Diana Swift

In a rapidly expanding therapeutic landscape, the American Gastroenterological Association (AGA) has issued updated practice guidelines for the pharmacological management of moderate to severe ulcerative colitis (UC) in adult outpatients.

“These are the first living guidelines published by a GI society, highlighting the interest and need to provide timely guidance to all stakeholders in a rapidly evolving field,” first author Siddharth Singh, MD, of the Division of Gastroenterology in the Department of Medicine at University of California, San Diego, said in an interview. Living guidance allows for ongoing revision of individual recommendations as new data emerge. Nearly 2 million Americans have UC.

 

Issued in Gastroenterology and updating the last guidance in 2020, the recommendations suggest more efficacious drugs should be used sooner. “Early use of advanced therapies including biologics and small-molecule drugs are more effective than 5-aminosalicylates [5-ASAs] or thiopurines and methotrexate for most patients with moderate to severe UC and those with poor prognostic factors,” coauthor and gastroenterologist Manasi Agrawal, MD, MS, an assistant professor of medicine at Icahn School of Medicine at Mount Sinai in New York City, said in an interview.

“We provide a practical guidance based on best-available evidence to make it easy for the treating clinician to make informed choices from the multiplicity of available treatments for UC,” added guidelines coauthor Ashwin Ananthakrishnan, MBBS, MPH, AGAF, a gastroenterologist at Massachusetts General Hospital in Boston.

 

The comprehensive, patient-centered document comes with this caveat from the AGA panel: “These guidelines are meant to be broad recommendations for management of patients with moderate to severe UC and are not intended to address the intricacies of individual patients,” they wrote. “Provider experience and patient values and preferences can inform treating providers and patients to reasonably choose alternative treatment options.”

One gastroenterologist who has been eagerly awaiting these guidelines but not involved in the panel is James D. Lewis, MD, MSCE, AGAF, a professor of medicine and epidemiology at Perelman School of Medicine at the University of Pennsylvania, Philadelphia. “The choice of medications for moderately to severely active UC has expanded tremendously in the past few years,” he said in an interview. “This resulted in the dismantling of the historical therapeutic pyramid.” And while there are many more treatment options, knowing which medication to use for which patient and in which sequence has become much more complicated. 

“These guidelines will be extremely helpful for clinicians trying to navigate this new era of UC care,” he said.

The guidelines also outline implementation considerations for optimal use in different scenarios. “Key considerations include patient-related factors such as age, frailty, other health conditions, consideration for pregnancy, patient preferences, and access to healthcare,” Agrawal said.

 

Specifics

Overall, the guidance recommends advanced or immunomodulatory therapy after failure of 5-ASAs rather than a step-up approach. Moderate to severe disease is defined as a Mayo endoscopic severity subscore of 2 or 3.

The recommendation may also apply to mild disease in the presence of a high burden of inflammation and a poor prognosis or steroid dependence or resistance.

The AGA guideline panelists took account of differences in treatment efficacy between drugs within the same therapeutic class and made their recommendations by specific drugs rather than therapy class.

Based on varying degrees of evidence certainty, the AGA recommends or suggests the following management specifics in adult outpatients with moderate to severe disease:

• Any of the following is recommended over no treatment: infliximab (Remicade), golimumab (Simponi), vedolizumab (Entyvio), tofacitinib (Xeljanz), upadacitinib (Rinvoq), ustekinumab (Stelara), ozanimod (Zeposia), etrasimod (Velsipity), risankizumab (Skyrizi), and guselkumab (Tremfya).
• Adalimumab (Humira), filgotinib (Jyseleca), and mirikizumab (Omvoh) are suggested over no treatment.
• Biosimilars to infliximab, adalimumab, and ustekinumab can be considered of equivalent efficacy to their originator drugs.
• For patients naive to advanced therapies, the AGA panel proposes using a higher-efficacy medication (eg, infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, and guselkumab) or an intermediate-efficacy medication (golimumab, ustekinumab, tofacitinib, filgotinib, and mirikizumab) rather than a lower-efficacy medication such as adalimumab.
• In patients previously exposed to advanced therapy, particularly tumor necrosis factor (TNF)–alpha antagonists, the panel suggests using a higher-efficacy medication (tofacitinib, upadacitinib, and ustekinumab) or an intermediate-efficacy agent (filgotinib, mirikizumab, risankizumab, and guselkumab) over a lower-efficacy medication (adalimumab, vedolizumab, ozanimod, and etrasimod).
• The panel suggests against the use of thiopurine monotherapy for inducing remission but suggests thiopurine monotherapy over no treatment for maintenance of (typically corticosteroid-induced) remission.
• The panel suggests against the use of methotrexate monotherapy for induction or maintenance of remission.
• Infliximab, adalimumab, and golimumab in combination with an immunomodulator are suggested over monotherapy.
• The panel makes no recommendation for or against non-TNF antagonist biologics in combination with an immunomodulator over non-TNF biologics alone.
• For patients in corticosteroid-free clinical remission for at least 6 months on combination therapy with TNF antagonists and immunomodulators, the panel suggests against withdrawing TNF antagonists but makes no recommendation for or against withdrawing immunomodulators.
• For those who have failed 5-ASAs and have escalated to immunomodulators or advanced therapies, the panel suggests stopping these agents. It suggests the early use of advanced therapies and/or immunomodulator therapy rather than gradual step-up after failure of 5-ASAs.

According to Lewis, the guidance will be useful to both community physicians and highly specialized gastroenterologists. “While few practicing physicians will be able to commit the entirety of the classifications in this guideline to memory, the tool is a quick reference resource to help providers and patients to choose between the many options,” he said.

However, he noted that not all patients and providers may have the same priorities as the guidelines. “There are a few nuances to the methods of the AGA guidelines. For example, the panel prioritized efficacy over safety because the incidence of serious adverse events secondary to medications is relatively rare.”

Lewis also noted that the way the panel classified higher-, intermediate-, and lower-efficacy medications sometimes produced surprising results. “For example, among patients naive to advanced therapies, the IL [interleukin]–23 inhibitors risankizumab and guselkumab were classified as higher efficacy, while the IL-12/23 inhibitor ustekinumab was considered intermediate efficacy,” he said. “These were reversed for patients with prior exposure to advanced therapies, where ustekinumab was considered higher efficacy and all three IL-23 inhibitors were considered intermediate efficacy.”

 

The Future

The panel identified several knowledge gaps that future studies should address. These include a paucity of head-to-head comparison trials, including active comparators to accurately inform positioning of different treatments and therapeutic mechanisms.

The panelists also noted a literature gap on the efficacy of different therapies in the setting of failure or intolerance to non-TNF antagonist advanced therapy, which could be relevant to drugs that may have a greater overlap in their therapeutic mechanisms — for instance, anti-trafficking agents.

They pointed to a paucity of data on how predictive models can inform future treatment selection in the real-world setting. “There is clearly a need for identifying biomarkers predictive of response to individual therapies, to facilitate optimal choice of therapies,” they wrote.

The panel also recognized that novel therapeutic strategies may soon be in use, including combination advanced therapy or episodic use of nonimmunogenic advanced therapies such as small molecules. “Further primary data are required to accurately inform the positioning of such strategies,” they wrote.

These guidelines were fully funded by the AGA Institute. Singh and Agrawal are supported by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), and Ananthakrishnan is supported by the NIDDK, as well as by the Leona M. and Harry B. Helmsley Charitable Trust and the Chleck Family Foundation. Singh disclosed Institutional research grants from Pfizer. Agrawal reported consulting for Douglas Pharmaceuticals. Several coauthors disclosed receiving consulting fees and/or research support from various private companies in the healthcare field. One author reported stock ownership stock in Exact Sciences. Lewis reported consulting, advisory board service, or data monitoring for Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, Gilead, Janssen Pharmaceuticals, Merck, Pfizer, Protagonist Therapeutics, and Sanofi. He received research funding or in-kind support from Nestle Health Science, Takeda, Janssen Pharmaceuticals, AbbVie, and Eli Lilly and has had educational grants from Janssen.

A version of this article appeared on Medscape.com.

In a rapidly expanding therapeutic landscape, the American Gastroenterological Association (AGA) has issued updated practice guidelines for the pharmacological management of moderate to severe ulcerative colitis (UC) in adult outpatients.

“These are the first living guidelines published by a GI society, highlighting the interest and need to provide timely guidance to all stakeholders in a rapidly evolving field,” first author Siddharth Singh, MD, of the Division of Gastroenterology in the Department of Medicine at University of California, San Diego, said in an interview. Living guidance allows for ongoing revision of individual recommendations as new data emerge. Nearly 2 million Americans have UC.

 

Issued in Gastroenterology and updating the last guidance in 2020, the recommendations suggest more efficacious drugs should be used sooner. “Early use of advanced therapies including biologics and small-molecule drugs are more effective than 5-aminosalicylates [5-ASAs] or thiopurines and methotrexate for most patients with moderate to severe UC and those with poor prognostic factors,” coauthor and gastroenterologist Manasi Agrawal, MD, MS, an assistant professor of medicine at Icahn School of Medicine at Mount Sinai in New York City, said in an interview.

“We provide a practical guidance based on best-available evidence to make it easy for the treating clinician to make informed choices from the multiplicity of available treatments for UC,” added guidelines coauthor Ashwin Ananthakrishnan, MBBS, MPH, AGAF, a gastroenterologist at Massachusetts General Hospital in Boston.

 

The comprehensive, patient-centered document comes with this caveat from the AGA panel: “These guidelines are meant to be broad recommendations for management of patients with moderate to severe UC and are not intended to address the intricacies of individual patients,” they wrote. “Provider experience and patient values and preferences can inform treating providers and patients to reasonably choose alternative treatment options.”

One gastroenterologist who has been eagerly awaiting these guidelines but not involved in the panel is James D. Lewis, MD, MSCE, AGAF, a professor of medicine and epidemiology at Perelman School of Medicine at the University of Pennsylvania, Philadelphia. “The choice of medications for moderately to severely active UC has expanded tremendously in the past few years,” he said in an interview. “This resulted in the dismantling of the historical therapeutic pyramid.” And while there are many more treatment options, knowing which medication to use for which patient and in which sequence has become much more complicated. 

“These guidelines will be extremely helpful for clinicians trying to navigate this new era of UC care,” he said.

The guidelines also outline implementation considerations for optimal use in different scenarios. “Key considerations include patient-related factors such as age, frailty, other health conditions, consideration for pregnancy, patient preferences, and access to healthcare,” Agrawal said.

 

Specifics

Overall, the guidance recommends advanced or immunomodulatory therapy after failure of 5-ASAs rather than a step-up approach. Moderate to severe disease is defined as a Mayo endoscopic severity subscore of 2 or 3.

The recommendation may also apply to mild disease in the presence of a high burden of inflammation and a poor prognosis or steroid dependence or resistance.

The AGA guideline panelists took account of differences in treatment efficacy between drugs within the same therapeutic class and made their recommendations by specific drugs rather than therapy class.

Based on varying degrees of evidence certainty, the AGA recommends or suggests the following management specifics in adult outpatients with moderate to severe disease:

• Any of the following is recommended over no treatment: infliximab (Remicade), golimumab (Simponi), vedolizumab (Entyvio), tofacitinib (Xeljanz), upadacitinib (Rinvoq), ustekinumab (Stelara), ozanimod (Zeposia), etrasimod (Velsipity), risankizumab (Skyrizi), and guselkumab (Tremfya).
• Adalimumab (Humira), filgotinib (Jyseleca), and mirikizumab (Omvoh) are suggested over no treatment.
• Biosimilars to infliximab, adalimumab, and ustekinumab can be considered of equivalent efficacy to their originator drugs.
• For patients naive to advanced therapies, the AGA panel proposes using a higher-efficacy medication (eg, infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, and guselkumab) or an intermediate-efficacy medication (golimumab, ustekinumab, tofacitinib, filgotinib, and mirikizumab) rather than a lower-efficacy medication such as adalimumab.
• In patients previously exposed to advanced therapy, particularly tumor necrosis factor (TNF)–alpha antagonists, the panel suggests using a higher-efficacy medication (tofacitinib, upadacitinib, and ustekinumab) or an intermediate-efficacy agent (filgotinib, mirikizumab, risankizumab, and guselkumab) over a lower-efficacy medication (adalimumab, vedolizumab, ozanimod, and etrasimod).
• The panel suggests against the use of thiopurine monotherapy for inducing remission but suggests thiopurine monotherapy over no treatment for maintenance of (typically corticosteroid-induced) remission.
• The panel suggests against the use of methotrexate monotherapy for induction or maintenance of remission.
• Infliximab, adalimumab, and golimumab in combination with an immunomodulator are suggested over monotherapy.
• The panel makes no recommendation for or against non-TNF antagonist biologics in combination with an immunomodulator over non-TNF biologics alone.
• For patients in corticosteroid-free clinical remission for at least 6 months on combination therapy with TNF antagonists and immunomodulators, the panel suggests against withdrawing TNF antagonists but makes no recommendation for or against withdrawing immunomodulators.
• For those who have failed 5-ASAs and have escalated to immunomodulators or advanced therapies, the panel suggests stopping these agents. It suggests the early use of advanced therapies and/or immunomodulator therapy rather than gradual step-up after failure of 5-ASAs.

According to Lewis, the guidance will be useful to both community physicians and highly specialized gastroenterologists. “While few practicing physicians will be able to commit the entirety of the classifications in this guideline to memory, the tool is a quick reference resource to help providers and patients to choose between the many options,” he said.

However, he noted that not all patients and providers may have the same priorities as the guidelines. “There are a few nuances to the methods of the AGA guidelines. For example, the panel prioritized efficacy over safety because the incidence of serious adverse events secondary to medications is relatively rare.”

Lewis also noted that the way the panel classified higher-, intermediate-, and lower-efficacy medications sometimes produced surprising results. “For example, among patients naive to advanced therapies, the IL [interleukin]–23 inhibitors risankizumab and guselkumab were classified as higher efficacy, while the IL-12/23 inhibitor ustekinumab was considered intermediate efficacy,” he said. “These were reversed for patients with prior exposure to advanced therapies, where ustekinumab was considered higher efficacy and all three IL-23 inhibitors were considered intermediate efficacy.”

 

The Future

The panel identified several knowledge gaps that future studies should address. These include a paucity of head-to-head comparison trials, including active comparators to accurately inform positioning of different treatments and therapeutic mechanisms.

The panelists also noted a literature gap on the efficacy of different therapies in the setting of failure or intolerance to non-TNF antagonist advanced therapy, which could be relevant to drugs that may have a greater overlap in their therapeutic mechanisms — for instance, anti-trafficking agents.

They pointed to a paucity of data on how predictive models can inform future treatment selection in the real-world setting. “There is clearly a need for identifying biomarkers predictive of response to individual therapies, to facilitate optimal choice of therapies,” they wrote.

The panel also recognized that novel therapeutic strategies may soon be in use, including combination advanced therapy or episodic use of nonimmunogenic advanced therapies such as small molecules. “Further primary data are required to accurately inform the positioning of such strategies,” they wrote.

These guidelines were fully funded by the AGA Institute. Singh and Agrawal are supported by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), and Ananthakrishnan is supported by the NIDDK, as well as by the Leona M. and Harry B. Helmsley Charitable Trust and the Chleck Family Foundation. Singh disclosed Institutional research grants from Pfizer. Agrawal reported consulting for Douglas Pharmaceuticals. Several coauthors disclosed receiving consulting fees and/or research support from various private companies in the healthcare field. One author reported stock ownership stock in Exact Sciences. Lewis reported consulting, advisory board service, or data monitoring for Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, Gilead, Janssen Pharmaceuticals, Merck, Pfizer, Protagonist Therapeutics, and Sanofi. He received research funding or in-kind support from Nestle Health Science, Takeda, Janssen Pharmaceuticals, AbbVie, and Eli Lilly and has had educational grants from Janssen.

A version of this article appeared on Medscape.com.

In a rapidly expanding therapeutic landscape, the American Gastroenterological Association (AGA) has issued updated practice guidelines for the pharmacological management of moderate to severe ulcerative colitis (UC) in adult outpatients.

