary clinical professor in the department of obstetrics, gynecology, and reproductive sciences at University of California San Diego Health, the former vice president of health policy at ACOG, past chair of the AMA/RUC, and current voting member of the AMA CPT editorial panel. She reported no relevant financial disclosures.

In a recent commentary published in Obstetrics & Gynecology, Katie L. Watson, JD, and Louise P. King, MD, JD, describe the issue of “double discrimination” in gynecologic surgery. The authors outlined how lower pay in a specialty where a majority of the surgeons and all of the patients are women may impact quality of care.

The commentary raises a number of concerns in gynecologic surgery that are important to discuss. Ob.gyn. as a whole is underpaid, as are many nonprocedural specialties such as family medicine and internal medicine. When ob.gyns. were predominantly men, the same situation existed – ob.gyns. were paid less than many other procedural specialties. While we’ve come a long way from the relative value unit (RVU) originally determined from the Harvard studies 30 years ago, there is room for additional improvement.

Several rationales were proposed by the authors to explain the disparities in pay between gynecologic surgery and those in urology: patient gender, surgeon gender, and length of training for gynecologic surgeons. The authors cited comparisons between urology and gynecology regarding “anatomically similar, sex-specific procedures” which require closer examination. Many of the code pairs selected were not actually comparable services. For example, management of Peyronie’s disease is a highly complex treatment performed by urologists that is not comparable with vaginectomy, yet this is an example of two codes used in the reference cited by the authors to conclude that surgeries on women are undervalued.

The overall RVUs for a procedure are also dependent upon the global period. The Centers for Medicare & Medicaid Services designated RVUs as the total amount of work before, during, and after a procedure. If a surgery has a 90-day global period, all the work for 90 days thereafter is bundled into the value, whereas if something is a zero-day global, only that day’s work is counted. A gynecologic surgeon who sees a patient back two or three times is coding and billing for those encounters in addition to that initial procedure.

Many of the code comparisons used in the analysis of gender in RVUs compared services with different global periods. Finally, some of the services that were compared had vastly different utilization. Some of the services and codes that were compared are performed extremely rarely and for that reason have not had their values reassessed over the years. There may be inequities in the RVUs for these services, but they will account for extremely little in overall compensation.

As a former chair of the American Medical Association’s RVS Update Committee (RUC), I spent years attempting to revalue ob.gyn. procedures. CMS assigns work RVUs based on physician work, practice expense, and professional liability insurance. The work is calculated using total physician time and intensity based on surveys completed by the specialty. The American College of Obstetrician and Gynecologist’s Committee on Health Economics and Coding, and the AMA RUC have worked diligently over many years to reassess potentially misvalued services. The ultimate RVUs assigned by CMS for gynecologic surgery are determined by the surveys completed by ACOG members. One issue we encountered with reexamining some procedures under RBRVS is that they have become so low volume that it has been difficult to justify the cost and effort to revalue them.

Lack of ob.gyn. training isn’t the full story

On average, ob.gyns. have between 18 and 24 months of surgical training, which is significantly less than other specialties. Lack of training in gynecologic surgery was proposed as another explanation for reduced compensation among female gynecologic surgeons. This is a complex issue not adequately explained by training time for gynecologic surgeons alone. While the number of trained ob.gyns. has increased in recent decades, the surgical volume has diminished and the workload of gynecologic surgery is far lower than it used to be. Surgical volume during and after training was much higher 35 years ago, prior to the advancements of procedures like endometrial ablation or tubal ligation. Women who had finished childbearing often underwent vaginal hysterectomies to manage contraception along with various other conditions.

With the advent of minimally invasive surgery, laparoscopic sterilization became possible, which has reduced the number of hysterectomies performed. Endometrial ablation is an office-based, noninvasive procedure. The development of the levonorgestrel IUD has helped manage abnormal bleeding, further reducing the need for hysterectomy.

This reduction in surgical volume does have an impact on quality of care. The model of tracking surgical outcomes at Kaiser Health System, as mentioned by the authors, could work well in some, but not all centers. A more approachable solution to address surgical volume for the average ob.gyn. would be to implement a mentoring and coaching process whereby recently trained ob.gyns. assist their senior partner(s) in surgery. This was the model years ago: I was trained by an ob.gyn. who was trained as a general surgeon. It was through the experience of assisting on each one of his cases – and him assisting on each one of my cases – that I received incredibly thorough surgical training.

These changes in practice, however, do not impact reimbursement. Rather than discrimination based on the gender of the surgeon, lower salaries in ob.gyn. are more likely to be the result of these and other factors.

The wage and quality gap in ob.gyn.

As a predominantly female surgical specialty, some of the disparity between gynecology and urology could be explained by how each specialty values its work. Here, gender plays a role in that when ob.gyns. are surveyed during the RUC process they may undervalue their work by reporting they can perform a procedure (and the before and after care) faster than what a urologist reports. The survey results may then result in lower RVUs.

Ob.gyn. is an overpopulated specialty for the number of surgeons needed to manage the volume of gynecologic surgery. When a health system wants to hire a general ob.gyn., it doesn’t have trouble finding one, while urologists are more challenging to recruit. This is not because of the structure of resource-based relative value scale (RBRVS) – despite the overall RVUs for gynecologic surgery, gynecologic oncologists are often paid well because health systems need them – but rather to the market economy of hiring physicians in specialty areas where there is demand.

Women are also chronically undervalued for the hours that we spend with patients. Data show that we spend more time with patients, which does not generate as many RVUs, but it generates better outcomes for patients. Evidence shows that women doctors in internal medicine and family medicine have better outcomes than doctors who are men.

On Jan. 1, 2021, Medicare and other payers implemented a new structure to reporting the level of office visit based on either medical decision-making or time spent on the date of encounter. Time spent with patients will now be rewarded – increased RVUs for increased time.

Part of the solution is value-based medicine and moving away from counting RVUs. This is also an opportunity to look at where time is spent in general ob.gyn. training and redistribute it, focusing on what trainees need for their education and not what hospitals need to service labor and delivery. We should step back and look creatively at optimizing the education and the training of ob.gyns., and where possible utilize other health care professionals such as nurse practitioners and midwives to address the uncomplicated obstetric needs of the hospital which could free up ob.gyn. trainees to obtain further surgical education.