“These are the first living guidelines published by a GI society, highlighting the interest and need to provide timely guidance to all stakeholders in a rapidly evolving field,” first author Siddharth Singh, MD, of the Division of Gastroenterology in the Department of Medicine at University of California, San Diego, said in an interview. Living guidance allows for ongoing revision of individual recommendations as new data emerge. Nearly 2 million Americans have UC.

 

Issued in Gastroenterology and updating the last guidance in 2020, the recommendations suggest more efficacious drugs should be used sooner. “Early use of advanced therapies including biologics and small-molecule drugs are more effective than 5-aminosalicylates [5-ASAs] or thiopurines and methotrexate for most patients with moderate to severe UC and those with poor prognostic factors,” coauthor and gastroenterologist Manasi Agrawal, MD, MS, an assistant professor of medicine at Icahn School of Medicine at Mount Sinai in New York City, said in an interview.

“We provide a practical guidance based on best-available evidence to make it easy for the treating clinician to make informed choices from the multiplicity of available treatments for UC,” added guidelines coauthor Ashwin Ananthakrishnan, MBBS, MPH, AGAF, a gastroenterologist at Massachusetts General Hospital in Boston.

 

The comprehensive, patient-centered document comes with this caveat from the AGA panel: “These guidelines are meant to be broad recommendations for management of patients with moderate to severe UC and are not intended to address the intricacies of individual patients,” they wrote. “Provider experience and patient values and preferences can inform treating providers and patients to reasonably choose alternative treatment options.”

One gastroenterologist who has been eagerly awaiting these guidelines but not involved in the panel is James D. Lewis, MD, MSCE, AGAF, a professor of medicine and epidemiology at Perelman School of Medicine at the University of Pennsylvania, Philadelphia. “The choice of medications for moderately to severely active UC has expanded tremendously in the past few years,” he said in an interview. “This resulted in the dismantling of the historical therapeutic pyramid.” And while there are many more treatment options, knowing which medication to use for which patient and in which sequence has become much more complicated. 

“These guidelines will be extremely helpful for clinicians trying to navigate this new era of UC care,” he said.

The guidelines also outline implementation considerations for optimal use in different scenarios. “Key considerations include patient-related factors such as age, frailty, other health conditions, consideration for pregnancy, patient preferences, and access to healthcare,” Agrawal said.

 

Specifics

Overall, the guidance recommends advanced or immunomodulatory therapy after failure of 5-ASAs rather than a step-up approach. Moderate to severe disease is defined as a Mayo endoscopic severity subscore of 2 or 3.

The recommendation may also apply to mild disease in the presence of a high burden of inflammation and a poor prognosis or steroid dependence or resistance.

The AGA guideline panelists took account of differences in treatment efficacy between drugs within the same therapeutic class and made their recommendations by specific drugs rather than therapy class.

Based on varying degrees of evidence certainty, the AGA recommends or suggests the following management specifics in adult outpatients with moderate to severe disease:

• Any of the following is recommended over no treatment: infliximab (Remicade), golimumab (Simponi), vedolizumab (Entyvio), tofacitinib (Xeljanz), upadacitinib (Rinvoq), ustekinumab (Stelara), ozanimod (Zeposia), etrasimod (Velsipity), risankizumab (Skyrizi), and guselkumab (Tremfya).
• Adalimumab (Humira), filgotinib (Jyseleca), and mirikizumab (Omvoh) are suggested over no treatment.
• Biosimilars to infliximab, adalimumab, and ustekinumab can be considered of equivalent efficacy to their originator drugs.
• For patients naive to advanced therapies, the AGA panel proposes using a higher-efficacy medication (eg, infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, and guselkumab) or an intermediate-efficacy medication (golimumab, ustekinumab, tofacitinib, filgotinib, and mirikizumab) rather than a lower-efficacy medication such as adalimumab.
• In patients previously exposed to advanced therapy, particularly tumor necrosis factor (TNF)–alpha antagonists, the panel suggests using a higher-efficacy medication (tofacitinib, upadacitinib, and ustekinumab) or an intermediate-efficacy agent (filgotinib, mirikizumab, risankizumab, and guselkumab) over a lower-efficacy medication (adalimumab, vedolizumab, ozanimod, and etrasimod).
• The panel suggests against the use of thiopurine monotherapy for inducing remission but suggests thiopurine monotherapy over no treatment for maintenance of (typically corticosteroid-induced) remission.
• The panel suggests against the use of methotrexate monotherapy for induction or maintenance of remission.
• Infliximab, adalimumab, and golimumab in combination with an immunomodulator are suggested over monotherapy.
• The panel makes no recommendation for or against non-TNF antagonist biologics in combination with an immunomodulator over non-TNF biologics alone.
• For patients in corticosteroid-free clinical remission for at least 6 months on combination therapy with TNF antagonists and immunomodulators, the panel suggests against withdrawing TNF antagonists but makes no recommendation for or against withdrawing immunomodulators.
• For those who have failed 5-ASAs and have escalated to immunomodulators or advanced therapies, the panel suggests stopping these agents. It suggests the early use of advanced therapies and/or immunomodulator therapy rather than gradual step-up after failure of 5-ASAs.

According to Lewis, the guidance will be useful to both community physicians and highly specialized gastroenterologists. “While few practicing physicians will be able to commit the entirety of the classifications in this guideline to memory, the tool is a quick reference resource to help providers and patients to choose between the many options,” he said.

However, he noted that not all patients and providers may have the same priorities as the guidelines. “There are a few nuances to the methods of the AGA guidelines. For example, the panel prioritized efficacy over safety because the incidence of serious adverse events secondary to medications is relatively rare.”

Lewis also noted that the way the panel classified higher-, intermediate-, and lower-efficacy medications sometimes produced surprising results. “For example, among patients naive to advanced therapies, the IL [interleukin]–23 inhibitors risankizumab and guselkumab were classified as higher efficacy, while the IL-12/23 inhibitor ustekinumab was considered intermediate efficacy,” he said. “These were reversed for patients with prior exposure to advanced therapies, where ustekinumab was considered higher efficacy and all three IL-23 inhibitors were considered intermediate efficacy.”

 

The Future

The panel identified several knowledge gaps that future studies should address. These include a paucity of head-to-head comparison trials, including active comparators to accurately inform positioning of different treatments and therapeutic mechanisms.

The panelists also noted a literature gap on the efficacy of different therapies in the setting of failure or intolerance to non-TNF antagonist advanced therapy, which could be relevant to drugs that may have a greater overlap in their therapeutic mechanisms — for instance, anti-trafficking agents.

They pointed to a paucity of data on how predictive models can inform future treatment selection in the real-world setting. “There is clearly a need for identifying biomarkers predictive of response to individual therapies, to facilitate optimal choice of therapies,” they wrote.

The panel also recognized that novel therapeutic strategies may soon be in use, including combination advanced therapy or episodic use of nonimmunogenic advanced therapies such as small molecules. “Further primary data are required to accurately inform the positioning of such strategies,” they wrote.

These guidelines were fully funded by the AGA Institute. Singh and Agrawal are supported by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), and Ananthakrishnan is supported by the NIDDK, as well as by the Leona M. and Harry B. Helmsley Charitable Trust and the Chleck Family Foundation. Singh disclosed Institutional research grants from Pfizer. Agrawal reported consulting for Douglas Pharmaceuticals. Several coauthors disclosed receiving consulting fees and/or research support from various private companies in the healthcare field. One author reported stock ownership stock in Exact Sciences. Lewis reported consulting, advisory board service, or data monitoring for Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, Gilead, Janssen Pharmaceuticals, Merck, Pfizer, Protagonist Therapeutics, and Sanofi. He received research funding or in-kind support from Nestle Health Science, Takeda, Janssen Pharmaceuticals, AbbVie, and Eli Lilly and has had educational grants from Janssen.

A version of this article appeared on Medscape.com.

Although hysterectomy remains the most common procedure for treating fibroids and fibroids are the leading indication for hysterectomy, its long-term sequelae make less invasive alternatives the better choice for managing most of these myometrial masses, an invited clinical practice paper in the New England Journal of Medicine (NEJM) asserts.

The practice summary also calls for earlier identification and treatment of fibroid disease and may raise awareness among general gynecologists and primary care physicians less familiar with newer treatments.

Based on a review of evidence and existing formal guidelines, the paper urges wider use of uterus-sparing approaches such as hormone therapy, uterine-artery embolization, focused ultrasound ablation, and radiofrequency ablation. Authored by ob.gyns. Elizabeth A. Stewart, MD, and Shannon K. Laughlin-Tommaso, MD, MPH, of the Mayo Clinic in Rochester, Minnesota, the document also features textbook-style diagrams illustrating procedures.

“To clarify, this is not a new guidance but an invited clinical practice paper,” Laughlin-Tommaso told this news organization. “I believe NEJM recognized the gap in knowledge among all providers, for early diagnosis of uterine fibroids, especially in young patients and those presenting with anemia.”

The less invasive treatments highlighted in the paper can help women recover faster and resume their normal activities more quickly, said Laughlin-Tommaso. “Additionally, many studies have now shown that there are health benefits to keeping the uterus and the ovaries.”

Despite multiple uterine-sparing options, however, a recent study in a commercially insured population found nearly 60% of fibroid patients undergoing hysterectomy had never received a prior conservative treatment.

Why hysterectomy for a benign condition? Hysterectomy, which is universally available in ob.gyn. practices, makes decision-making easier for medical providers and patients, Laughlin-Tommaso explained. “It’s the only treatment that is definitive in that patients will not have bleeding or fibroids in the future and providers don’t have to determine which fibroids to treat or remove.”

More common in Black women, fibroids affect up to 80% of persons with a uterus during their lifetime and up to 50% have symptoms such as heavy and prolonged menstrual bleeding, anemia-associated fatigue, pelvic pressure, and menstrual and nonmenstrual pain, the authors noted. These lesions can also compress nearby structures causing painful intercourse, constipation, and urinary frequency, urgency, or retention.

In 2021 the American College of Obstetricians and Gynecologists issued a practice bulletin on the management of symptomatic uterine leiomyomas, similarly endorsing individualized care that accounts for the desire to preserve fertility or the uterus, increase quality of life, and reduce symptoms. It, too, recommended medical management as first-line treatment for symptomatic fibroids.

“This paper will be helpful for clinicians by covering some of the newer options such as gonadotropin-releasing hormone antagonists introduced in the past 5 years and tailoring treatment to patients depending on whether they still want to conceive,” Sandra M. Hurtado, MD, an ob.gyn. and an assistant professor at UTHealth Houston Medical Center and McGovern Medical School in Houston, Texas, said in an interview. “And the illustrations will be useful to doctors who are not gynecologists and will help to explain the interventional options to patients,” added Hurtado, who was not involved in the paper.

Offering another outside perspective on the paper, Charles J. Ascher-Walsh, MD, senior system vice chair for gynecology and division director of urogynecology in the Raquel and Jaime Gilinski Department of Obstetrics, Gynecology and Reproductive Science at Mount Sinai in New York City, called it a useful though not new summary. Reaching the wider audience of NEJM may raise awareness of newer fibroid therapies among general, nonspecialist ob.gyns., whose practices may concentrate largely on obstetrics, he added, “and the excellent illustrations clarify the treatment options.” In his view, broader awareness may increase much-needed funding for this neglected area of research.

Among the paper’s recommendations:

Diagnosis

Pelvic ultrasonography is the most cost-effective imaging method, providing information on size, location, and number of fibroids and ruling out adnexal masses. It is limited, however, by less-accurate resolution if the uterine volume is greater than 375 mL or if fibroids number more than four.

Medical Alternatives to Hysterectomy

Early diagnosis and first-line medical therapies are recommended.

Contraceptive hormones to control heavy menstrual bleeding are the first step in most algorithms for treating fibroid-related bleeding, despite low-quality evidence.

Nonsteroidal anti-inflammatory agents and tranexamic acid during menstruation also limit heavy menses but have more evidence of efficacy for idiopathic heavy menses.

Gonadotropin-releasing hormone (GnRH) agonists in depot form are approved for short-term preoperative therapy. While they cause amenorrhea in nearly 90% of patients and reduce uterine volume by 30%-60%, they have a high incidence of hypogonadal symptoms, including bone loss and hot flushes. They also cause a “steroidal flare” when the stored gonadotropins are released and cause subsequent heavy menstrual bleeding with the rapid decrease in estrogen levels. 

Oral GnRH antagonist combinations are a major therapeutic advance, pairing a GnRH antagonist (such as elagolix or relugolix, which rapidly inhibit ovarian steroidogenesis) with estradiol and progestin at doses equivalent to systemic levels in the early follicular phase of the menstrual cycle.

In clinical trials these combinations decreased heavy menstrual bleeding by 50%-75%, pain by 40%-50%, and bulk-related symptoms through a 10% decrease in uterine volume. Side effects are few, with hot flushes, headaches, and nausea occurring in fewer than 20% of participants.
 

Smaller fibroids in the submucosal to intramural spaces can be treated transcervically, while larger lesions of any type or smaller subserosa fibroids are treated abdominally.

Uterine-artery embolization uses minimally invasive radiologically guided catheterization to release embolic particles directly into both uterine arteries. This process causes ischemic infarction of the fibroids and decreases bleeding, pain, and bulk-related symptoms.

Other procedures shrink individual fibroids with energy that creates coagulative necrosis. These include focused ultrasound ablation (with MRI or ultrasound guidance) and radiofrequency ablation (with laparoscopic or transcervical ultrasound guidance).

Unlike uterine-artery embolization, which treats all fibroids concurrently, these therapies require individual targeting of fibroids.

Radiofrequency ablation can be done concurrently with other surgical therapies, such as laparoscopic excision of endometriosis or hysteroscopic myomectomy.

Myomectomy, or the surgical removal of fibroids, is most often used in persons actively seeking pregnancy or having very large fibroids in whom shrinkage would be inadequate. Most guidelines recommend surgical excision rather than shrinking procedures to optimize fertility. However, myomectomy often commits patients to future cesarean section, which increases pregnancy-related morbidity.

Although myomectomy is seen as superior to uterine-artery embolization for improving quality of life, both approaches provide substantial symptom relief.
 

Recurrence

Incidence of recurring fibroids is high, with, for example, new fibroids developing in approximately 50% of persons within 5 years of myomectomy.

Earlier this year, a large cohort study reported that myomectomy was best for avoiding reintervention after surgical leiomyoma management.

Reintervention rates vary according to procedure, patient age, disease extent, and symptoms and can be as high as 33% up to 5 years after treatment, with lower percentages seen among persons older than 45 years of age.
 

Hysterectomy

Minimally invasive hysterectomy is recommended. Drawbacks to hysterectomy include perioperative risk and concomitant oophorectomy, which was common until the early 2000s when large cohort studies showed elevated risks of death, cardiovascular disease, dementia, and other illnesses compared with hysterectomy plus ovarian conservation. Oophorectomy but not hysterectomy rates have since decreased.

Still needing study, according to Laughlin-Tommaso are the underlying reasons for health disparities in fibroids, especially among Black and Latina individuals. “Some studies have found associations with vitamin D deficiency and with stress and racism,” she said.

Looking ahead, the authors stressed the need for a fibroid risk-prediction model, a staging system, and large randomized trials of treatment effectiveness. Also needed are methods for primary and secondary prevention. “Earlier screening and medical treatment in primary care settings could potentially minimize morbidity and the incidence of unnecessary hysterectomies, and primary care–based screening trials are warranted,” they wrote.
 

In addition to procedural illustrations the practice document includes a vignette of a 33-year-old never-pregnant Black woman (but desiring motherhood) with heavy menstrual bleeding, abdominal bloating, and non–iron deficiency anemia. Evaluation for thalassemia and sickle cell anemia is negative, but ultrasonography reveals an enlarged uterus with multiple fibroids and normal ovaries.

In line with the clinical review, the authors prescribe oral GnRH agonist combination therapy, plus iron and multivitamin supplementation, and recommend annual reassessment — earlier if pregnancy is desired or if symptoms escalate. Since the patient prioritizes fertility, hysterectomy would be appropriate only if she had biopsy-proven cancer. 

The authors received no external funding for this practice paper, but both have funding from the National Institutes of Health for fibroid research. Laughlin-Tommaso reported royalties from UpToDate. Stewart reported research support from the Agency for Healthcare Research and Quality, and speaking, data-monitoring, and consulting fees for various private companies, including AbbVie, Anylam Pharmaceuticals, ASKA Pharma, and Myovant Sciences. She holds a patent on treatment for abnormal uterine bleeding and has been involved in CME for various medical educational agencies. Hurtado and Ascher-Walsh had no relevant conflicts of interest to declare.
 

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

Although hysterectomy remains the most common procedure for treating fibroids and fibroids are the leading indication for hysterectomy, its long-term sequelae make less invasive alternatives the better choice for managing most of these myometrial masses, an invited clinical practice paper in the New England Journal of Medicine (NEJM) asserts.

The practice summary also calls for earlier identification and treatment of fibroid disease and may raise awareness among general gynecologists and primary care physicians less familiar with newer treatments.

Based on a review of evidence and existing formal guidelines, the paper urges wider use of uterus-sparing approaches such as hormone therapy, uterine-artery embolization, focused ultrasound ablation, and radiofrequency ablation. Authored by ob.gyns. Elizabeth A. Stewart, MD, and Shannon K. Laughlin-Tommaso, MD, MPH, of the Mayo Clinic in Rochester, Minnesota, the document also features textbook-style diagrams illustrating procedures.

“To clarify, this is not a new guidance but an invited clinical practice paper,” Laughlin-Tommaso told this news organization. “I believe NEJM recognized the gap in knowledge among all providers, for early diagnosis of uterine fibroids, especially in young patients and those presenting with anemia.”

The less invasive treatments highlighted in the paper can help women recover faster and resume their normal activities more quickly, said Laughlin-Tommaso. “Additionally, many studies have now shown that there are health benefits to keeping the uterus and the ovaries.”

Despite multiple uterine-sparing options, however, a recent study in a commercially insured population found nearly 60% of fibroid patients undergoing hysterectomy had never received a prior conservative treatment.

Why hysterectomy for a benign condition? Hysterectomy, which is universally available in ob.gyn. practices, makes decision-making easier for medical providers and patients, Laughlin-Tommaso explained. “It’s the only treatment that is definitive in that patients will not have bleeding or fibroids in the future and providers don’t have to determine which fibroids to treat or remove.”

More common in Black women, fibroids affect up to 80% of persons with a uterus during their lifetime and up to 50% have symptoms such as heavy and prolonged menstrual bleeding, anemia-associated fatigue, pelvic pressure, and menstrual and nonmenstrual pain, the authors noted. These lesions can also compress nearby structures causing painful intercourse, constipation, and urinary frequency, urgency, or retention.

In 2021 the American College of Obstetricians and Gynecologists issued a practice bulletin on the management of symptomatic uterine leiomyomas, similarly endorsing individualized care that accounts for the desire to preserve fertility or the uterus, increase quality of life, and reduce symptoms. It, too, recommended medical management as first-line treatment for symptomatic fibroids.

“This paper will be helpful for clinicians by covering some of the newer options such as gonadotropin-releasing hormone antagonists introduced in the past 5 years and tailoring treatment to patients depending on whether they still want to conceive,” Sandra M. Hurtado, MD, an ob.gyn. and an assistant professor at UTHealth Houston Medical Center and McGovern Medical School in Houston, Texas, said in an interview. “And the illustrations will be useful to doctors who are not gynecologists and will help to explain the interventional options to patients,” added Hurtado, who was not involved in the paper.

Offering another outside perspective on the paper, Charles J. Ascher-Walsh, MD, senior system vice chair for gynecology and division director of urogynecology in the Raquel and Jaime Gilinski Department of Obstetrics, Gynecology and Reproductive Science at Mount Sinai in New York City, called it a useful though not new summary. Reaching the wider audience of NEJM may raise awareness of newer fibroid therapies among general, nonspecialist ob.gyns., whose practices may concentrate largely on obstetrics, he added, “and the excellent illustrations clarify the treatment options.” In his view, broader awareness may increase much-needed funding for this neglected area of research.

Among the paper’s recommendations:

Diagnosis

Pelvic ultrasonography is the most cost-effective imaging method, providing information on size, location, and number of fibroids and ruling out adnexal masses. It is limited, however, by less-accurate resolution if the uterine volume is greater than 375 mL or if fibroids number more than four.

Medical Alternatives to Hysterectomy

Early diagnosis and first-line medical therapies are recommended.

Contraceptive hormones to control heavy menstrual bleeding are the first step in most algorithms for treating fibroid-related bleeding, despite low-quality evidence.

Nonsteroidal anti-inflammatory agents and tranexamic acid during menstruation also limit heavy menses but have more evidence of efficacy for idiopathic heavy menses.

Gonadotropin-releasing hormone (GnRH) agonists in depot form are approved for short-term preoperative therapy. While they cause amenorrhea in nearly 90% of patients and reduce uterine volume by 30%-60%, they have a high incidence of hypogonadal symptoms, including bone loss and hot flushes. They also cause a “steroidal flare” when the stored gonadotropins are released and cause subsequent heavy menstrual bleeding with the rapid decrease in estrogen levels. 

Oral GnRH antagonist combinations are a major therapeutic advance, pairing a GnRH antagonist (such as elagolix or relugolix, which rapidly inhibit ovarian steroidogenesis) with estradiol and progestin at doses equivalent to systemic levels in the early follicular phase of the menstrual cycle.

In clinical trials these combinations decreased heavy menstrual bleeding by 50%-75%, pain by 40%-50%, and bulk-related symptoms through a 10% decrease in uterine volume. Side effects are few, with hot flushes, headaches, and nausea occurring in fewer than 20% of participants.
 

Smaller fibroids in the submucosal to intramural spaces can be treated transcervically, while larger lesions of any type or smaller subserosa fibroids are treated abdominally.

Uterine-artery embolization uses minimally invasive radiologically guided catheterization to release embolic particles directly into both uterine arteries. This process causes ischemic infarction of the fibroids and decreases bleeding, pain, and bulk-related symptoms.

Other procedures shrink individual fibroids with energy that creates coagulative necrosis. These include focused ultrasound ablation (with MRI or ultrasound guidance) and radiofrequency ablation (with laparoscopic or transcervical ultrasound guidance).

Unlike uterine-artery embolization, which treats all fibroids concurrently, these therapies require individual targeting of fibroids.

Radiofrequency ablation can be done concurrently with other surgical therapies, such as laparoscopic excision of endometriosis or hysteroscopic myomectomy.

Myomectomy, or the surgical removal of fibroids, is most often used in persons actively seeking pregnancy or having very large fibroids in whom shrinkage would be inadequate. Most guidelines recommend surgical excision rather than shrinking procedures to optimize fertility. However, myomectomy often commits patients to future cesarean section, which increases pregnancy-related morbidity.

Although myomectomy is seen as superior to uterine-artery embolization for improving quality of life, both approaches provide substantial symptom relief.
 

Recurrence

Incidence of recurring fibroids is high, with, for example, new fibroids developing in approximately 50% of persons within 5 years of myomectomy.

Earlier this year, a large cohort study reported that myomectomy was best for avoiding reintervention after surgical leiomyoma management.

Reintervention rates vary according to procedure, patient age, disease extent, and symptoms and can be as high as 33% up to 5 years after treatment, with lower percentages seen among persons older than 45 years of age.
 

Hysterectomy

Minimally invasive hysterectomy is recommended. Drawbacks to hysterectomy include perioperative risk and concomitant oophorectomy, which was common until the early 2000s when large cohort studies showed elevated risks of death, cardiovascular disease, dementia, and other illnesses compared with hysterectomy plus ovarian conservation. Oophorectomy but not hysterectomy rates have since decreased.

Still needing study, according to Laughlin-Tommaso are the underlying reasons for health disparities in fibroids, especially among Black and Latina individuals. “Some studies have found associations with vitamin D deficiency and with stress and racism,” she said.

Looking ahead, the authors stressed the need for a fibroid risk-prediction model, a staging system, and large randomized trials of treatment effectiveness. Also needed are methods for primary and secondary prevention. “Earlier screening and medical treatment in primary care settings could potentially minimize morbidity and the incidence of unnecessary hysterectomies, and primary care–based screening trials are warranted,” they wrote.
 

In addition to procedural illustrations the practice document includes a vignette of a 33-year-old never-pregnant Black woman (but desiring motherhood) with heavy menstrual bleeding, abdominal bloating, and non–iron deficiency anemia. Evaluation for thalassemia and sickle cell anemia is negative, but ultrasonography reveals an enlarged uterus with multiple fibroids and normal ovaries.

In line with the clinical review, the authors prescribe oral GnRH agonist combination therapy, plus iron and multivitamin supplementation, and recommend annual reassessment — earlier if pregnancy is desired or if symptoms escalate. Since the patient prioritizes fertility, hysterectomy would be appropriate only if she had biopsy-proven cancer. 

The authors received no external funding for this practice paper, but both have funding from the National Institutes of Health for fibroid research. Laughlin-Tommaso reported royalties from UpToDate. Stewart reported research support from the Agency for Healthcare Research and Quality, and speaking, data-monitoring, and consulting fees for various private companies, including AbbVie, Anylam Pharmaceuticals, ASKA Pharma, and Myovant Sciences. She holds a patent on treatment for abnormal uterine bleeding and has been involved in CME for various medical educational agencies. Hurtado and Ascher-Walsh had no relevant conflicts of interest to declare.
 

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

Although hysterectomy remains the most common procedure for treating fibroids and fibroids are the leading indication for hysterectomy, its long-term sequelae make less invasive alternatives the better choice for managing most of these myometrial masses, an invited clinical practice paper in the New England Journal of Medicine (NEJM) asserts.

The practice summary also calls for earlier identification and treatment of fibroid disease and may raise awareness among general gynecologists and primary care physicians less familiar with newer treatments.

Based on a review of evidence and existing formal guidelines, the paper urges wider use of uterus-sparing approaches such as hormone therapy, uterine-artery embolization, focused ultrasound ablation, and radiofrequency ablation. Authored by ob.gyns. Elizabeth A. Stewart, MD, and Shannon K. Laughlin-Tommaso, MD, MPH, of the Mayo Clinic in Rochester, Minnesota, the document also features textbook-style diagrams illustrating procedures.

“To clarify, this is not a new guidance but an invited clinical practice paper,” Laughlin-Tommaso told this news organization. “I believe NEJM recognized the gap in knowledge among all providers, for early diagnosis of uterine fibroids, especially in young patients and those presenting with anemia.”

The less invasive treatments highlighted in the paper can help women recover faster and resume their normal activities more quickly, said Laughlin-Tommaso. “Additionally, many studies have now shown that there are health benefits to keeping the uterus and the ovaries.”

Despite multiple uterine-sparing options, however, a recent study in a commercially insured population found nearly 60% of fibroid patients undergoing hysterectomy had never received a prior conservative treatment.

Why hysterectomy for a benign condition? Hysterectomy, which is universally available in ob.gyn. practices, makes decision-making easier for medical providers and patients, Laughlin-Tommaso explained. “It’s the only treatment that is definitive in that patients will not have bleeding or fibroids in the future and providers don’t have to determine which fibroids to treat or remove.”

More common in Black women, fibroids affect up to 80% of persons with a uterus during their lifetime and up to 50% have symptoms such as heavy and prolonged menstrual bleeding, anemia-associated fatigue, pelvic pressure, and menstrual and nonmenstrual pain, the authors noted. These lesions can also compress nearby structures causing painful intercourse, constipation, and urinary frequency, urgency, or retention.

In 2021 the American College of Obstetricians and Gynecologists issued a practice bulletin on the management of symptomatic uterine leiomyomas, similarly endorsing individualized care that accounts for the desire to preserve fertility or the uterus, increase quality of life, and reduce symptoms. It, too, recommended medical management as first-line treatment for symptomatic fibroids.

“This paper will be helpful for clinicians by covering some of the newer options such as gonadotropin-releasing hormone antagonists introduced in the past 5 years and tailoring treatment to patients depending on whether they still want to conceive,” Sandra M. Hurtado, MD, an ob.gyn. and an assistant professor at UTHealth Houston Medical Center and McGovern Medical School in Houston, Texas, said in an interview. “And the illustrations will be useful to doctors who are not gynecologists and will help to explain the interventional options to patients,” added Hurtado, who was not involved in the paper.

Offering another outside perspective on the paper, Charles J. Ascher-Walsh, MD, senior system vice chair for gynecology and division director of urogynecology in the Raquel and Jaime Gilinski Department of Obstetrics, Gynecology and Reproductive Science at Mount Sinai in New York City, called it a useful though not new summary. Reaching the wider audience of NEJM may raise awareness of newer fibroid therapies among general, nonspecialist ob.gyns., whose practices may concentrate largely on obstetrics, he added, “and the excellent illustrations clarify the treatment options.” In his view, broader awareness may increase much-needed funding for this neglected area of research.

Among the paper’s recommendations:

Diagnosis

Pelvic ultrasonography is the most cost-effective imaging method, providing information on size, location, and number of fibroids and ruling out adnexal masses. It is limited, however, by less-accurate resolution if the uterine volume is greater than 375 mL or if fibroids number more than four.

Medical Alternatives to Hysterectomy

Early diagnosis and first-line medical therapies are recommended.

Contraceptive hormones to control heavy menstrual bleeding are the first step in most algorithms for treating fibroid-related bleeding, despite low-quality evidence.

Nonsteroidal anti-inflammatory agents and tranexamic acid during menstruation also limit heavy menses but have more evidence of efficacy for idiopathic heavy menses.

Gonadotropin-releasing hormone (GnRH) agonists in depot form are approved for short-term preoperative therapy. While they cause amenorrhea in nearly 90% of patients and reduce uterine volume by 30%-60%, they have a high incidence of hypogonadal symptoms, including bone loss and hot flushes. They also cause a “steroidal flare” when the stored gonadotropins are released and cause subsequent heavy menstrual bleeding with the rapid decrease in estrogen levels. 

Oral GnRH antagonist combinations are a major therapeutic advance, pairing a GnRH antagonist (such as elagolix or relugolix, which rapidly inhibit ovarian steroidogenesis) with estradiol and progestin at doses equivalent to systemic levels in the early follicular phase of the menstrual cycle.

In clinical trials these combinations decreased heavy menstrual bleeding by 50%-75%, pain by 40%-50%, and bulk-related symptoms through a 10% decrease in uterine volume. Side effects are few, with hot flushes, headaches, and nausea occurring in fewer than 20% of participants.
 

Smaller fibroids in the submucosal to intramural spaces can be treated transcervically, while larger lesions of any type or smaller subserosa fibroids are treated abdominally.

Uterine-artery embolization uses minimally invasive radiologically guided catheterization to release embolic particles directly into both uterine arteries. This process causes ischemic infarction of the fibroids and decreases bleeding, pain, and bulk-related symptoms.

Other procedures shrink individual fibroids with energy that creates coagulative necrosis. These include focused ultrasound ablation (with MRI or ultrasound guidance) and radiofrequency ablation (with laparoscopic or transcervical ultrasound guidance).

Unlike uterine-artery embolization, which treats all fibroids concurrently, these therapies require individual targeting of fibroids.

Radiofrequency ablation can be done concurrently with other surgical therapies, such as laparoscopic excision of endometriosis or hysteroscopic myomectomy.

Myomectomy, or the surgical removal of fibroids, is most often used in persons actively seeking pregnancy or having very large fibroids in whom shrinkage would be inadequate. Most guidelines recommend surgical excision rather than shrinking procedures to optimize fertility. However, myomectomy often commits patients to future cesarean section, which increases pregnancy-related morbidity.

Although myomectomy is seen as superior to uterine-artery embolization for improving quality of life, both approaches provide substantial symptom relief.
 

Recurrence

Incidence of recurring fibroids is high, with, for example, new fibroids developing in approximately 50% of persons within 5 years of myomectomy.

Earlier this year, a large cohort study reported that myomectomy was best for avoiding reintervention after surgical leiomyoma management.