To be clear, gender discrimination in compensation is prevalent and a persistent problem in medicine – ob.gyn. is no exception. Many ob.gyns. are employed by large health systems with payment structures and incentives that don’t align with those of the physician or the patient. There is definite misalignment in the way salaries are determined. Transparency on salaries is a critical component of addressing the pay gap that exists between women and men in medicine and in other industries.

The pay gap as it relates to reimbursement for gynecologic surgery, however, is a more complex matter that relates to how the RBRVS system was developed nearly 30 years ago when gynecologic surgery was not predominantly performed by women.

Dr. Levy is a voluntary clinical professor in the department of obstetrics, gynecology, and reproductive sciences at University of California San Diego Health, the former vice president of health policy at ACOG, past chair of the AMA/RUC, and current voting member of the AMA CPT editorial panel. She reported no relevant financial disclosures.

Before COVID-19, postural orthostatic tachycardia syndrome (POTS) was one of those diseases that many people, including physicians, dismissed.

“They thought it was just anxious, crazy young women,” said Pam R. Taub, MD, who runs the cardiac rehabilitation program at the University of California, San Diego.

The cryptic autonomic condition was estimated to affect 1-3 million Americans before the pandemic hit. Now case reports confirm that it is a manifestation of postacute sequelae of SARS-CoV-2 infection (PASC), or so-called long-haul COVID-19.

“I’m excited that this condition that has been so often the ugly stepchild of both cardiology and neurology is getting some attention,” said Dr. Taub. She said she is hopeful that the National Institutes of Health’s commitment to PASC research will benefit patients affected by the cardiovascular dysautonomia characterized by orthostatic intolerance in the absence of orthostatic hypotension.

Postinfection POTS is not exclusive to SARS-CoV-2. It has been reported after Lyme disease and Epstein-Barr virus infections, for example. One theory is that some of the antibodies generated against the virus cross react and damage the autonomic nervous system, which regulates heart rate and blood pressure, Dr. Taub explained.

It is not known whether COVID-19 is more likely to trigger POTS than are other infections or whether the rise in cases merely reflects the fact that more than 115 million people worldwide have been infected with the novel coronavirus.

Medscape

Low blood volume, dysregulation of the autonomic nervous system, and autoimmunity may all play a role in POTS, perhaps leading to distinct subtypes, according to a State of the Science document from the NIH; the National Heart, Lung, and Blood Institute; and the National Institute of Neurological Disorders and Stroke.

In Dr. Taub’s experience, “The truth is that patients actually have a mix of the subtypes.”

Kamal Shouman, MD, an autonomic neurologist at Mayo Clinic, Rochester, Minn., said in an interview that he has seen patients present with post–COVID-19 POTS in “all flavors,” including “neuropathic POTS, which is thought of as the classic postinfectious phenomenon.”

Why does it mostly affect athletic women?

The condition, which can be the result of dehydration or prolonged bed rest, leading to deconditioning, affects women disproportionately.

According to Manesh Patel, MD, if a patient with POTS who is not a young woman is presented on medical rounds, the response is, “Tell me again why you think this patient has POTS.”

Mitchel L. Zoler/MDedge News

Poor (wo)man’s tilt test and treatment options

POTS is typically diagnosed with a tilt test and transcranial Doppler. Dr. Taub described her “poor man’s tilt test” of asking the patient to lie down for 5-10 minutes and then having the patient stand up.

She likes the fact that transcranial Doppler helps validate the brain fog that patients report, which can be dismissed as “just your excuse for not wanting to work.” If blood perfusion to the brain is cut by 40%-50%, “how are you going to think clearly?” she said.

Dr. Shouman noted that overall volume expansion with salt water, compression garments, and a graduated exercise program play a major role in the rehabilitation of all POTS patients.

He likes to tailor treatments to the most likely underlying cause. But patients should first undergo a medical assessment by their internists to make sure there isn’t a primary lung or heart problem.

“Once the decision is made for them to be evaluated in the autonomic practice and [a] POTS diagnosis is made, I think it is very useful to determine what type of POTS,” he said.

With hyperadrenergic POTS, “you are looking at a standing norepinephrine level of over 600 pg/mL or so.” For these patients, drugs such as ivabradine or beta-blockers can help, he noted.

Dr. Taub recently conducted a small study that showed a benefit with the selective I_f channel blocker ivabradine for patients with hyperadrenergic POTS unrelated to COVID-19. She tends to favor ivabradine over beta-blockers because it lowers heart rate but not blood pressure. In addition, beta-blockers can exacerbate fatigue and brain fog.

A small crossover study will compare propranolol and ivabradine in POTS. For someone who is very hypovolemic, “you might try a salt tablet or a prescription drug like fludrocortisone,” Dr. Taub explained.

Another problem that patients with POTS experience is an inability to exercise because of orthostatic intolerance. Recumbent exercise targets deconditioning and can tamp down the hyperadrenergic effect. Dr. Shouman’s approach is to start gradually with swimming or the use of a recumbent bike or a rowing machine.

Dr. Taub recommends wearables to patients because POTS is “a very dynamic condition” that is easy to overmedicate or undermedicate. If it’s a good day, the patients are well hydrated, and the standing heart rate is only 80 bpm, she tells them they could titrate down their second dose of ivabradine, for example. The feedback from wearables also helps patients manage their exercise response.

For Dr. Shouman, wearables are not always as accurate as he would like. He tells his patients that it’s okay to use one as long as it doesn’t become a source of anxiety such that they’re constantly checking it.
 

POTS hope: A COVID-19 silver lining?

With increasing attention being paid to long-haul COVID-19, are there any concerns that POTS will get lost among the myriad symptoms connected to PASC?

Dr. Shouman cautioned, “Not all long COVID is POTS,” and said that clinicians at long-haul clinics should be able to recognize the different conditions “when POTS is suspected. I think it is useful for those providers to make the appropriate referral for POTS clinic autonomic assessment.”