Reintervention rates vary according to procedure, patient age, disease extent, and symptoms and can be as high as 33% up to 5 years after treatment, with lower percentages seen among persons older than 45 years of age.
 

Hysterectomy

Minimally invasive hysterectomy is recommended. Drawbacks to hysterectomy include perioperative risk and concomitant oophorectomy, which was common until the early 2000s when large cohort studies showed elevated risks of death, cardiovascular disease, dementia, and other illnesses compared with hysterectomy plus ovarian conservation. Oophorectomy but not hysterectomy rates have since decreased.

Still needing study, according to Laughlin-Tommaso are the underlying reasons for health disparities in fibroids, especially among Black and Latina individuals. “Some studies have found associations with vitamin D deficiency and with stress and racism,” she said.

Looking ahead, the authors stressed the need for a fibroid risk-prediction model, a staging system, and large randomized trials of treatment effectiveness. Also needed are methods for primary and secondary prevention. “Earlier screening and medical treatment in primary care settings could potentially minimize morbidity and the incidence of unnecessary hysterectomies, and primary care–based screening trials are warranted,” they wrote.
 

In addition to procedural illustrations the practice document includes a vignette of a 33-year-old never-pregnant Black woman (but desiring motherhood) with heavy menstrual bleeding, abdominal bloating, and non–iron deficiency anemia. Evaluation for thalassemia and sickle cell anemia is negative, but ultrasonography reveals an enlarged uterus with multiple fibroids and normal ovaries.

In line with the clinical review, the authors prescribe oral GnRH agonist combination therapy, plus iron and multivitamin supplementation, and recommend annual reassessment — earlier if pregnancy is desired or if symptoms escalate. Since the patient prioritizes fertility, hysterectomy would be appropriate only if she had biopsy-proven cancer. 

The authors received no external funding for this practice paper, but both have funding from the National Institutes of Health for fibroid research. Laughlin-Tommaso reported royalties from UpToDate. Stewart reported research support from the Agency for Healthcare Research and Quality, and speaking, data-monitoring, and consulting fees for various private companies, including AbbVie, Anylam Pharmaceuticals, ASKA Pharma, and Myovant Sciences. She holds a patent on treatment for abnormal uterine bleeding and has been involved in CME for various medical educational agencies. Hurtado and Ascher-Walsh had no relevant conflicts of interest to declare.
 

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

The majority of patients may safely take glucagon-like peptide 1 receptor agonists (GLP-1 RAs) before elective surgery and gastrointestinal endoscopies, according to updated guidance from five medical societies.

The new guidance, contrasting with earlier recommendations, says these incrementally used agents can be taken up until the day of surgery, but patients are advised to follow a liquid diet for 24 hours before the procedure. The decision to proceed with endoscopy and other procedures should be based on shared decision-making with the patient and interdisciplinary care teams in conjunction with minimization of the aspiration risk from delayed gastric emptying, the guidance stresses.

The five endorsing organizations are the American Society for Metabolic and Bariatric Surgery, American Society of Anesthesiologists (ASA), American Gastroenterological Association, International Society of Perioperative Care of Patients with Obesity, and Society of American Gastrointestinal and Endoscopic Surgeons. The societies emphasize that the statement is intended as guidance only and is not an evidence-based formal guideline.

GLP-1 RAs are known to delay gastric emptying, raising concerns about regurgitation, aspiration, and airway compromise during anesthesia. Rare serious adverse events have also been observed, prompting the ASA in 2023 to recommend holding these agents for 1 week for the injectable form and 1 day for the oral form before all procedures requiring anesthesia. 

 

University of Michigan

That abundance of caution, however, had negative impacts of its own. “This guidance has led to cancellations and postponements of many endoscopic and surgical procedures or required patients to undergo general anesthesia who may otherwise have had their procedures performed under moderate sedation,” said guidance coauthor Allison R. Schulman, MD, MPH, an associate professor of medicine and surgery and chief of endoscopy at the University of Michigan in Ann Arbor. “Nearly all institutions have been forced to revise preprocedural protocols, despite a lack of high-level evidence to suggest that these adjustments are necessary.”

“Studies have yielded mixed results as to whether patients on GLP-1s are at increased risk of these events, and the limited data available are inconsistent,” Schulman said. “As a result, there are inconsistencies in the recommendations from various societies leading to growing uncertainty with proceduralists on how to provide safe, effective, and timely procedural care to patients taking GLP-1 RAs.”

The new joint-society guidance may alleviate some of the uncertainty. Among the recommendations:

• Continuing GLP-1 RAs in the perioperative period should be based on shared decision-making with the patient and all care teams balancing the metabolic need for the GLP-1 RA with individual patient risk.
• Certain variables may increase the risk for delayed gastric emptying and aspiration with the periprocedural use of GLP-1 RAs: escalation phase — This phase vs the maintenance phase is associated with a higher risk for delayed gastric emptying; higher dose — the higher the dose, the greater the risk for gastrointestinal (GI) side effects; weekly dosing — GI side effects are more common with weekly vs daily formulations; presence of GI symptoms — nausea, vomiting, abdominal pain, dyspepsia, and constipation may suggest delayed gastric emptying; and medical problems beyond GLP-1 RA indications with GI effects — assess for such conditions as bowel dysmotility, gastroparesis, and Parkinson’s disease.
• Risk factors should be assessed in advance to allow sufficient time to adjust preoperative care, including diet modification and medication bridging if GLP-1 RA cessation is deemed advisable.
• If retained gastric contents are a concern on the day of a procedure, point-of-care gastric ultrasound could be used to assess aspiration risk, resources permitting.
• The aspiration risk from delayed gastric emptying should be minimized by preoperative diet modification and/or altering the anesthesia plan to consider rapid sequence induction of general anesthesia for tracheal intubation. A 24-hour preoperative liquid diet, as before colonoscopy and bariatric surgery, can be utilized when delayed gastric emptying is a concern.
• When concern about retained gastric contents exists on procedure day, providers should engage patients in a shared decision-making model and consider the benefits and risks of rapid-sequence induction of general anesthesia for tracheal intubation to minimize aspiration risk vs procedure cancellation.

“Safe continuation of surgery and gastrointestinal endoscopy, and prevention of procedure cancellation, for patients on GLP-1 RAs can be prioritized following the recommendations above, as would occur for other patient populations with gastroparesis,” the guidance panel wrote.

 

Digestive Health Center of Huntington

Commenting on the statement but not involved in it, David B. Purow, MD, managing director of the Digestive Health Center at Northwell Health/Huntington Hospital in Huntington, New York, said the recommendations will encourage clinicians to be more discerning about actual risk in individual cases rather than follow the previous blanket recommendation to stop these agents before procedures requiring sedation. 

While GLP-1 RAs were prescribed for the relatively small number of patients with diabetes, he said, the risk was not apparent but became clearer with the widespread use of these agents for weight loss — often unregulated and undisclosed to care providers.

“The pendulum shifted too far the other way, and now it’s shifted back,” he said in an interview. “The new guidance is great because now we can be more thoughtful about managing individual patients.” He cited, for instance, the recommendations on the greater risk in patients in the dose escalation phase or on higher doses, and the risk-reducing measure of a liquid diet for 24 hours before surgery.

His center is already using point-of-care ultrasound and recently had a case in which a patient who forgot and took his GLP-1 RA before a scheduled procedure was found on ultrasound to have a full stomach. “In some cases, these drugs can cause an almost gastroparesis level of delayed emptying,” Purow said.

Purow thinks this early guidance will probably progress to firm guidelines within a year. Schulman is more cautious. “Our understanding of this complex topic is increasing rapidly, and ongoing clinical research will ultimately lead to evidence-based guidelines in this changing landscape,” she said.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Schulman is a consultant for Apollo Endosurgery, Boston Scientific, Olympus, Microtech, and Fractyl. Purow had no competing interests to declare.

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

The majority of patients may safely take glucagon-like peptide 1 receptor agonists (GLP-1 RAs) before elective surgery and gastrointestinal endoscopies, according to updated guidance from five medical societies.

The new guidance, contrasting with earlier recommendations, says these incrementally used agents can be taken up until the day of surgery, but patients are advised to follow a liquid diet for 24 hours before the procedure. The decision to proceed with endoscopy and other procedures should be based on shared decision-making with the patient and interdisciplinary care teams in conjunction with minimization of the aspiration risk from delayed gastric emptying, the guidance stresses.

The five endorsing organizations are the American Society for Metabolic and Bariatric Surgery, American Society of Anesthesiologists (ASA), American Gastroenterological Association, International Society of Perioperative Care of Patients with Obesity, and Society of American Gastrointestinal and Endoscopic Surgeons. The societies emphasize that the statement is intended as guidance only and is not an evidence-based formal guideline.

GLP-1 RAs are known to delay gastric emptying, raising concerns about regurgitation, aspiration, and airway compromise during anesthesia. Rare serious adverse events have also been observed, prompting the ASA in 2023 to recommend holding these agents for 1 week for the injectable form and 1 day for the oral form before all procedures requiring anesthesia. 

 

University of Michigan

That abundance of caution, however, had negative impacts of its own. “This guidance has led to cancellations and postponements of many endoscopic and surgical procedures or required patients to undergo general anesthesia who may otherwise have had their procedures performed under moderate sedation,” said guidance coauthor Allison R. Schulman, MD, MPH, an associate professor of medicine and surgery and chief of endoscopy at the University of Michigan in Ann Arbor. “Nearly all institutions have been forced to revise preprocedural protocols, despite a lack of high-level evidence to suggest that these adjustments are necessary.”

“Studies have yielded mixed results as to whether patients on GLP-1s are at increased risk of these events, and the limited data available are inconsistent,” Schulman said. “As a result, there are inconsistencies in the recommendations from various societies leading to growing uncertainty with proceduralists on how to provide safe, effective, and timely procedural care to patients taking GLP-1 RAs.”

The new joint-society guidance may alleviate some of the uncertainty. Among the recommendations:

• Continuing GLP-1 RAs in the perioperative period should be based on shared decision-making with the patient and all care teams balancing the metabolic need for the GLP-1 RA with individual patient risk.
• Certain variables may increase the risk for delayed gastric emptying and aspiration with the periprocedural use of GLP-1 RAs: escalation phase — This phase vs the maintenance phase is associated with a higher risk for delayed gastric emptying; higher dose — the higher the dose, the greater the risk for gastrointestinal (GI) side effects; weekly dosing — GI side effects are more common with weekly vs daily formulations; presence of GI symptoms — nausea, vomiting, abdominal pain, dyspepsia, and constipation may suggest delayed gastric emptying; and medical problems beyond GLP-1 RA indications with GI effects — assess for such conditions as bowel dysmotility, gastroparesis, and Parkinson’s disease.
• Risk factors should be assessed in advance to allow sufficient time to adjust preoperative care, including diet modification and medication bridging if GLP-1 RA cessation is deemed advisable.
• If retained gastric contents are a concern on the day of a procedure, point-of-care gastric ultrasound could be used to assess aspiration risk, resources permitting.
• The aspiration risk from delayed gastric emptying should be minimized by preoperative diet modification and/or altering the anesthesia plan to consider rapid sequence induction of general anesthesia for tracheal intubation. A 24-hour preoperative liquid diet, as before colonoscopy and bariatric surgery, can be utilized when delayed gastric emptying is a concern.
• When concern about retained gastric contents exists on procedure day, providers should engage patients in a shared decision-making model and consider the benefits and risks of rapid-sequence induction of general anesthesia for tracheal intubation to minimize aspiration risk vs procedure cancellation.

“Safe continuation of surgery and gastrointestinal endoscopy, and prevention of procedure cancellation, for patients on GLP-1 RAs can be prioritized following the recommendations above, as would occur for other patient populations with gastroparesis,” the guidance panel wrote.

 

Digestive Health Center of Huntington

Commenting on the statement but not involved in it, David B. Purow, MD, managing director of the Digestive Health Center at Northwell Health/Huntington Hospital in Huntington, New York, said the recommendations will encourage clinicians to be more discerning about actual risk in individual cases rather than follow the previous blanket recommendation to stop these agents before procedures requiring sedation. 

While GLP-1 RAs were prescribed for the relatively small number of patients with diabetes, he said, the risk was not apparent but became clearer with the widespread use of these agents for weight loss — often unregulated and undisclosed to care providers.

“The pendulum shifted too far the other way, and now it’s shifted back,” he said in an interview. “The new guidance is great because now we can be more thoughtful about managing individual patients.” He cited, for instance, the recommendations on the greater risk in patients in the dose escalation phase or on higher doses, and the risk-reducing measure of a liquid diet for 24 hours before surgery.

His center is already using point-of-care ultrasound and recently had a case in which a patient who forgot and took his GLP-1 RA before a scheduled procedure was found on ultrasound to have a full stomach. “In some cases, these drugs can cause an almost gastroparesis level of delayed emptying,” Purow said.

Purow thinks this early guidance will probably progress to firm guidelines within a year. Schulman is more cautious. “Our understanding of this complex topic is increasing rapidly, and ongoing clinical research will ultimately lead to evidence-based guidelines in this changing landscape,” she said.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Schulman is a consultant for Apollo Endosurgery, Boston Scientific, Olympus, Microtech, and Fractyl. Purow had no competing interests to declare.

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

The majority of patients may safely take glucagon-like peptide 1 receptor agonists (GLP-1 RAs) before elective surgery and gastrointestinal endoscopies, according to updated guidance from five medical societies.

The new guidance, contrasting with earlier recommendations, says these incrementally used agents can be taken up until the day of surgery, but patients are advised to follow a liquid diet for 24 hours before the procedure. The decision to proceed with endoscopy and other procedures should be based on shared decision-making with the patient and interdisciplinary care teams in conjunction with minimization of the aspiration risk from delayed gastric emptying, the guidance stresses.

The five endorsing organizations are the American Society for Metabolic and Bariatric Surgery, American Society of Anesthesiologists (ASA), American Gastroenterological Association, International Society of Perioperative Care of Patients with Obesity, and Society of American Gastrointestinal and Endoscopic Surgeons. The societies emphasize that the statement is intended as guidance only and is not an evidence-based formal guideline.

GLP-1 RAs are known to delay gastric emptying, raising concerns about regurgitation, aspiration, and airway compromise during anesthesia. Rare serious adverse events have also been observed, prompting the ASA in 2023 to recommend holding these agents for 1 week for the injectable form and 1 day for the oral form before all procedures requiring anesthesia. 

 

University of Michigan

That abundance of caution, however, had negative impacts of its own. “This guidance has led to cancellations and postponements of many endoscopic and surgical procedures or required patients to undergo general anesthesia who may otherwise have had their procedures performed under moderate sedation,” said guidance coauthor Allison R. Schulman, MD, MPH, an associate professor of medicine and surgery and chief of endoscopy at the University of Michigan in Ann Arbor. “Nearly all institutions have been forced to revise preprocedural protocols, despite a lack of high-level evidence to suggest that these adjustments are necessary.”

“Studies have yielded mixed results as to whether patients on GLP-1s are at increased risk of these events, and the limited data available are inconsistent,” Schulman said. “As a result, there are inconsistencies in the recommendations from various societies leading to growing uncertainty with proceduralists on how to provide safe, effective, and timely procedural care to patients taking GLP-1 RAs.”

The new joint-society guidance may alleviate some of the uncertainty. Among the recommendations:

• Continuing GLP-1 RAs in the perioperative period should be based on shared decision-making with the patient and all care teams balancing the metabolic need for the GLP-1 RA with individual patient risk.
• Certain variables may increase the risk for delayed gastric emptying and aspiration with the periprocedural use of GLP-1 RAs: escalation phase — This phase vs the maintenance phase is associated with a higher risk for delayed gastric emptying; higher dose — the higher the dose, the greater the risk for gastrointestinal (GI) side effects; weekly dosing — GI side effects are more common with weekly vs daily formulations; presence of GI symptoms — nausea, vomiting, abdominal pain, dyspepsia, and constipation may suggest delayed gastric emptying; and medical problems beyond GLP-1 RA indications with GI effects — assess for such conditions as bowel dysmotility, gastroparesis, and Parkinson’s disease.
• Risk factors should be assessed in advance to allow sufficient time to adjust preoperative care, including diet modification and medication bridging if GLP-1 RA cessation is deemed advisable.
• If retained gastric contents are a concern on the day of a procedure, point-of-care gastric ultrasound could be used to assess aspiration risk, resources permitting.
• The aspiration risk from delayed gastric emptying should be minimized by preoperative diet modification and/or altering the anesthesia plan to consider rapid sequence induction of general anesthesia for tracheal intubation. A 24-hour preoperative liquid diet, as before colonoscopy and bariatric surgery, can be utilized when delayed gastric emptying is a concern.
• When concern about retained gastric contents exists on procedure day, providers should engage patients in a shared decision-making model and consider the benefits and risks of rapid-sequence induction of general anesthesia for tracheal intubation to minimize aspiration risk vs procedure cancellation.

“Safe continuation of surgery and gastrointestinal endoscopy, and prevention of procedure cancellation, for patients on GLP-1 RAs can be prioritized following the recommendations above, as would occur for other patient populations with gastroparesis,” the guidance panel wrote.

 

Digestive Health Center of Huntington

Commenting on the statement but not involved in it, David B. Purow, MD, managing director of the Digestive Health Center at Northwell Health/Huntington Hospital in Huntington, New York, said the recommendations will encourage clinicians to be more discerning about actual risk in individual cases rather than follow the previous blanket recommendation to stop these agents before procedures requiring sedation. 

While GLP-1 RAs were prescribed for the relatively small number of patients with diabetes, he said, the risk was not apparent but became clearer with the widespread use of these agents for weight loss — often unregulated and undisclosed to care providers.

“The pendulum shifted too far the other way, and now it’s shifted back,” he said in an interview. “The new guidance is great because now we can be more thoughtful about managing individual patients.” He cited, for instance, the recommendations on the greater risk in patients in the dose escalation phase or on higher doses, and the risk-reducing measure of a liquid diet for 24 hours before surgery.

His center is already using point-of-care ultrasound and recently had a case in which a patient who forgot and took his GLP-1 RA before a scheduled procedure was found on ultrasound to have a full stomach. “In some cases, these drugs can cause an almost gastroparesis level of delayed emptying,” Purow said.

Purow thinks this early guidance will probably progress to firm guidelines within a year. Schulman is more cautious. “Our understanding of this complex topic is increasing rapidly, and ongoing clinical research will ultimately lead to evidence-based guidelines in this changing landscape,” she said.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Schulman is a consultant for Apollo Endosurgery, Boston Scientific, Olympus, Microtech, and Fractyl. Purow had no competing interests to declare.

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

Vaccination against human papilloma virus (HPV), a group of more than 200 viruses infecting at least 50% of sexually active people over their lifetimes, has proved more than 90% effective for preventing several diseases caused by high-risk HPV types. 

Gardasil 4: 2006 

It started in 2006 with the approval of Human Papillomavirus Quadrivalent, types 6, 11, 16, and 18 (Gardasil 4). Merck’s vaccine began to lower rates of cervical cancer, a major global killer of women.

“It’s fair to say the vaccine has been an American and a global public health success story in reducing rates of cervical cancer,” Paula M. Cuccaro, PhD, assistant professor of health promotion and behavioral sciences at University of Texas School of Public Health, Houston, said in an interview.

How does a common virus trigger such a lethal gynecologic malignancy? “It knocks out two important cancer suppressor genes in cells,” explained Christina Annunziata,MD, PhD, a medical oncologist and senior vice president of extramural discovery science for the American Cancer Society. HPV oncoproteins are encoded by the E6 and E7 genes. As in other DNA tumor viruses, the E6 and E7 proteins functionally inactivate the tumor suppressor proteins p53 and pRB, respectively.
 

US Prevalence

Despite screening and vaccination, cervical cancer is still very much around. This year, 13,820 new cases of invasive cervical cancer will be diagnosed in the United States, and approximately 4360 women will die of it, according to the American Cancer Society. Even before the advent of Gardasil 4, incidence rates had already decreased by more than half from the mid-1970s to the mid-2000s, thanks largely to Pap smear screening programs for treatable premalignant lesions. “The US rate had dropped to about 20 per 100,000 women even before Gardasil 4,” said Annunziata. “After the introduction of the first vaccine, it decreased to 7 per 100,000, a decrease of about 30%, but it remains plateaued now at about the same level.”

Although the past decade has seen rates generally stabilize, there have been some changes in different age groups. In women ages 30-44, rates increased 1.7% each year from 2012 to 2019, while rates declined 11% each year for women ages 20-24— probably reflecting the impact of the first wave of prevention from Gardasil 4.

In one 2021 population-based study of US cancer registry data from 1999 to 2017, rates of both cervical squamous cell carcinoma and adenocarcinoma dropped. The largest declines occurred in females 15-20 years old, the age group most likely to be vaccinated against HPV but not typically screened, suggesting a vaccine-related effect.
 

Gardasil 9: 2014

With the 2014 approval of the vaccine’s second iteration, Gardasil 9, which replaced Gardasil 4 and targeted 9 HPV strains, immunization has taken broader aim. The strains covered by Gardasil 9 protect against oropharyngeal and other head and neck cancers — as well as penile, anal, vulvar, and vaginal malignancies and premalignancies, and genital warts in both sexes ages 9-45. 

It may be years, however, before the impact of the newer polyvalent formulation is felt. “While the first vaccine has been successful against the prevalent strains of HPV linked to cervical cancer, it’s a little early to call it for the newer vaccine since oropharyngeal cancers tend to develop later in older men,” Cuccaro said. “But the types of HPV linked to mouth and throat cancers and covered by the newer vaccines are much less prevalent in those who are vaccinated. The strains not covered in the vaccine you see are equally present in the vaccinated and non-vaccinated.”

Angela L. Myers, MD, MPH, division director of infectious diseases and medical director of the Center for Wellbeing at Children’s Mercy in Kansas City, Missouri, added, “Unlike for cervical cancer, there are no screening programs for oropharyngeal lesions, so you have to wait to see rates until actual cancer develops.”

A 2023 review reported that HPV vaccination reduced levels of oropharyngeal HPV positivity in men, strengthening the case for pangender immunization. 

And in a recent phase 3 doubled-blind trial, GARDASIL 9 reduced the incidence of anogenital persistent infection caused by nine types of HPV compared with a placebo. 
 

Increasing Uptake

The current public health aim is to have 80% of young people in the targeted age group vaccinated with two doses. Today, uptake among those 9-26 years old stands at about 78% of girls and 75% of boys for the first dose, said Annunziata. “But it’s only about 61% for the two doses in the current series, and we want to improve that.” 

Some parents may still harbor fears that immunizing teens and tweens — both the American Academy of Pediatrics and the American Cancer Society recommend immunization at age 9 — will open the door to precocious sexual activity. 

“But overall, uptake in tweens and young teens has increased because the messaging has changed,” said Myers, with the rationale now focusing on cancer prevention not sexual-infection prophylaxis. “This is similar to the hepatitis B vaccine, which used to be given to young adults and is now given to newborns to prevent cancer.” 

Cuccaro added that a proactive presentation by healthcare professionals has a significant effect on vaccine uptake and increases the odds of vaccination ninefold. “Providers should take a presumptive approach and avoid just offering the vaccine as an option. It should be included with regular childhood vaccinations,” she said. “And the advantage of starting early at age 9 is that you can spread the doses out across other regular childhood vaccinations, whereas if you start at age 11, you need to add the HPV vaccine to three other vaccines that are given at that time.” 

After age 15, three doses are necessary. “Providers should stress to parents that it’s most effective when given before young people become sexually active and exposed to HPV,” Cuccaro said. And Myers stressed that despite the vaccine’s effectiveness, routine screening for cervical premalignancies is still important. 

Despite increasing coverage, vaccination rates have some distance to go before the public health target of at least 80% uptake of the series in the targeted age group, Cuccaro cautioned.

On the global stage, barriers to immunization remain, but the World Health Organization has endorsed a campaign to eradicate cervical cancer through HPV vaccination. It has predicted that the 21st century may be the last to experience HPV-associated cancers, currently responsible for more than 300,000 annual deaths worldwide.
 

A Brief History of HPV Vaccines

• 1951. Cervical cancer patient Henrietta Lacks’ rapidly dividing cervical cells are collected by George Otto Gey at Johns Hopkins Hospital. They create the first immortal cell line (HeLa) used to study cancers and vaccines worldwide.
• 1976. Harald zur Hausen suggests that genital wart-associated HPV, not herpes simplex, is the probable cause of cervical cancer.
• 1983. HPV is confirmed as a cause of cancer.
• 1991. The first HPV vaccine is developed.
• 2002. Proof of principle and protective efficacy for the monovalent HPV 16 are shown.
• 2006. Merck’s Gardasil 4 (HPV 4) is FDA approved in girls ages 9-26 for protection against strains 6, 11, 16, and 18 — the cause of more than 70% of cervical cancer cases.
• 2009. Approval of Gardasil 4 is expanded to boys ages 9-26 for the prevention of genital warts.
• 2009. The FDA approves GlaxoSmithKline’s Cervarix (HPV 16 and 18) for girls and young women. The vaccine was withdrawn from the US market in 2016 following the success of Gardasil 9 but is used abroad for HPV cancer prevention.
• 2014. The 9-valent recombinant vaccine Gardasil 9 is FDA approved for protection against several low-risk, wart-causing HPV strains as well as the high-risk cancer strains targeted by HPV 4.
• 2018. The FDA expands approval to include females and males 27-45 years old.
• 2020. The FDA extends approval of Gardasil 9 to include prevention not only of cervical cancer but also, vaginal, vulvar, anal, oropharyngeal, and other head and neck cancers.

Annunziata, Cuccaro, and Myers had no competing interests to declare.
 

A version of this article appeared on Medscape.com.

Vaccination against human papilloma virus (HPV), a group of more than 200 viruses infecting at least 50% of sexually active people over their lifetimes, has proved more than 90% effective for preventing several diseases caused by high-risk HPV types. 

Gardasil 4: 2006 

It started in 2006 with the approval of Human Papillomavirus Quadrivalent, types 6, 11, 16, and 18 (Gardasil 4). Merck’s vaccine began to lower rates of cervical cancer, a major global killer of women.

“It’s fair to say the vaccine has been an American and a global public health success story in reducing rates of cervical cancer,” Paula M. Cuccaro, PhD, assistant professor of health promotion and behavioral sciences at University of Texas School of Public Health, Houston, said in an interview.

How does a common virus trigger such a lethal gynecologic malignancy? “It knocks out two important cancer suppressor genes in cells,” explained Christina Annunziata,MD, PhD, a medical oncologist and senior vice president of extramural discovery science for the American Cancer Society. HPV oncoproteins are encoded by the E6 and E7 genes. As in other DNA tumor viruses, the E6 and E7 proteins functionally inactivate the tumor suppressor proteins p53 and pRB, respectively.
 

US Prevalence

Despite screening and vaccination, cervical cancer is still very much around. This year, 13,820 new cases of invasive cervical cancer will be diagnosed in the United States, and approximately 4360 women will die of it, according to the American Cancer Society. Even before the advent of Gardasil 4, incidence rates had already decreased by more than half from the mid-1970s to the mid-2000s, thanks largely to Pap smear screening programs for treatable premalignant lesions. “The US rate had dropped to about 20 per 100,000 women even before Gardasil 4,” said Annunziata. “After the introduction of the first vaccine, it decreased to 7 per 100,000, a decrease of about 30%, but it remains plateaued now at about the same level.”

Although the past decade has seen rates generally stabilize, there have been some changes in different age groups. In women ages 30-44, rates increased 1.7% each year from 2012 to 2019, while rates declined 11% each year for women ages 20-24— probably reflecting the impact of the first wave of prevention from Gardasil 4.

In one 2021 population-based study of US cancer registry data from 1999 to 2017, rates of both cervical squamous cell carcinoma and adenocarcinoma dropped. The largest declines occurred in females 15-20 years old, the age group most likely to be vaccinated against HPV but not typically screened, suggesting a vaccine-related effect.
 

Gardasil 9: 2014

With the 2014 approval of the vaccine’s second iteration, Gardasil 9, which replaced Gardasil 4 and targeted 9 HPV strains, immunization has taken broader aim. The strains covered by Gardasil 9 protect against oropharyngeal and other head and neck cancers — as well as penile, anal, vulvar, and vaginal malignancies and premalignancies, and genital warts in both sexes ages 9-45. 

It may be years, however, before the impact of the newer polyvalent formulation is felt. “While the first vaccine has been successful against the prevalent strains of HPV linked to cervical cancer, it’s a little early to call it for the newer vaccine since oropharyngeal cancers tend to develop later in older men,” Cuccaro said. “But the types of HPV linked to mouth and throat cancers and covered by the newer vaccines are much less prevalent in those who are vaccinated. The strains not covered in the vaccine you see are equally present in the vaccinated and non-vaccinated.”

Angela L. Myers, MD, MPH, division director of infectious diseases and medical director of the Center for Wellbeing at Children’s Mercy in Kansas City, Missouri, added, “Unlike for cervical cancer, there are no screening programs for oropharyngeal lesions, so you have to wait to see rates until actual cancer develops.”

A 2023 review reported that HPV vaccination reduced levels of oropharyngeal HPV positivity in men, strengthening the case for pangender immunization. 

And in a recent phase 3 doubled-blind trial, GARDASIL 9 reduced the incidence of anogenital persistent infection caused by nine types of HPV compared with a placebo. 
 

Increasing Uptake

The current public health aim is to have 80% of young people in the targeted age group vaccinated with two doses. Today, uptake among those 9-26 years old stands at about 78% of girls and 75% of boys for the first dose, said Annunziata. “But it’s only about 61% for the two doses in the current series, and we want to improve that.” 

Some parents may still harbor fears that immunizing teens and tweens — both the American Academy of Pediatrics and the American Cancer Society recommend immunization at age 9 — will open the door to precocious sexual activity. 

“But overall, uptake in tweens and young teens has increased because the messaging has changed,” said Myers, with the rationale now focusing on cancer prevention not sexual-infection prophylaxis. “This is similar to the hepatitis B vaccine, which used to be given to young adults and is now given to newborns to prevent cancer.” 

Cuccaro added that a proactive presentation by healthcare professionals has a significant effect on vaccine uptake and increases the odds of vaccination ninefold. “Providers should take a presumptive approach and avoid just offering the vaccine as an option. It should be included with regular childhood vaccinations,” she said. “And the advantage of starting early at age 9 is that you can spread the doses out across other regular childhood vaccinations, whereas if you start at age 11, you need to add the HPV vaccine to three other vaccines that are given at that time.” 

After age 15, three doses are necessary. “Providers should stress to parents that it’s most effective when given before young people become sexually active and exposed to HPV,” Cuccaro said. And Myers stressed that despite the vaccine’s effectiveness, routine screening for cervical premalignancies is still important. 

Despite increasing coverage, vaccination rates have some distance to go before the public health target of at least 80% uptake of the series in the targeted age group, Cuccaro cautioned.

On the global stage, barriers to immunization remain, but the World Health Organization has endorsed a campaign to eradicate cervical cancer through HPV vaccination. It has predicted that the 21st century may be the last to experience HPV-associated cancers, currently responsible for more than 300,000 annual deaths worldwide.
 