He and his colleagues at Mayo have seen quite a few patients who have post–COVID-19 autonomic dysfunction, such as vasodepressor syncope, not just POTS. They plan to write about this soon.

“Of all the things I treat in cardiology, this is the most complex, because there’s so many different systems involved,” said Dr. Taub, who has seen patients recover fully from POTS. “There’s a spectrum, and there’s people that are definitely on one end of the spectrum where they have very severe diseases.”

For her, the important message is, “No matter where you are on the spectrum, there are things we can do to make your symptoms better.” And with grant funding for PASC research, “hopefully we will address the mechanisms of disease, and we’ll be able to cure this,” she said.

Dr. Patel has served as a consultant for Bayer, Janssen, AstraZeneca, and Heartflow and has received research grants from Bayer, Janssen, AstraZeneca, and the National Heart, Lung, and Blood Institute. Dr. Shouman reports no relevant financial relationships. Dr. Taub has served as a consultant for Amgen, Bayer, Esperion, Boehringer Ingelheim, Novo Nordisk, and Sanofi; is a shareholder in Epirium Bio; and has received research grants from the National Institutes of Health, the American Heart Association, and the Department of Homeland Security/FEMA.

A version of this article first appeared on Medscape.com.

Before COVID-19, postural orthostatic tachycardia syndrome (POTS) was one of those diseases that many people, including physicians, dismissed.

“They thought it was just anxious, crazy young women,” said Pam R. Taub, MD, who runs the cardiac rehabilitation program at the University of California, San Diego.

The cryptic autonomic condition was estimated to affect 1-3 million Americans before the pandemic hit. Now case reports confirm that it is a manifestation of postacute sequelae of SARS-CoV-2 infection (PASC), or so-called long-haul COVID-19.

“I’m excited that this condition that has been so often the ugly stepchild of both cardiology and neurology is getting some attention,” said Dr. Taub. She said she is hopeful that the National Institutes of Health’s commitment to PASC research will benefit patients affected by the cardiovascular dysautonomia characterized by orthostatic intolerance in the absence of orthostatic hypotension.

Postinfection POTS is not exclusive to SARS-CoV-2. It has been reported after Lyme disease and Epstein-Barr virus infections, for example. One theory is that some of the antibodies generated against the virus cross react and damage the autonomic nervous system, which regulates heart rate and blood pressure, Dr. Taub explained.

It is not known whether COVID-19 is more likely to trigger POTS than are other infections or whether the rise in cases merely reflects the fact that more than 115 million people worldwide have been infected with the novel coronavirus.

Medscape

Low blood volume, dysregulation of the autonomic nervous system, and autoimmunity may all play a role in POTS, perhaps leading to distinct subtypes, according to a State of the Science document from the NIH; the National Heart, Lung, and Blood Institute; and the National Institute of Neurological Disorders and Stroke.

In Dr. Taub’s experience, “The truth is that patients actually have a mix of the subtypes.”

Kamal Shouman, MD, an autonomic neurologist at Mayo Clinic, Rochester, Minn., said in an interview that he has seen patients present with post–COVID-19 POTS in “all flavors,” including “neuropathic POTS, which is thought of as the classic postinfectious phenomenon.”

Why does it mostly affect athletic women?

The condition, which can be the result of dehydration or prolonged bed rest, leading to deconditioning, affects women disproportionately.

According to Manesh Patel, MD, if a patient with POTS who is not a young woman is presented on medical rounds, the response is, “Tell me again why you think this patient has POTS.”

Mitchel L. Zoler/MDedge News

Poor (wo)man’s tilt test and treatment options

POTS is typically diagnosed with a tilt test and transcranial Doppler. Dr. Taub described her “poor man’s tilt test” of asking the patient to lie down for 5-10 minutes and then having the patient stand up.

She likes the fact that transcranial Doppler helps validate the brain fog that patients report, which can be dismissed as “just your excuse for not wanting to work.” If blood perfusion to the brain is cut by 40%-50%, “how are you going to think clearly?” she said.

Dr. Shouman noted that overall volume expansion with salt water, compression garments, and a graduated exercise program play a major role in the rehabilitation of all POTS patients.

He likes to tailor treatments to the most likely underlying cause. But patients should first undergo a medical assessment by their internists to make sure there isn’t a primary lung or heart problem.

“Once the decision is made for them to be evaluated in the autonomic practice and [a] POTS diagnosis is made, I think it is very useful to determine what type of POTS,” he said.

With hyperadrenergic POTS, “you are looking at a standing norepinephrine level of over 600 pg/mL or so.” For these patients, drugs such as ivabradine or beta-blockers can help, he noted.

Dr. Taub recently conducted a small study that showed a benefit with the selective I_f channel blocker ivabradine for patients with hyperadrenergic POTS unrelated to COVID-19. She tends to favor ivabradine over beta-blockers because it lowers heart rate but not blood pressure. In addition, beta-blockers can exacerbate fatigue and brain fog.

A small crossover study will compare propranolol and ivabradine in POTS. For someone who is very hypovolemic, “you might try a salt tablet or a prescription drug like fludrocortisone,” Dr. Taub explained.

Another problem that patients with POTS experience is an inability to exercise because of orthostatic intolerance. Recumbent exercise targets deconditioning and can tamp down the hyperadrenergic effect. Dr. Shouman’s approach is to start gradually with swimming or the use of a recumbent bike or a rowing machine.

Dr. Taub recommends wearables to patients because POTS is “a very dynamic condition” that is easy to overmedicate or undermedicate. If it’s a good day, the patients are well hydrated, and the standing heart rate is only 80 bpm, she tells them they could titrate down their second dose of ivabradine, for example. The feedback from wearables also helps patients manage their exercise response.

For Dr. Shouman, wearables are not always as accurate as he would like. He tells his patients that it’s okay to use one as long as it doesn’t become a source of anxiety such that they’re constantly checking it.
 

POTS hope: A COVID-19 silver lining?