A Brief History of HPV Vaccines

• 1951. Cervical cancer patient Henrietta Lacks’ rapidly dividing cervical cells are collected by George Otto Gey at Johns Hopkins Hospital. They create the first immortal cell line (HeLa) used to study cancers and vaccines worldwide.
• 1976. Harald zur Hausen suggests that genital wart-associated HPV, not herpes simplex, is the probable cause of cervical cancer.
• 1983. HPV is confirmed as a cause of cancer.
• 1991. The first HPV vaccine is developed.
• 2002. Proof of principle and protective efficacy for the monovalent HPV 16 are shown.
• 2006. Merck’s Gardasil 4 (HPV 4) is FDA approved in girls ages 9-26 for protection against strains 6, 11, 16, and 18 — the cause of more than 70% of cervical cancer cases.
• 2009. Approval of Gardasil 4 is expanded to boys ages 9-26 for the prevention of genital warts.
• 2009. The FDA approves GlaxoSmithKline’s Cervarix (HPV 16 and 18) for girls and young women. The vaccine was withdrawn from the US market in 2016 following the success of Gardasil 9 but is used abroad for HPV cancer prevention.
• 2014. The 9-valent recombinant vaccine Gardasil 9 is FDA approved for protection against several low-risk, wart-causing HPV strains as well as the high-risk cancer strains targeted by HPV 4.
• 2018. The FDA expands approval to include females and males 27-45 years old.
• 2020. The FDA extends approval of Gardasil 9 to include prevention not only of cervical cancer but also, vaginal, vulvar, anal, oropharyngeal, and other head and neck cancers.

Annunziata, Cuccaro, and Myers had no competing interests to declare.
 

A version of this article appeared on Medscape.com.

Vaccination against human papilloma virus (HPV), a group of more than 200 viruses infecting at least 50% of sexually active people over their lifetimes, has proved more than 90% effective for preventing several diseases caused by high-risk HPV types. 

Gardasil 4: 2006 

It started in 2006 with the approval of Human Papillomavirus Quadrivalent, types 6, 11, 16, and 18 (Gardasil 4). Merck’s vaccine began to lower rates of cervical cancer, a major global killer of women.

“It’s fair to say the vaccine has been an American and a global public health success story in reducing rates of cervical cancer,” Paula M. Cuccaro, PhD, assistant professor of health promotion and behavioral sciences at University of Texas School of Public Health, Houston, said in an interview.

How does a common virus trigger such a lethal gynecologic malignancy? “It knocks out two important cancer suppressor genes in cells,” explained Christina Annunziata,MD, PhD, a medical oncologist and senior vice president of extramural discovery science for the American Cancer Society. HPV oncoproteins are encoded by the E6 and E7 genes. As in other DNA tumor viruses, the E6 and E7 proteins functionally inactivate the tumor suppressor proteins p53 and pRB, respectively.
 

US Prevalence

Despite screening and vaccination, cervical cancer is still very much around. This year, 13,820 new cases of invasive cervical cancer will be diagnosed in the United States, and approximately 4360 women will die of it, according to the American Cancer Society. Even before the advent of Gardasil 4, incidence rates had already decreased by more than half from the mid-1970s to the mid-2000s, thanks largely to Pap smear screening programs for treatable premalignant lesions. “The US rate had dropped to about 20 per 100,000 women even before Gardasil 4,” said Annunziata. “After the introduction of the first vaccine, it decreased to 7 per 100,000, a decrease of about 30%, but it remains plateaued now at about the same level.”

Although the past decade has seen rates generally stabilize, there have been some changes in different age groups. In women ages 30-44, rates increased 1.7% each year from 2012 to 2019, while rates declined 11% each year for women ages 20-24— probably reflecting the impact of the first wave of prevention from Gardasil 4.

In one 2021 population-based study of US cancer registry data from 1999 to 2017, rates of both cervical squamous cell carcinoma and adenocarcinoma dropped. The largest declines occurred in females 15-20 years old, the age group most likely to be vaccinated against HPV but not typically screened, suggesting a vaccine-related effect.
 

Gardasil 9: 2014

With the 2014 approval of the vaccine’s second iteration, Gardasil 9, which replaced Gardasil 4 and targeted 9 HPV strains, immunization has taken broader aim. The strains covered by Gardasil 9 protect against oropharyngeal and other head and neck cancers — as well as penile, anal, vulvar, and vaginal malignancies and premalignancies, and genital warts in both sexes ages 9-45. 

It may be years, however, before the impact of the newer polyvalent formulation is felt. “While the first vaccine has been successful against the prevalent strains of HPV linked to cervical cancer, it’s a little early to call it for the newer vaccine since oropharyngeal cancers tend to develop later in older men,” Cuccaro said. “But the types of HPV linked to mouth and throat cancers and covered by the newer vaccines are much less prevalent in those who are vaccinated. The strains not covered in the vaccine you see are equally present in the vaccinated and non-vaccinated.”

Angela L. Myers, MD, MPH, division director of infectious diseases and medical director of the Center for Wellbeing at Children’s Mercy in Kansas City, Missouri, added, “Unlike for cervical cancer, there are no screening programs for oropharyngeal lesions, so you have to wait to see rates until actual cancer develops.”

A 2023 review reported that HPV vaccination reduced levels of oropharyngeal HPV positivity in men, strengthening the case for pangender immunization. 

And in a recent phase 3 doubled-blind trial, GARDASIL 9 reduced the incidence of anogenital persistent infection caused by nine types of HPV compared with a placebo. 
 

Increasing Uptake

The current public health aim is to have 80% of young people in the targeted age group vaccinated with two doses. Today, uptake among those 9-26 years old stands at about 78% of girls and 75% of boys for the first dose, said Annunziata. “But it’s only about 61% for the two doses in the current series, and we want to improve that.” 

Some parents may still harbor fears that immunizing teens and tweens — both the American Academy of Pediatrics and the American Cancer Society recommend immunization at age 9 — will open the door to precocious sexual activity. 

“But overall, uptake in tweens and young teens has increased because the messaging has changed,” said Myers, with the rationale now focusing on cancer prevention not sexual-infection prophylaxis. “This is similar to the hepatitis B vaccine, which used to be given to young adults and is now given to newborns to prevent cancer.” 

Cuccaro added that a proactive presentation by healthcare professionals has a significant effect on vaccine uptake and increases the odds of vaccination ninefold. “Providers should take a presumptive approach and avoid just offering the vaccine as an option. It should be included with regular childhood vaccinations,” she said. “And the advantage of starting early at age 9 is that you can spread the doses out across other regular childhood vaccinations, whereas if you start at age 11, you need to add the HPV vaccine to three other vaccines that are given at that time.” 

After age 15, three doses are necessary. “Providers should stress to parents that it’s most effective when given before young people become sexually active and exposed to HPV,” Cuccaro said. And Myers stressed that despite the vaccine’s effectiveness, routine screening for cervical premalignancies is still important. 

Despite increasing coverage, vaccination rates have some distance to go before the public health target of at least 80% uptake of the series in the targeted age group, Cuccaro cautioned.

On the global stage, barriers to immunization remain, but the World Health Organization has endorsed a campaign to eradicate cervical cancer through HPV vaccination. It has predicted that the 21st century may be the last to experience HPV-associated cancers, currently responsible for more than 300,000 annual deaths worldwide.
 

A Brief History of HPV Vaccines

• 1951. Cervical cancer patient Henrietta Lacks’ rapidly dividing cervical cells are collected by George Otto Gey at Johns Hopkins Hospital. They create the first immortal cell line (HeLa) used to study cancers and vaccines worldwide.
• 1976. Harald zur Hausen suggests that genital wart-associated HPV, not herpes simplex, is the probable cause of cervical cancer.
• 1983. HPV is confirmed as a cause of cancer.
• 1991. The first HPV vaccine is developed.
• 2002. Proof of principle and protective efficacy for the monovalent HPV 16 are shown.
• 2006. Merck’s Gardasil 4 (HPV 4) is FDA approved in girls ages 9-26 for protection against strains 6, 11, 16, and 18 — the cause of more than 70% of cervical cancer cases.
• 2009. Approval of Gardasil 4 is expanded to boys ages 9-26 for the prevention of genital warts.
• 2009. The FDA approves GlaxoSmithKline’s Cervarix (HPV 16 and 18) for girls and young women. The vaccine was withdrawn from the US market in 2016 following the success of Gardasil 9 but is used abroad for HPV cancer prevention.
• 2014. The 9-valent recombinant vaccine Gardasil 9 is FDA approved for protection against several low-risk, wart-causing HPV strains as well as the high-risk cancer strains targeted by HPV 4.
• 2018. The FDA expands approval to include females and males 27-45 years old.
• 2020. The FDA extends approval of Gardasil 9 to include prevention not only of cervical cancer but also, vaginal, vulvar, anal, oropharyngeal, and other head and neck cancers.

Annunziata, Cuccaro, and Myers had no competing interests to declare.
 

A version of this article appeared on Medscape.com.

Noninvasive surveillance with multitarget stool DNA testing or fecal immunochemical testing (FIT) could potentially match colonoscopy for reducing long-term colorectal cancer (CRC) incidence and mortality. It might also reduce colonoscopies by an estimated 15%-41%.

The greatest reduction would likely be achieved by annual FIT-based surveillance, especially with FIT FOB-Gold at a threshold of at least 32 µg/g feces, according to findings from the Dutch MOCCAS study published in Gastroenterology.

In this cross-sectional observational study, the multitarget DNA test outperformed FIT for detecting advanced precursor lesions, especially serrated polyps. According to long-term-impact mathematical modeling, however, DNA-based surveillance would be more costly than colonoscopy surveillance, whereas FIT would save costs.

“With the worldwide implementation of FIT-based screening programs, following a positive test, many more people enter surveillance programs after polypectomy. This results in an increased pressure on the colonoscopy capacity and healthcare budgets,” lead author Beatriz Carvalho, PhD, a molecular biologist in the Department of Pathology of the Netherlands Cancer Institute in Amsterdam, said in an interview.

Netherlands Cancer Institute

Stanford University

Study Details

The cross-sectional observational study included individuals aged 50-75 years who provided stool samples for the DNA test and two FITs. Test accuracy was calculated for all surveillance indications.

For the post-polypectomy indication only, which is the most common and associated with a relatively low CRC risk, the long-term impact of stool-based surveillance was evaluated with the Adenoma and Serrated Pathway to Colorectal Cancer model. Stool-based strategies were simulated to tune each test’s positivity threshold to obtain strategies that are at least as effective as colonoscopy surveillance.

A total of 3453 individuals had results for all stool tests and colonoscopy; among them, 2226 had previously undergone polypectomy, 1003 had a history of CRC, and 224 had a familial risk.

Areas under the receiver operating characteristic curve for advanced neoplasia were as follows:

• 0.72 (95% CI, 0.69-0.75) for the multitarget stool DNA test
• 0.61 (95% CI, 0.58-0.64) for the FIT OC-SENSOR 
• 0.59 (95% CI, 0.56-0.61) for the FIT FOB-Gold 

Stool-based surveillance was estimated to be at least as effective as colonoscopy surveillance and required 5.6 to 9.5 stool tests over a person’s lifetime. DNA-based surveillance was more costly than colonoscopy surveillance, whereas FIT-based surveillance saved costs.

“These findings provide a basis to embark on a prospective intervention study to assess the clinical utility of FIT as an alternative to colonoscopy surveillance in a post-polypectomy CRC surveillance population,” the authors wrote.

In the United States, Ladabaum said, it would likely be possible to find FIT-based strategies that closely approximate or match surveillance colonoscopy — “if we could deploy FIT with the required flexibility, for example, by adjusting the threshold and if the reference surveillance standard were somewhat relaxed compared with current guidelines.”

He worries, however, that if FIT for screening and FIT for surveillance were optimized at different hemoglobin detection thresholds, “there could be confusion and room for error in real-world clinical implementation.”

The authors called for research to increase understanding of the mechanisms underlying progression from adenomas to malignancy over time, which may yield better biomarkers to improve stool test accuracy.

This study was funded by the Alpe d’HuZes charity and the Dutch Cancer Society. Exact Sciences provided test equipment and performed multitarget stool DNA test analysis. Sentinel Diagnostics provided equipment and reagents.

Carvalho and Veerle M. H. Coupé, PhD, disclosed several patents pending and/or issued. Other coauthors disclosed multiple financial relationships with private companies, including Exact Sciences and Sentinel, for research support, travel, board membership, advisory or speaker fees, consulting, employment, stock ownership, or patents.

Ladabaum disclosed no competing interests relevant to his comments.

A version of this article appeared on Medscape.com.

Noninvasive surveillance with multitarget stool DNA testing or fecal immunochemical testing (FIT) could potentially match colonoscopy for reducing long-term colorectal cancer (CRC) incidence and mortality. It might also reduce colonoscopies by an estimated 15%-41%.

The greatest reduction would likely be achieved by annual FIT-based surveillance, especially with FIT FOB-Gold at a threshold of at least 32 µg/g feces, according to findings from the Dutch MOCCAS study published in Gastroenterology.

In this cross-sectional observational study, the multitarget DNA test outperformed FIT for detecting advanced precursor lesions, especially serrated polyps. According to long-term-impact mathematical modeling, however, DNA-based surveillance would be more costly than colonoscopy surveillance, whereas FIT would save costs.

“With the worldwide implementation of FIT-based screening programs, following a positive test, many more people enter surveillance programs after polypectomy. This results in an increased pressure on the colonoscopy capacity and healthcare budgets,” lead author Beatriz Carvalho, PhD, a molecular biologist in the Department of Pathology of the Netherlands Cancer Institute in Amsterdam, said in an interview.

Netherlands Cancer Institute

Stanford University

Study Details

The cross-sectional observational study included individuals aged 50-75 years who provided stool samples for the DNA test and two FITs. Test accuracy was calculated for all surveillance indications.

For the post-polypectomy indication only, which is the most common and associated with a relatively low CRC risk, the long-term impact of stool-based surveillance was evaluated with the Adenoma and Serrated Pathway to Colorectal Cancer model. Stool-based strategies were simulated to tune each test’s positivity threshold to obtain strategies that are at least as effective as colonoscopy surveillance.

A total of 3453 individuals had results for all stool tests and colonoscopy; among them, 2226 had previously undergone polypectomy, 1003 had a history of CRC, and 224 had a familial risk.

Areas under the receiver operating characteristic curve for advanced neoplasia were as follows:

• 0.72 (95% CI, 0.69-0.75) for the multitarget stool DNA test
• 0.61 (95% CI, 0.58-0.64) for the FIT OC-SENSOR 
• 0.59 (95% CI, 0.56-0.61) for the FIT FOB-Gold 

Stool-based surveillance was estimated to be at least as effective as colonoscopy surveillance and required 5.6 to 9.5 stool tests over a person’s lifetime. DNA-based surveillance was more costly than colonoscopy surveillance, whereas FIT-based surveillance saved costs.

“These findings provide a basis to embark on a prospective intervention study to assess the clinical utility of FIT as an alternative to colonoscopy surveillance in a post-polypectomy CRC surveillance population,” the authors wrote.

In the United States, Ladabaum said, it would likely be possible to find FIT-based strategies that closely approximate or match surveillance colonoscopy — “if we could deploy FIT with the required flexibility, for example, by adjusting the threshold and if the reference surveillance standard were somewhat relaxed compared with current guidelines.”

He worries, however, that if FIT for screening and FIT for surveillance were optimized at different hemoglobin detection thresholds, “there could be confusion and room for error in real-world clinical implementation.”

The authors called for research to increase understanding of the mechanisms underlying progression from adenomas to malignancy over time, which may yield better biomarkers to improve stool test accuracy.

This study was funded by the Alpe d’HuZes charity and the Dutch Cancer Society. Exact Sciences provided test equipment and performed multitarget stool DNA test analysis. Sentinel Diagnostics provided equipment and reagents.

Carvalho and Veerle M. H. Coupé, PhD, disclosed several patents pending and/or issued. Other coauthors disclosed multiple financial relationships with private companies, including Exact Sciences and Sentinel, for research support, travel, board membership, advisory or speaker fees, consulting, employment, stock ownership, or patents.

Ladabaum disclosed no competing interests relevant to his comments.

A version of this article appeared on Medscape.com.

Noninvasive surveillance with multitarget stool DNA testing or fecal immunochemical testing (FIT) could potentially match colonoscopy for reducing long-term colorectal cancer (CRC) incidence and mortality. It might also reduce colonoscopies by an estimated 15%-41%.

The greatest reduction would likely be achieved by annual FIT-based surveillance, especially with FIT FOB-Gold at a threshold of at least 32 µg/g feces, according to findings from the Dutch MOCCAS study published in Gastroenterology.

In this cross-sectional observational study, the multitarget DNA test outperformed FIT for detecting advanced precursor lesions, especially serrated polyps. According to long-term-impact mathematical modeling, however, DNA-based surveillance would be more costly than colonoscopy surveillance, whereas FIT would save costs.

“With the worldwide implementation of FIT-based screening programs, following a positive test, many more people enter surveillance programs after polypectomy. This results in an increased pressure on the colonoscopy capacity and healthcare budgets,” lead author Beatriz Carvalho, PhD, a molecular biologist in the Department of Pathology of the Netherlands Cancer Institute in Amsterdam, said in an interview.

Netherlands Cancer Institute

Stanford University

Study Details

The cross-sectional observational study included individuals aged 50-75 years who provided stool samples for the DNA test and two FITs. Test accuracy was calculated for all surveillance indications.

For the post-polypectomy indication only, which is the most common and associated with a relatively low CRC risk, the long-term impact of stool-based surveillance was evaluated with the Adenoma and Serrated Pathway to Colorectal Cancer model. Stool-based strategies were simulated to tune each test’s positivity threshold to obtain strategies that are at least as effective as colonoscopy surveillance.

A total of 3453 individuals had results for all stool tests and colonoscopy; among them, 2226 had previously undergone polypectomy, 1003 had a history of CRC, and 224 had a familial risk.

Areas under the receiver operating characteristic curve for advanced neoplasia were as follows:

• 0.72 (95% CI, 0.69-0.75) for the multitarget stool DNA test
• 0.61 (95% CI, 0.58-0.64) for the FIT OC-SENSOR 
• 0.59 (95% CI, 0.56-0.61) for the FIT FOB-Gold 

Stool-based surveillance was estimated to be at least as effective as colonoscopy surveillance and required 5.6 to 9.5 stool tests over a person’s lifetime. DNA-based surveillance was more costly than colonoscopy surveillance, whereas FIT-based surveillance saved costs.

“These findings provide a basis to embark on a prospective intervention study to assess the clinical utility of FIT as an alternative to colonoscopy surveillance in a post-polypectomy CRC surveillance population,” the authors wrote.

In the United States, Ladabaum said, it would likely be possible to find FIT-based strategies that closely approximate or match surveillance colonoscopy — “if we could deploy FIT with the required flexibility, for example, by adjusting the threshold and if the reference surveillance standard were somewhat relaxed compared with current guidelines.”

He worries, however, that if FIT for screening and FIT for surveillance were optimized at different hemoglobin detection thresholds, “there could be confusion and room for error in real-world clinical implementation.”

The authors called for research to increase understanding of the mechanisms underlying progression from adenomas to malignancy over time, which may yield better biomarkers to improve stool test accuracy.

This study was funded by the Alpe d’HuZes charity and the Dutch Cancer Society. Exact Sciences provided test equipment and performed multitarget stool DNA test analysis. Sentinel Diagnostics provided equipment and reagents.

Carvalho and Veerle M. H. Coupé, PhD, disclosed several patents pending and/or issued. Other coauthors disclosed multiple financial relationships with private companies, including Exact Sciences and Sentinel, for research support, travel, board membership, advisory or speaker fees, consulting, employment, stock ownership, or patents.

Ladabaum disclosed no competing interests relevant to his comments.

A version of this article appeared on Medscape.com.

Premenstrual disorders (PMDs), including premenstrual dysphoric disorder (PMDD), adversely affect the lives of millions of women worldwide. Most girls and women — as many as 80%-90%— will experience some premenstrual discomfort such as irritability, depressed mood, food or alcohol cravings, bloating, body aches, breast pain, constipation, or fatigue.

Diagnosable menstrual disorders include, collectively, premenstrual syndrome (PMS); PMDD, formerly called late luteal phase dysphoric disorder; and premenstrual worsening of another medical condition.

The most debilitating of these is PMDD, which has an estimated prevalence of about 4%-8% in women of reproductive age, according to obstetrician/gynecologist Hoosna Haque, MD, assistant professor of medicine at Columbia University Irving Medical Center in New York City.

“It’s difficult to be sure because this condition is underreported,” said Luu D. Ireland, MD, MPH, assistant professor of obstetrics and gynecology at UMass Memorial Medical Center in Worcester, Massachusetts. “But more women are coming forward, and there’s more discussion and media coverage of this condition.”

Occurring in the same post-follicular timeframe as PMS, PMDD takes cyclical discomfort to a more intense level, with a trifecta of affective comorbidities, somatic manifestations, and behavioral changes, all of which can seriously impair daily functioning, including work, physical activities, and personal relationships. Romantic and marital relationships can be particularly impaired.

Although recent cost figures are lacking, PMDs exact a considerable economic toll with increased direct healthcare costs from doctor visits and pharmaceuticals. A 2010 study found that US women with PMS were more likely to accrue in excess of $500 in healthcare visit costs over 2 years, and the figure would likely be higher today. PMDs also increase work/school absenteeism and reduce productivity.
 

Etiology

Brain areas that regulate emotion and behavior contain receptors for estrogen, progesterone, and other sex hormones, which affect the functioning of neurotransmitter systems influencing mood and thinking. Although the precise pathophysiology remains unclear, PMDD is likely multifactorial and results in a heightened sensitivity to normal fluctuations in estrogen and progesterone during the luteal phase of the menstrual cycle and dysfunction of the serotonin and gamma-aminobutyric acid neurotransmitter systems.

Patients with PMDD have lower levels of cortisol and beta-endorphins during both the follicular and luteal phases, suggesting abnormalities in the hypothalamic-pituitary-gonadal axis (HPGA), which is consistent with dysregulation in mood disorders.
 

Risk Factors

These include family history, past traumatic events, smoking, chronic pain syndrome, and obesity. There may be a genetic component as recent studies have suggested the involvement of the gene that codes for the serotonergic 5HT1A receptor and allelic variants of ESR1 in the development of PMS/PMDD.

A particularly concerning aspect of PMDs of any sort is their possible association with a higher risk for death from non-natural causes. In a recent Swedish study, which did not distinguish between PMDs in general and PMDD in particular, patients had an almost 60% greater risk for death from non-natural causes and nearly twice the risk for death by suicide compared with women without PMDs.

Those diagnosed with a PMD at an early age showed excess mortality, and the risk for suicide was elevated regardless of age. “These findings support the need for careful follow-up for young women with PMDs and the need for suicide prevention strategies,” wrote lead author Marion Opatowski, PhD, a medical epidemiologist at Karolinska Institutet in Stockholm, Sweden. “Women with severe PMDD should definitely be monitored for suicidal thoughts or behavior and they should have an emergency outreach plan in place,” Haque added.
 

Diagnosis

Although the somatic manifestations of PMDD resemble those of PMS, they are more severe and associated psychological symptoms are greater. “In my experience, PMDD symptoms can last the whole 2 weeks of the luteal phase, whereas PMS might occur a couple of days before menstruation,” said Ireland.

Symptoms include labile mood, nervousness, hopelessness, anger and aggressiveness, as well as tension and irritability. Those affected may have suicidal thoughts or even behaviors. In addition to a lethargic loss of interest in normal activities, patients with PMDD may feel paranoid, confused, exhausted, or out of control and experience insomnia or hypersomnia. They may have trouble concentrating or remembering. Some patients with PMDD may already be prone to attention-deficit/hyperactivity disorder and non–cycle-related depression, anxiety, and panic attacks.

Diagnosis is based on the presence of any five of the typical affective, somatic, or behavioral symptoms outlined above in the week before onset of menses.

“It’s important to do a careful diagnosis for PMDD and rule out other underlying conditions such as existing depressive or anxiety disorders,” said Haque. “Symptoms tend to be more intense in periods of high hormonal fluctuation such as in the postpartum and perimenopause periods. Women with PMDD should be monitored for postpartum depression.”

PMDD is considered both a gynecologic-genitourinary disorder and an affective condition.

In 2013, it was controversially included as a depressive disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Strongly advocated by some patients, psychiatrists, and pharmaceutical companies, its inclusion was criticized by psychologists and generalists, who feared it would lead to overdiagnosis and pathologization of normal female hormonal changes. Women’s advocates protested that this inclusion would stigmatize female biology and harm their advance in society and the workplace, while some doctors continued to dismiss PMDD as not a serious concern.
 

Treatments

In its latest clinical practice guideline on PMDs, the American College of Obstetricians and Gynecologists (ACOG), for which Ireland served as the lead author, recommends that most patients with PMDD get medical treatment and outlines the following therapies, based on varying degrees of evidence strength.

Antidepressants. These may benefit patients with strong affective symptoms. Selective serotonin reuptake inhibitors such as sertraline (Zoloft), citalopram (Celexa), escitalopram (Lexapro), or fluoxetine (Prozac) are first choices.

Antidepressants may interrupt aberrant signaling in the HPGA, the circuit linking brain and ovaries and regulating the reproductive cycle. Serotonin norepinephrine reuptake inhibitor venlafaxine (Effexor) may also improve symptoms, but other types of antidepressants have not proven effective.

“The response to these well-tolerated drugs is rapid and can happen in the first 2 days,” said Ireland. The drugs may be taken either just in the luteal period or over the month, especially by patients with chronic depression or anxiety.

Hormonal therapy. ACOG recommends the use of combined oral contraceptives (COCs), gonadotropin-releasing hormone (GnRH) agonists to induce anovulation (with combined add-back hormones), progestin-only methods, and noncontraceptive continuous estrogen formulations. It notes, however, that COCs have not been more effective than placebo in reducing depressive symptom scores.

If symptoms do not improve over two to three cycles, an alternate therapy should be considered. Haque recommends an assessment after three cycles and then yearly.

Some women in her practice take both antidepressant and hormone therapy. “Unfortunately, there are no new pharmaceutical treatments on the horizon, but we have good ones already and we would love for patients to utilize them more often,” Ireland said.

Nonsteroidal anti-inflammatory drugs. Limited evidence shows these may reduce physical symptoms such as abdominal cramps, headaches, and general body aches, as well as some mood-related symptoms, which may be an indirect effect of pain alleviation.

Surgery. For women with the most severe intractable symptoms, bilateral oophorectomy with or without hysterectomy may be a last-resort option when medical management has failed. A trial period of GnRH agonist therapy (with or without adjunctive estrogen add-back treatment) is advised before surgery to predict a patient’s response to surgical management.

Acupuncture. ACOG suggests that acupuncture may help manage physical and affective premenstrual symptoms.

Diet. The usual dietary advice for premenstrual symptoms — such as consuming less caffeine, sugar, or alcohol and eating smaller, more frequent meals — is unlikely to help women with PMDD.

Exercise. Although it has not been well studied for PMDD, aerobic exercises such as walking, swimming, and biking tend to improve mood and energy levels in general. Exercise may reduce symptoms through several pathways, including effects on beta-endorphin, cortisol, and ovarian hormone levels.

Supplements. Vitamin B6, calcium and magnesium supplements, and herbal remedies are not supported by consistent or compelling evidence of efficacy. ACOG conditionally recommends calcium supplementation of 100-200 mg/d in adults to help manage physical and affective symptoms.

A small study suggested that supplemental zinc may improve both physical and psychological symptoms.

Cognitive-behavioral therapy. This treatment aims to interrupt negative and irrational thought patterns and may include awareness and education, as well as relaxation techniques, problem-solving and coping skills, and stress management. It has been associated with small to moderate improvement in anxiety and depression, said Ireland.

Peer support. Patients should consider joining a support group. The International Association for Premenstrual Disorders can help patients connect and develop coping skills.

The bottom line is that people with strong symptomatic evidence of PMDD should have medical intervention — to the benefit of their health and quality of life. Screening for PMDD should be part of women’s wellness examinations, said Ireland. “The impact of PMDD should not be minimized or dismissed,” said Haque. “And patients need to know there are very effective treatments.”

Ireland and Haque had no competing interests with regard to their comments.
 

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

Premenstrual disorders (PMDs), including premenstrual dysphoric disorder (PMDD), adversely affect the lives of millions of women worldwide. Most girls and women — as many as 80%-90%— will experience some premenstrual discomfort such as irritability, depressed mood, food or alcohol cravings, bloating, body aches, breast pain, constipation, or fatigue.

Diagnosable menstrual disorders include, collectively, premenstrual syndrome (PMS); PMDD, formerly called late luteal phase dysphoric disorder; and premenstrual worsening of another medical condition.

The most debilitating of these is PMDD, which has an estimated prevalence of about 4%-8% in women of reproductive age, according to obstetrician/gynecologist Hoosna Haque, MD, assistant professor of medicine at Columbia University Irving Medical Center in New York City.

“It’s difficult to be sure because this condition is underreported,” said Luu D. Ireland, MD, MPH, assistant professor of obstetrics and gynecology at UMass Memorial Medical Center in Worcester, Massachusetts. “But more women are coming forward, and there’s more discussion and media coverage of this condition.”

Occurring in the same post-follicular timeframe as PMS, PMDD takes cyclical discomfort to a more intense level, with a trifecta of affective comorbidities, somatic manifestations, and behavioral changes, all of which can seriously impair daily functioning, including work, physical activities, and personal relationships. Romantic and marital relationships can be particularly impaired.

Although recent cost figures are lacking, PMDs exact a considerable economic toll with increased direct healthcare costs from doctor visits and pharmaceuticals. A 2010 study found that US women with PMS were more likely to accrue in excess of $500 in healthcare visit costs over 2 years, and the figure would likely be higher today. PMDs also increase work/school absenteeism and reduce productivity.
 

Etiology

Brain areas that regulate emotion and behavior contain receptors for estrogen, progesterone, and other sex hormones, which affect the functioning of neurotransmitter systems influencing mood and thinking. Although the precise pathophysiology remains unclear, PMDD is likely multifactorial and results in a heightened sensitivity to normal fluctuations in estrogen and progesterone during the luteal phase of the menstrual cycle and dysfunction of the serotonin and gamma-aminobutyric acid neurotransmitter systems.

Patients with PMDD have lower levels of cortisol and beta-endorphins during both the follicular and luteal phases, suggesting abnormalities in the hypothalamic-pituitary-gonadal axis (HPGA), which is consistent with dysregulation in mood disorders.
 

Risk Factors

These include family history, past traumatic events, smoking, chronic pain syndrome, and obesity. There may be a genetic component as recent studies have suggested the involvement of the gene that codes for the serotonergic 5HT1A receptor and allelic variants of ESR1 in the development of PMS/PMDD.

A particularly concerning aspect of PMDs of any sort is their possible association with a higher risk for death from non-natural causes. In a recent Swedish study, which did not distinguish between PMDs in general and PMDD in particular, patients had an almost 60% greater risk for death from non-natural causes and nearly twice the risk for death by suicide compared with women without PMDs.

Those diagnosed with a PMD at an early age showed excess mortality, and the risk for suicide was elevated regardless of age. “These findings support the need for careful follow-up for young women with PMDs and the need for suicide prevention strategies,” wrote lead author Marion Opatowski, PhD, a medical epidemiologist at Karolinska Institutet in Stockholm, Sweden. “Women with severe PMDD should definitely be monitored for suicidal thoughts or behavior and they should have an emergency outreach plan in place,” Haque added.
 

Diagnosis

Although the somatic manifestations of PMDD resemble those of PMS, they are more severe and associated psychological symptoms are greater. “In my experience, PMDD symptoms can last the whole 2 weeks of the luteal phase, whereas PMS might occur a couple of days before menstruation,” said Ireland.

Symptoms include labile mood, nervousness, hopelessness, anger and aggressiveness, as well as tension and irritability. Those affected may have suicidal thoughts or even behaviors. In addition to a lethargic loss of interest in normal activities, patients with PMDD may feel paranoid, confused, exhausted, or out of control and experience insomnia or hypersomnia. They may have trouble concentrating or remembering. Some patients with PMDD may already be prone to attention-deficit/hyperactivity disorder and non–cycle-related depression, anxiety, and panic attacks.

Diagnosis is based on the presence of any five of the typical affective, somatic, or behavioral symptoms outlined above in the week before onset of menses.