With increasing attention being paid to long-haul COVID-19, are there any concerns that POTS will get lost among the myriad symptoms connected to PASC?

Dr. Shouman cautioned, “Not all long COVID is POTS,” and said that clinicians at long-haul clinics should be able to recognize the different conditions “when POTS is suspected. I think it is useful for those providers to make the appropriate referral for POTS clinic autonomic assessment.”

He and his colleagues at Mayo have seen quite a few patients who have post–COVID-19 autonomic dysfunction, such as vasodepressor syncope, not just POTS. They plan to write about this soon.

“Of all the things I treat in cardiology, this is the most complex, because there’s so many different systems involved,” said Dr. Taub, who has seen patients recover fully from POTS. “There’s a spectrum, and there’s people that are definitely on one end of the spectrum where they have very severe diseases.”

For her, the important message is, “No matter where you are on the spectrum, there are things we can do to make your symptoms better.” And with grant funding for PASC research, “hopefully we will address the mechanisms of disease, and we’ll be able to cure this,” she said.

Dr. Patel has served as a consultant for Bayer, Janssen, AstraZeneca, and Heartflow and has received research grants from Bayer, Janssen, AstraZeneca, and the National Heart, Lung, and Blood Institute. Dr. Shouman reports no relevant financial relationships. Dr. Taub has served as a consultant for Amgen, Bayer, Esperion, Boehringer Ingelheim, Novo Nordisk, and Sanofi; is a shareholder in Epirium Bio; and has received research grants from the National Institutes of Health, the American Heart Association, and the Department of Homeland Security/FEMA.

A version of this article first appeared on Medscape.com.

Before COVID-19, postural orthostatic tachycardia syndrome (POTS) was one of those diseases that many people, including physicians, dismissed.

“They thought it was just anxious, crazy young women,” said Pam R. Taub, MD, who runs the cardiac rehabilitation program at the University of California, San Diego.

The cryptic autonomic condition was estimated to affect 1-3 million Americans before the pandemic hit. Now case reports confirm that it is a manifestation of postacute sequelae of SARS-CoV-2 infection (PASC), or so-called long-haul COVID-19.

“I’m excited that this condition that has been so often the ugly stepchild of both cardiology and neurology is getting some attention,” said Dr. Taub. She said she is hopeful that the National Institutes of Health’s commitment to PASC research will benefit patients affected by the cardiovascular dysautonomia characterized by orthostatic intolerance in the absence of orthostatic hypotension.

Postinfection POTS is not exclusive to SARS-CoV-2. It has been reported after Lyme disease and Epstein-Barr virus infections, for example. One theory is that some of the antibodies generated against the virus cross react and damage the autonomic nervous system, which regulates heart rate and blood pressure, Dr. Taub explained.

It is not known whether COVID-19 is more likely to trigger POTS than are other infections or whether the rise in cases merely reflects the fact that more than 115 million people worldwide have been infected with the novel coronavirus.

Medscape

Low blood volume, dysregulation of the autonomic nervous system, and autoimmunity may all play a role in POTS, perhaps leading to distinct subtypes, according to a State of the Science document from the NIH; the National Heart, Lung, and Blood Institute; and the National Institute of Neurological Disorders and Stroke.

In Dr. Taub’s experience, “The truth is that patients actually have a mix of the subtypes.”

Kamal Shouman, MD, an autonomic neurologist at Mayo Clinic, Rochester, Minn., said in an interview that he has seen patients present with post–COVID-19 POTS in “all flavors,” including “neuropathic POTS, which is thought of as the classic postinfectious phenomenon.”

Why does it mostly affect athletic women?

The condition, which can be the result of dehydration or prolonged bed rest, leading to deconditioning, affects women disproportionately.

According to Manesh Patel, MD, if a patient with POTS who is not a young woman is presented on medical rounds, the response is, “Tell me again why you think this patient has POTS.”

Mitchel L. Zoler/MDedge News

Poor (wo)man’s tilt test and treatment options

POTS is typically diagnosed with a tilt test and transcranial Doppler. Dr. Taub described her “poor man’s tilt test” of asking the patient to lie down for 5-10 minutes and then having the patient stand up.

She likes the fact that transcranial Doppler helps validate the brain fog that patients report, which can be dismissed as “just your excuse for not wanting to work.” If blood perfusion to the brain is cut by 40%-50%, “how are you going to think clearly?” she said.

Dr. Shouman noted that overall volume expansion with salt water, compression garments, and a graduated exercise program play a major role in the rehabilitation of all POTS patients.

He likes to tailor treatments to the most likely underlying cause. But patients should first undergo a medical assessment by their internists to make sure there isn’t a primary lung or heart problem.

“Once the decision is made for them to be evaluated in the autonomic practice and [a] POTS diagnosis is made, I think it is very useful to determine what type of POTS,” he said.

With hyperadrenergic POTS, “you are looking at a standing norepinephrine level of over 600 pg/mL or so.” For these patients, drugs such as ivabradine or beta-blockers can help, he noted.

Dr. Taub recently conducted a small study that showed a benefit with the selective I_f channel blocker ivabradine for patients with hyperadrenergic POTS unrelated to COVID-19. She tends to favor ivabradine over beta-blockers because it lowers heart rate but not blood pressure. In addition, beta-blockers can exacerbate fatigue and brain fog.

A small crossover study will compare propranolol and ivabradine in POTS. For someone who is very hypovolemic, “you might try a salt tablet or a prescription drug like fludrocortisone,” Dr. Taub explained.

Another problem that patients with POTS experience is an inability to exercise because of orthostatic intolerance. Recumbent exercise targets deconditioning and can tamp down the hyperadrenergic effect. Dr. Shouman’s approach is to start gradually with swimming or the use of a recumbent bike or a rowing machine.

Dr. Taub recommends wearables to patients because POTS is “a very dynamic condition” that is easy to overmedicate or undermedicate. If it’s a good day, the patients are well hydrated, and the standing heart rate is only 80 bpm, she tells them they could titrate down their second dose of ivabradine, for example. The feedback from wearables also helps patients manage their exercise response.

For Dr. Shouman, wearables are not always as accurate as he would like. He tells his patients that it’s okay to use one as long as it doesn’t become a source of anxiety such that they’re constantly checking it.
 

POTS hope: A COVID-19 silver lining?

With increasing attention being paid to long-haul COVID-19, are there any concerns that POTS will get lost among the myriad symptoms connected to PASC?

Dr. Shouman cautioned, “Not all long COVID is POTS,” and said that clinicians at long-haul clinics should be able to recognize the different conditions “when POTS is suspected. I think it is useful for those providers to make the appropriate referral for POTS clinic autonomic assessment.”

He and his colleagues at Mayo have seen quite a few patients who have post–COVID-19 autonomic dysfunction, such as vasodepressor syncope, not just POTS. They plan to write about this soon.

“Of all the things I treat in cardiology, this is the most complex, because there’s so many different systems involved,” said Dr. Taub, who has seen patients recover fully from POTS. “There’s a spectrum, and there’s people that are definitely on one end of the spectrum where they have very severe diseases.”

For her, the important message is, “No matter where you are on the spectrum, there are things we can do to make your symptoms better.” And with grant funding for PASC research, “hopefully we will address the mechanisms of disease, and we’ll be able to cure this,” she said.

Dr. Patel has served as a consultant for Bayer, Janssen, AstraZeneca, and Heartflow and has received research grants from Bayer, Janssen, AstraZeneca, and the National Heart, Lung, and Blood Institute. Dr. Shouman reports no relevant financial relationships. Dr. Taub has served as a consultant for Amgen, Bayer, Esperion, Boehringer Ingelheim, Novo Nordisk, and Sanofi; is a shareholder in Epirium Bio; and has received research grants from the National Institutes of Health, the American Heart Association, and the Department of Homeland Security/FEMA.

A version of this article first appeared on Medscape.com.

To the Editor:

Cutaneous amyloidosis can be secondary to many causes. We describe a case of amyloidosis that was secondary to the deposition of an antiretroviral drug enfuvirtide and clinically presented as bullae over the anterior abdominal wall.

A 65-year-old man with HIV presented with pink vesicles and flaccid bullae on the anterolateral aspect of the lower abdomen (Figure 1) in areas of self-administered subcutaneous injections of enfuvirtide. He reported tissue swelling with a yellow discoloration immediately after injections that would spontaneously subside after a few minutes.

In summary, several types of cutaneous amyloidosis occur, including secondary cutaneous involvement by systemic amyloidosis and drug-induced amyloidosis, and notable histopathologic overlap exists between these types. Given the differing treatment requirements depending on the type of cutaneous amyloidosis, obtaining an appropriate clinical history, including the patient’s medication list, is important to ensure the correct diagnosis is reached. Protein analysis with mass spectrometry can be used if the nature of the amyloid remains indeterminate.

To the Editor:

Cutaneous amyloidosis can be secondary to many causes. We describe a case of amyloidosis that was secondary to the deposition of an antiretroviral drug enfuvirtide and clinically presented as bullae over the anterior abdominal wall.

A 65-year-old man with HIV presented with pink vesicles and flaccid bullae on the anterolateral aspect of the lower abdomen (Figure 1) in areas of self-administered subcutaneous injections of enfuvirtide. He reported tissue swelling with a yellow discoloration immediately after injections that would spontaneously subside after a few minutes.

In summary, several types of cutaneous amyloidosis occur, including secondary cutaneous involvement by systemic amyloidosis and drug-induced amyloidosis, and notable histopathologic overlap exists between these types. Given the differing treatment requirements depending on the type of cutaneous amyloidosis, obtaining an appropriate clinical history, including the patient’s medication list, is important to ensure the correct diagnosis is reached. Protein analysis with mass spectrometry can be used if the nature of the amyloid remains indeterminate.

To the Editor:

Cutaneous amyloidosis can be secondary to many causes. We describe a case of amyloidosis that was secondary to the deposition of an antiretroviral drug enfuvirtide and clinically presented as bullae over the anterior abdominal wall.

A 65-year-old man with HIV presented with pink vesicles and flaccid bullae on the anterolateral aspect of the lower abdomen (Figure 1) in areas of self-administered subcutaneous injections of enfuvirtide. He reported tissue swelling with a yellow discoloration immediately after injections that would spontaneously subside after a few minutes.

In summary, several types of cutaneous amyloidosis occur, including secondary cutaneous involvement by systemic amyloidosis and drug-induced amyloidosis, and notable histopathologic overlap exists between these types. Given the differing treatment requirements depending on the type of cutaneous amyloidosis, obtaining an appropriate clinical history, including the patient’s medication list, is important to ensure the correct diagnosis is reached. Protein analysis with mass spectrometry can be used if the nature of the amyloid remains indeterminate.

Approximately 20% of shoe allergens are not detected with the current screening series, according to a retrospective study of more than 30,000 patients.

Contact allergy to shoes remains a common but difficult problem for many reasons, including the limited information from shoe manufacturers, differences in shoe manufacturing processes, and changes in shoe trends, said Raina Bembry, MD, a dermatitis research fellow at Duke University, Durham, N.C., in a presentation at the annual meeting of the American Contact Dermatitis Society.

The North American Contact Dermatitis Group (NACDG) published data on shoe allergens from 2001-2004 in a 2007 review. To update this information to reflect changes in shoe manufacturing and trends, she and her coinvestigators characterized demographics, clinical characteristics, patch test results, and occupational data for NACDG patients with shoe contact allergy. They identified 33,661 patients who were patch tested with the standard series with or without a supplemental allergen between 2005 and 2018; over half were over aged 40.

The primary focus was individuals with a confirmed shoe (defined as shoes, boots, sandals, or slippers) as the source of a screening allergen or supplemental allergen, a positive patch test, and the foot as one of three sites of involvement. A total of 352 individuals met these criteria and had a confirmed final diagnosis of allergic contact dermatitis, Dr. Bembry said. Compared with individuals who had positive patch tests without a confirmed diagnosis, those with confirmed allergic dermatitis were significantly more likely to be male (odds ratio, 3.36) and less likely to be over aged 40 years (OR, 0.49).

The most common NACDG screening allergen, potassium dichromate, was found in 29.8% of the study population, followed by p-tert-butylphenol formaldehyde resin in 20.1%, thiuram mix (13.3%), mixed dialkyl thioureas (12.6%) and carba mix (12%).

Notably, 29.8% of the patients showed positive patch test reactions to supplemental allergens, and 12.2% only reacted to supplemental allergens, Dr. Bembry said.

The results were limited by several factors, including referral selection bias, reliance on clinical judgment for patch test interpretations, and lack of data on the specifics of the supplemental allergens other than the source code, she said. In addition, the study does not identify nonshoe sources of foot contact allergy, and six screening allergens were not testing during this study period.

Overall, the findings were similar to those from previous studies in that patients affected with contact dermatitis from shoe allergens tended to be younger and male, with no occupational relevance to the reaction, said Dr. Bembry.

The finding that almost 20% of allergens were not found with the screening series emphasizes the value of testing not only relevant supplemental allergens, but also patient products and shoe components, she concluded.

Dr. Bembry had no financial conflicts to disclose. Coauthor Amber Atwater, MD, the immediate past president of the ACDS, and associate professor of dermatology at Duke University, disclosed receiving the Pfizer Independent Grant for Learning & Change and consulting for Henkel.

Approximately 20% of shoe allergens are not detected with the current screening series, according to a retrospective study of more than 30,000 patients.

Contact allergy to shoes remains a common but difficult problem for many reasons, including the limited information from shoe manufacturers, differences in shoe manufacturing processes, and changes in shoe trends, said Raina Bembry, MD, a dermatitis research fellow at Duke University, Durham, N.C., in a presentation at the annual meeting of the American Contact Dermatitis Society.

The North American Contact Dermatitis Group (NACDG) published data on shoe allergens from 2001-2004 in a 2007 review. To update this information to reflect changes in shoe manufacturing and trends, she and her coinvestigators characterized demographics, clinical characteristics, patch test results, and occupational data for NACDG patients with shoe contact allergy. They identified 33,661 patients who were patch tested with the standard series with or without a supplemental allergen between 2005 and 2018; over half were over aged 40.

The primary focus was individuals with a confirmed shoe (defined as shoes, boots, sandals, or slippers) as the source of a screening allergen or supplemental allergen, a positive patch test, and the foot as one of three sites of involvement. A total of 352 individuals met these criteria and had a confirmed final diagnosis of allergic contact dermatitis, Dr. Bembry said. Compared with individuals who had positive patch tests without a confirmed diagnosis, those with confirmed allergic dermatitis were significantly more likely to be male (odds ratio, 3.36) and less likely to be over aged 40 years (OR, 0.49).

The most common NACDG screening allergen, potassium dichromate, was found in 29.8% of the study population, followed by p-tert-butylphenol formaldehyde resin in 20.1%, thiuram mix (13.3%), mixed dialkyl thioureas (12.6%) and carba mix (12%).

Notably, 29.8% of the patients showed positive patch test reactions to supplemental allergens, and 12.2% only reacted to supplemental allergens, Dr. Bembry said.

The results were limited by several factors, including referral selection bias, reliance on clinical judgment for patch test interpretations, and lack of data on the specifics of the supplemental allergens other than the source code, she said. In addition, the study does not identify nonshoe sources of foot contact allergy, and six screening allergens were not testing during this study period.

Overall, the findings were similar to those from previous studies in that patients affected with contact dermatitis from shoe allergens tended to be younger and male, with no occupational relevance to the reaction, said Dr. Bembry.

The finding that almost 20% of allergens were not found with the screening series emphasizes the value of testing not only relevant supplemental allergens, but also patient products and shoe components, she concluded.

Dr. Bembry had no financial conflicts to disclose. Coauthor Amber Atwater, MD, the immediate past president of the ACDS, and associate professor of dermatology at Duke University, disclosed receiving the Pfizer Independent Grant for Learning & Change and consulting for Henkel.

Approximately 20% of shoe allergens are not detected with the current screening series, according to a retrospective study of more than 30,000 patients.

Contact allergy to shoes remains a common but difficult problem for many reasons, including the limited information from shoe manufacturers, differences in shoe manufacturing processes, and changes in shoe trends, said Raina Bembry, MD, a dermatitis research fellow at Duke University, Durham, N.C., in a presentation at the annual meeting of the American Contact Dermatitis Society.

The North American Contact Dermatitis Group (NACDG) published data on shoe allergens from 2001-2004 in a 2007 review. To update this information to reflect changes in shoe manufacturing and trends, she and her coinvestigators characterized demographics, clinical characteristics, patch test results, and occupational data for NACDG patients with shoe contact allergy. They identified 33,661 patients who were patch tested with the standard series with or without a supplemental allergen between 2005 and 2018; over half were over aged 40.

The primary focus was individuals with a confirmed shoe (defined as shoes, boots, sandals, or slippers) as the source of a screening allergen or supplemental allergen, a positive patch test, and the foot as one of three sites of involvement. A total of 352 individuals met these criteria and had a confirmed final diagnosis of allergic contact dermatitis, Dr. Bembry said. Compared with individuals who had positive patch tests without a confirmed diagnosis, those with confirmed allergic dermatitis were significantly more likely to be male (odds ratio, 3.36) and less likely to be over aged 40 years (OR, 0.49).

The most common NACDG screening allergen, potassium dichromate, was found in 29.8% of the study population, followed by p-tert-butylphenol formaldehyde resin in 20.1%, thiuram mix (13.3%), mixed dialkyl thioureas (12.6%) and carba mix (12%).

Notably, 29.8% of the patients showed positive patch test reactions to supplemental allergens, and 12.2% only reacted to supplemental allergens, Dr. Bembry said.

The results were limited by several factors, including referral selection bias, reliance on clinical judgment for patch test interpretations, and lack of data on the specifics of the supplemental allergens other than the source code, she said. In addition, the study does not identify nonshoe sources of foot contact allergy, and six screening allergens were not testing during this study period.

Overall, the findings were similar to those from previous studies in that patients affected with contact dermatitis from shoe allergens tended to be younger and male, with no occupational relevance to the reaction, said Dr. Bembry.

The finding that almost 20% of allergens were not found with the screening series emphasizes the value of testing not only relevant supplemental allergens, but also patient products and shoe components, she concluded.

Dr. Bembry had no financial conflicts to disclose. Coauthor Amber Atwater, MD, the immediate past president of the ACDS, and associate professor of dermatology at Duke University, disclosed receiving the Pfizer Independent Grant for Learning & Change and consulting for Henkel.

Febuxostat (Uloric) was not associated with increased cardiovascular risk in patients with gout when compared to those who used allopurinol, in an analysis of new users of the drugs in Medicare fee-for-service claims data from the period of 2008-2016.

The findings, published March 25 in the Journal of the American Heart Association, update and echo the results from a similar previous study by the same Brigham and Women’s Hospital research group that covered 2008-2013 Medicare claims data. That original claims data study from 2018 sought to confirm the findings of the postmarketing surveillance CARES (Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities) trial that led to a boxed warning for increased risk of cardiovascular and all-cause mortality vs. allopurinol. The trial, however, did not show a higher rate of major adverse cardiovascular events (MACE) overall with febuxostat.

The recency of the new data with more febuxostat-exposed patients overall provides greater reassurance on the safety of the drug, corresponding author Seoyoung C. Kim, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, said in an interview. “We also were able to get data on cause of death, which we did not have before when we conducted our first paper.”

Dr. Kim said she was not surprised by any of the findings, which were consistent with the results of her earlier work. “Our result on CV death also was consistent and reassuring,” she noted.

The newest Medicare claims study also corroborates results from FAST (Febuxostat Versus Allopurinol Streamlined Trial), a separate postmarketing surveillance study that was ordered by the European Medicines Agency after febuxostat’s approval in 2009. It showed that the two drugs were noninferior to each other for the risk of all-cause mortality or a composite cardiovascular outcome (hospitalization for nonfatal myocardial infarction, biomarker-positive acute coronary syndrome, nonfatal stroke, or cardiovascular death).

“While CARES showed higher CV death and all-cause death rates in febuxostat compared to allopurinol, FAST did not,” Dr. Kim noted. “Our study of more than 111,000 older gout patients treated with either febuxostat or allopurinol in real-world settings also did not find a difference in the risk of MACE, CV mortality, or all-cause mortality,” she added. “Taking these data all together, I think we can be more certain about the CV safety of febuxostat when its use is clinically indicated or needed,” she said.

Study details

Dr. Kim, first author Ajinkya Pawar, PhD, of Brigham and Women’s, and colleagues identified 467,461 people with gout aged 65 years and older who had been enrolled in Medicare for at least a year. They then used propensity-score matching to compare 27,881 first-time users of febuxostat with 83,643 first-time users of allopurinol on the primary outcome of the incidence of major adverse cardiovascular events (MACE), defined as the first occurrence of myocardial infarction, stroke, or cardiovascular mortality.

In the updated study, the mean follow‐up periods for febuxostat and allopurinol were 284 days and 339 days, respectively. Overall, febuxostat was noninferior to allopurinol with regard to MACE (hazard ratio, 0.99; 95% confidence interval, 0.93-1.05), and the results were consistent among patients with baseline CVD (HR, 0.94). In addition, rates of secondary outcomes of MI, stroke, and cardiovascular mortality were not significantly different between febuxostat and allopurinol patients, except for all-cause mortality (HR, 0.92; 95% CI, 0.87-0.98).

The study findings were limited mainly by the potential bias caused by nonadherence to medications, and potential for residual confounding and misclassification bias, the researchers noted.

However, the study was strengthened by its incident new-user design that allowed only patients with no use of either medication for a year before the first dispensing and its active comparator design, and the data are generalizable to the greater population of older gout patients, they said.

Consequently, the data from this large, real-world study support the safety of febuxostat with regard to cardiovascular risk in gout patients, including those with baseline cardiovascular disease, they concluded.

The study was supported by the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital. Dr. Kim disclosed research grants to Brigham and Women’s Hospital from Roche, Pfizer, AbbVie, and Bristol‐Myers Squibb for unrelated studies. Another author reported serving as the principal investigator with research grants from Vertex, Bayer, and Novartis to Brigham and Women’s Hospital for unrelated projects.

Febuxostat (Uloric) was not associated with increased cardiovascular risk in patients with gout when compared to those who used allopurinol, in an analysis of new users of the drugs in Medicare fee-for-service claims data from the period of 2008-2016.

The findings, published March 25 in the Journal of the American Heart Association, update and echo the results from a similar previous study by the same Brigham and Women’s Hospital research group that covered 2008-2013 Medicare claims data. That original claims data study from 2018 sought to confirm the findings of the postmarketing surveillance CARES (Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities) trial that led to a boxed warning for increased risk of cardiovascular and all-cause mortality vs. allopurinol. The trial, however, did not show a higher rate of major adverse cardiovascular events (MACE) overall with febuxostat.

The recency of the new data with more febuxostat-exposed patients overall provides greater reassurance on the safety of the drug, corresponding author Seoyoung C. Kim, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, said in an interview. “We also were able to get data on cause of death, which we did not have before when we conducted our first paper.”

Dr. Kim said she was not surprised by any of the findings, which were consistent with the results of her earlier work. “Our result on CV death also was consistent and reassuring,” she noted.

The newest Medicare claims study also corroborates results from FAST (Febuxostat Versus Allopurinol Streamlined Trial), a separate postmarketing surveillance study that was ordered by the European Medicines Agency after febuxostat’s approval in 2009. It showed that the two drugs were noninferior to each other for the risk of all-cause mortality or a composite cardiovascular outcome (hospitalization for nonfatal myocardial infarction, biomarker-positive acute coronary syndrome, nonfatal stroke, or cardiovascular death).

“While CARES showed higher CV death and all-cause death rates in febuxostat compared to allopurinol, FAST did not,” Dr. Kim noted. “Our study of more than 111,000 older gout patients treated with either febuxostat or allopurinol in real-world settings also did not find a difference in the risk of MACE, CV mortality, or all-cause mortality,” she added. “Taking these data all together, I think we can be more certain about the CV safety of febuxostat when its use is clinically indicated or needed,” she said.

Study details

Dr. Kim, first author Ajinkya Pawar, PhD, of Brigham and Women’s, and colleagues identified 467,461 people with gout aged 65 years and older who had been enrolled in Medicare for at least a year. They then used propensity-score matching to compare 27,881 first-time users of febuxostat with 83,643 first-time users of allopurinol on the primary outcome of the incidence of major adverse cardiovascular events (MACE), defined as the first occurrence of myocardial infarction, stroke, or cardiovascular mortality.

In the updated study, the mean follow‐up periods for febuxostat and allopurinol were 284 days and 339 days, respectively. Overall, febuxostat was noninferior to allopurinol with regard to MACE (hazard ratio, 0.99; 95% confidence interval, 0.93-1.05), and the results were consistent among patients with baseline CVD (HR, 0.94). In addition, rates of secondary outcomes of MI, stroke, and cardiovascular mortality were not significantly different between febuxostat and allopurinol patients, except for all-cause mortality (HR, 0.92; 95% CI, 0.87-0.98).

The study findings were limited mainly by the potential bias caused by nonadherence to medications, and potential for residual confounding and misclassification bias, the researchers noted.

However, the study was strengthened by its incident new-user design that allowed only patients with no use of either medication for a year before the first dispensing and its active comparator design, and the data are generalizable to the greater population of older gout patients, they said.

Consequently, the data from this large, real-world study support the safety of febuxostat with regard to cardiovascular risk in gout patients, including those with baseline cardiovascular disease, they concluded.

The study was supported by the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital. Dr. Kim disclosed research grants to Brigham and Women’s Hospital from Roche, Pfizer, AbbVie, and Bristol‐Myers Squibb for unrelated studies. Another author reported serving as the principal investigator with research grants from Vertex, Bayer, and Novartis to Brigham and Women’s Hospital for unrelated projects.

Febuxostat (Uloric) was not associated with increased cardiovascular risk in patients with gout when compared to those who used allopurinol, in an analysis of new users of the drugs in Medicare fee-for-service claims data from the period of 2008-2016.

The findings, published March 25 in the Journal of the American Heart Association, update and echo the results from a similar previous study by the same Brigham and Women’s Hospital research group that covered 2008-2013 Medicare claims data. That original claims data study from 2018 sought to confirm the findings of the postmarketing surveillance CARES (Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities) trial that led to a boxed warning for increased risk of cardiovascular and all-cause mortality vs. allopurinol. The trial, however, did not show a higher rate of major adverse cardiovascular events (MACE) overall with febuxostat.

The recency of the new data with more febuxostat-exposed patients overall provides greater reassurance on the safety of the drug, corresponding author Seoyoung C. Kim, MD, of Brigham and Women’s Hospital and Harvard Medical School, Boston, said in an interview. “We also were able to get data on cause of death, which we did not have before when we conducted our first paper.”

Dr. Kim said she was not surprised by any of the findings, which were consistent with the results of her earlier work. “Our result on CV death also was consistent and reassuring,” she noted.

The newest Medicare claims study also corroborates results from FAST (Febuxostat Versus Allopurinol Streamlined Trial), a separate postmarketing surveillance study that was ordered by the European Medicines Agency after febuxostat’s approval in 2009. It showed that the two drugs were noninferior to each other for the risk of all-cause mortality or a composite cardiovascular outcome (hospitalization for nonfatal myocardial infarction, biomarker-positive acute coronary syndrome, nonfatal stroke, or cardiovascular death).

“While CARES showed higher CV death and all-cause death rates in febuxostat compared to allopurinol, FAST did not,” Dr. Kim noted. “Our study of more than 111,000 older gout patients treated with either febuxostat or allopurinol in real-world settings also did not find a difference in the risk of MACE, CV mortality, or all-cause mortality,” she added. “Taking these data all together, I think we can be more certain about the CV safety of febuxostat when its use is clinically indicated or needed,” she said.

Study details

Dr. Kim, first author Ajinkya Pawar, PhD, of Brigham and Women’s, and colleagues identified 467,461 people with gout aged 65 years and older who had been enrolled in Medicare for at least a year. They then used propensity-score matching to compare 27,881 first-time users of febuxostat with 83,643 first-time users of allopurinol on the primary outcome of the incidence of major adverse cardiovascular events (MACE), defined as the first occurrence of myocardial infarction, stroke, or cardiovascular mortality.

In the updated study, the mean follow‐up periods for febuxostat and allopurinol were 284 days and 339 days, respectively. Overall, febuxostat was noninferior to allopurinol with regard to MACE (hazard ratio, 0.99; 95% confidence interval, 0.93-1.05), and the results were consistent among patients with baseline CVD (HR, 0.94). In addition, rates of secondary outcomes of MI, stroke, and cardiovascular mortality were not significantly different between febuxostat and allopurinol patients, except for all-cause mortality (HR, 0.92; 95% CI, 0.87-0.98).

The study findings were limited mainly by the potential bias caused by nonadherence to medications, and potential for residual confounding and misclassification bias, the researchers noted.

However, the study was strengthened by its incident new-user design that allowed only patients with no use of either medication for a year before the first dispensing and its active comparator design, and the data are generalizable to the greater population of older gout patients, they said.

Consequently, the data from this large, real-world study support the safety of febuxostat with regard to cardiovascular risk in gout patients, including those with baseline cardiovascular disease, they concluded.

The study was supported by the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital. Dr. Kim disclosed research grants to Brigham and Women’s Hospital from Roche, Pfizer, AbbVie, and Bristol‐Myers Squibb for unrelated studies. Another author reported serving as the principal investigator with research grants from Vertex, Bayer, and Novartis to Brigham and Women’s Hospital for unrelated projects.