“It’s important to do a careful diagnosis for PMDD and rule out other underlying conditions such as existing depressive or anxiety disorders,” said Haque. “Symptoms tend to be more intense in periods of high hormonal fluctuation such as in the postpartum and perimenopause periods. Women with PMDD should be monitored for postpartum depression.”

PMDD is considered both a gynecologic-genitourinary disorder and an affective condition.

In 2013, it was controversially included as a depressive disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Strongly advocated by some patients, psychiatrists, and pharmaceutical companies, its inclusion was criticized by psychologists and generalists, who feared it would lead to overdiagnosis and pathologization of normal female hormonal changes. Women’s advocates protested that this inclusion would stigmatize female biology and harm their advance in society and the workplace, while some doctors continued to dismiss PMDD as not a serious concern.
 

Treatments

In its latest clinical practice guideline on PMDs, the American College of Obstetricians and Gynecologists (ACOG), for which Ireland served as the lead author, recommends that most patients with PMDD get medical treatment and outlines the following therapies, based on varying degrees of evidence strength.

Antidepressants. These may benefit patients with strong affective symptoms. Selective serotonin reuptake inhibitors such as sertraline (Zoloft), citalopram (Celexa), escitalopram (Lexapro), or fluoxetine (Prozac) are first choices.

Antidepressants may interrupt aberrant signaling in the HPGA, the circuit linking brain and ovaries and regulating the reproductive cycle. Serotonin norepinephrine reuptake inhibitor venlafaxine (Effexor) may also improve symptoms, but other types of antidepressants have not proven effective.

“The response to these well-tolerated drugs is rapid and can happen in the first 2 days,” said Ireland. The drugs may be taken either just in the luteal period or over the month, especially by patients with chronic depression or anxiety.

Hormonal therapy. ACOG recommends the use of combined oral contraceptives (COCs), gonadotropin-releasing hormone (GnRH) agonists to induce anovulation (with combined add-back hormones), progestin-only methods, and noncontraceptive continuous estrogen formulations. It notes, however, that COCs have not been more effective than placebo in reducing depressive symptom scores.

If symptoms do not improve over two to three cycles, an alternate therapy should be considered. Haque recommends an assessment after three cycles and then yearly.

Some women in her practice take both antidepressant and hormone therapy. “Unfortunately, there are no new pharmaceutical treatments on the horizon, but we have good ones already and we would love for patients to utilize them more often,” Ireland said.

Nonsteroidal anti-inflammatory drugs. Limited evidence shows these may reduce physical symptoms such as abdominal cramps, headaches, and general body aches, as well as some mood-related symptoms, which may be an indirect effect of pain alleviation.

Surgery. For women with the most severe intractable symptoms, bilateral oophorectomy with or without hysterectomy may be a last-resort option when medical management has failed. A trial period of GnRH agonist therapy (with or without adjunctive estrogen add-back treatment) is advised before surgery to predict a patient’s response to surgical management.

Acupuncture. ACOG suggests that acupuncture may help manage physical and affective premenstrual symptoms.

Diet. The usual dietary advice for premenstrual symptoms — such as consuming less caffeine, sugar, or alcohol and eating smaller, more frequent meals — is unlikely to help women with PMDD.

Exercise. Although it has not been well studied for PMDD, aerobic exercises such as walking, swimming, and biking tend to improve mood and energy levels in general. Exercise may reduce symptoms through several pathways, including effects on beta-endorphin, cortisol, and ovarian hormone levels.

Supplements. Vitamin B6, calcium and magnesium supplements, and herbal remedies are not supported by consistent or compelling evidence of efficacy. ACOG conditionally recommends calcium supplementation of 100-200 mg/d in adults to help manage physical and affective symptoms.

A small study suggested that supplemental zinc may improve both physical and psychological symptoms.

Cognitive-behavioral therapy. This treatment aims to interrupt negative and irrational thought patterns and may include awareness and education, as well as relaxation techniques, problem-solving and coping skills, and stress management. It has been associated with small to moderate improvement in anxiety and depression, said Ireland.

Peer support. Patients should consider joining a support group. The International Association for Premenstrual Disorders can help patients connect and develop coping skills.

The bottom line is that people with strong symptomatic evidence of PMDD should have medical intervention — to the benefit of their health and quality of life. Screening for PMDD should be part of women’s wellness examinations, said Ireland. “The impact of PMDD should not be minimized or dismissed,” said Haque. “And patients need to know there are very effective treatments.”

Ireland and Haque had no competing interests with regard to their comments.
 

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

Premenstrual disorders (PMDs), including premenstrual dysphoric disorder (PMDD), adversely affect the lives of millions of women worldwide. Most girls and women — as many as 80%-90%— will experience some premenstrual discomfort such as irritability, depressed mood, food or alcohol cravings, bloating, body aches, breast pain, constipation, or fatigue.

Diagnosable menstrual disorders include, collectively, premenstrual syndrome (PMS); PMDD, formerly called late luteal phase dysphoric disorder; and premenstrual worsening of another medical condition.

The most debilitating of these is PMDD, which has an estimated prevalence of about 4%-8% in women of reproductive age, according to obstetrician/gynecologist Hoosna Haque, MD, assistant professor of medicine at Columbia University Irving Medical Center in New York City.

“It’s difficult to be sure because this condition is underreported,” said Luu D. Ireland, MD, MPH, assistant professor of obstetrics and gynecology at UMass Memorial Medical Center in Worcester, Massachusetts. “But more women are coming forward, and there’s more discussion and media coverage of this condition.”

Occurring in the same post-follicular timeframe as PMS, PMDD takes cyclical discomfort to a more intense level, with a trifecta of affective comorbidities, somatic manifestations, and behavioral changes, all of which can seriously impair daily functioning, including work, physical activities, and personal relationships. Romantic and marital relationships can be particularly impaired.

Although recent cost figures are lacking, PMDs exact a considerable economic toll with increased direct healthcare costs from doctor visits and pharmaceuticals. A 2010 study found that US women with PMS were more likely to accrue in excess of $500 in healthcare visit costs over 2 years, and the figure would likely be higher today. PMDs also increase work/school absenteeism and reduce productivity.
 

Etiology

Brain areas that regulate emotion and behavior contain receptors for estrogen, progesterone, and other sex hormones, which affect the functioning of neurotransmitter systems influencing mood and thinking. Although the precise pathophysiology remains unclear, PMDD is likely multifactorial and results in a heightened sensitivity to normal fluctuations in estrogen and progesterone during the luteal phase of the menstrual cycle and dysfunction of the serotonin and gamma-aminobutyric acid neurotransmitter systems.

Patients with PMDD have lower levels of cortisol and beta-endorphins during both the follicular and luteal phases, suggesting abnormalities in the hypothalamic-pituitary-gonadal axis (HPGA), which is consistent with dysregulation in mood disorders.
 

Risk Factors

These include family history, past traumatic events, smoking, chronic pain syndrome, and obesity. There may be a genetic component as recent studies have suggested the involvement of the gene that codes for the serotonergic 5HT1A receptor and allelic variants of ESR1 in the development of PMS/PMDD.

A particularly concerning aspect of PMDs of any sort is their possible association with a higher risk for death from non-natural causes. In a recent Swedish study, which did not distinguish between PMDs in general and PMDD in particular, patients had an almost 60% greater risk for death from non-natural causes and nearly twice the risk for death by suicide compared with women without PMDs.

Those diagnosed with a PMD at an early age showed excess mortality, and the risk for suicide was elevated regardless of age. “These findings support the need for careful follow-up for young women with PMDs and the need for suicide prevention strategies,” wrote lead author Marion Opatowski, PhD, a medical epidemiologist at Karolinska Institutet in Stockholm, Sweden. “Women with severe PMDD should definitely be monitored for suicidal thoughts or behavior and they should have an emergency outreach plan in place,” Haque added.
 

Diagnosis

Although the somatic manifestations of PMDD resemble those of PMS, they are more severe and associated psychological symptoms are greater. “In my experience, PMDD symptoms can last the whole 2 weeks of the luteal phase, whereas PMS might occur a couple of days before menstruation,” said Ireland.

Symptoms include labile mood, nervousness, hopelessness, anger and aggressiveness, as well as tension and irritability. Those affected may have suicidal thoughts or even behaviors. In addition to a lethargic loss of interest in normal activities, patients with PMDD may feel paranoid, confused, exhausted, or out of control and experience insomnia or hypersomnia. They may have trouble concentrating or remembering. Some patients with PMDD may already be prone to attention-deficit/hyperactivity disorder and non–cycle-related depression, anxiety, and panic attacks.

Diagnosis is based on the presence of any five of the typical affective, somatic, or behavioral symptoms outlined above in the week before onset of menses.

“It’s important to do a careful diagnosis for PMDD and rule out other underlying conditions such as existing depressive or anxiety disorders,” said Haque. “Symptoms tend to be more intense in periods of high hormonal fluctuation such as in the postpartum and perimenopause periods. Women with PMDD should be monitored for postpartum depression.”

PMDD is considered both a gynecologic-genitourinary disorder and an affective condition.

In 2013, it was controversially included as a depressive disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Strongly advocated by some patients, psychiatrists, and pharmaceutical companies, its inclusion was criticized by psychologists and generalists, who feared it would lead to overdiagnosis and pathologization of normal female hormonal changes. Women’s advocates protested that this inclusion would stigmatize female biology and harm their advance in society and the workplace, while some doctors continued to dismiss PMDD as not a serious concern.
 

Treatments

In its latest clinical practice guideline on PMDs, the American College of Obstetricians and Gynecologists (ACOG), for which Ireland served as the lead author, recommends that most patients with PMDD get medical treatment and outlines the following therapies, based on varying degrees of evidence strength.

Antidepressants. These may benefit patients with strong affective symptoms. Selective serotonin reuptake inhibitors such as sertraline (Zoloft), citalopram (Celexa), escitalopram (Lexapro), or fluoxetine (Prozac) are first choices.

Antidepressants may interrupt aberrant signaling in the HPGA, the circuit linking brain and ovaries and regulating the reproductive cycle. Serotonin norepinephrine reuptake inhibitor venlafaxine (Effexor) may also improve symptoms, but other types of antidepressants have not proven effective.

“The response to these well-tolerated drugs is rapid and can happen in the first 2 days,” said Ireland. The drugs may be taken either just in the luteal period or over the month, especially by patients with chronic depression or anxiety.

Hormonal therapy. ACOG recommends the use of combined oral contraceptives (COCs), gonadotropin-releasing hormone (GnRH) agonists to induce anovulation (with combined add-back hormones), progestin-only methods, and noncontraceptive continuous estrogen formulations. It notes, however, that COCs have not been more effective than placebo in reducing depressive symptom scores.

If symptoms do not improve over two to three cycles, an alternate therapy should be considered. Haque recommends an assessment after three cycles and then yearly.

Some women in her practice take both antidepressant and hormone therapy. “Unfortunately, there are no new pharmaceutical treatments on the horizon, but we have good ones already and we would love for patients to utilize them more often,” Ireland said.

Nonsteroidal anti-inflammatory drugs. Limited evidence shows these may reduce physical symptoms such as abdominal cramps, headaches, and general body aches, as well as some mood-related symptoms, which may be an indirect effect of pain alleviation.

Surgery. For women with the most severe intractable symptoms, bilateral oophorectomy with or without hysterectomy may be a last-resort option when medical management has failed. A trial period of GnRH agonist therapy (with or without adjunctive estrogen add-back treatment) is advised before surgery to predict a patient’s response to surgical management.

Acupuncture. ACOG suggests that acupuncture may help manage physical and affective premenstrual symptoms.

Diet. The usual dietary advice for premenstrual symptoms — such as consuming less caffeine, sugar, or alcohol and eating smaller, more frequent meals — is unlikely to help women with PMDD.

Exercise. Although it has not been well studied for PMDD, aerobic exercises such as walking, swimming, and biking tend to improve mood and energy levels in general. Exercise may reduce symptoms through several pathways, including effects on beta-endorphin, cortisol, and ovarian hormone levels.

Supplements. Vitamin B6, calcium and magnesium supplements, and herbal remedies are not supported by consistent or compelling evidence of efficacy. ACOG conditionally recommends calcium supplementation of 100-200 mg/d in adults to help manage physical and affective symptoms.

A small study suggested that supplemental zinc may improve both physical and psychological symptoms.

Cognitive-behavioral therapy. This treatment aims to interrupt negative and irrational thought patterns and may include awareness and education, as well as relaxation techniques, problem-solving and coping skills, and stress management. It has been associated with small to moderate improvement in anxiety and depression, said Ireland.

Peer support. Patients should consider joining a support group. The International Association for Premenstrual Disorders can help patients connect and develop coping skills.

The bottom line is that people with strong symptomatic evidence of PMDD should have medical intervention — to the benefit of their health and quality of life. Screening for PMDD should be part of women’s wellness examinations, said Ireland. “The impact of PMDD should not be minimized or dismissed,” said Haque. “And patients need to know there are very effective treatments.”

Ireland and Haque had no competing interests with regard to their comments.
 

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

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) given to adolescents with obesity was associated with a one-third decreased risk for suicidal ideation and suicide attempts compared with lifestyle intervention alone, a large international retrospective study found.

A study published in JAMA Pediatrics suggested that GLP-1 RAs such as semaglutide, liraglutide, and tirzepatide, which are widely used to treat type 2 diabetes (T2D), have a favorable psychiatric safety profile and open up potential avenues for prospective studies of psychiatric outcomes in adolescents with obesity.

Investigators Liya Kerem, MD, MSc, and Joshua Stokar, MD, of Hadassah University Medical Center in Jerusalem, Israel, reported that the reduced risk in GLP-1 RA recipients was maintained up to 3 years follow-up compared with propensity score–matched controls treated with behavioral interventions alone.

“These findings support the notion that childhood obesity does not result from lack of willpower and shed light on underlying mechanisms that can be targeted by pharmacotherapy.” Kerem and Stokar wrote.

Other research has suggested these agents have neurobiologic effects unrelated to weight loss that positively affect mood and mental health.
 

Study Details

The analysis included data from December 2019 to June 2024, drawn from 120 international healthcare organizations, mainly in the United States. A total of 4052 racially and ethnically diverse adolescents with obesity (aged 12-18 years [mean age, about 15.5 years]) being treated with an anti-obesity intervention were identified for the GLP-1 RA cohort and 50,112 for the control cohort. The arms were balanced for baseline demographic characteristics, psychiatric medications and comorbidities, and diagnoses associated with socioeconomic status and healthcare access.

Propensity score matching (PSM) resulted in 3456 participants in each of two balanced cohorts.

Before PSM, intervention patients were older (mean age, 15.5 vs 14.7 years), were more likely to be female (59% vs 49%), and had a higher body mass index (41.9 vs 33.8). They also had a higher prevalence of diabetes (40% vs 4%) and treatment with antidiabetic medications.

GLP-1 RA recipients also had a history of psychiatric diagnoses (17% vs 9% for mood disorders) and psychiatric medications (18% vs 7% for antidepressants). Previous use of non–GLP-1 RA anti-obesity medications was uncommon in the cohort overall, although more common in the GLP-1 RA cohort (2.5% vs 0.2% for phentermine).

Prescription of GLP-1 RA was associated with a 33% reduced risk for suicidal ideation or attempts over 12 months of follow-up: 1.45% vs 2.26% (hazard ratio [HR], 0.67; 95% CI, 0.47-0.95; P = .02). It was also associated with a higher rate of gastrointestinal symptoms: 6.9% vs 5.4% (HR, 1.41; 95% CI, 1.12-1.78; P = .003). There was no difference in rates of upper respiratory tract infections (URTIs), although some research suggests these agents reduce URTIs.
 

Mechanisms

The etiology of childhood obesity is complex and multifactorial, the authors wrote, and genetic predisposition to adiposity, an obesogenic environment, and a sedentary lifestyle synergistically contribute to its development. Variants in genes active in the hypothalamic appetite-regulation neurocircuitry appear to be associated with the development of childhood and adolescent obesity.

The authors noted that adolescence carries an increased risk for psychiatric disorders and suicidal ideation. “The amelioration of obesity could indirectly improve these psychiatric comorbidities,” they wrote. In addition, preclinical studies suggested that GLP-1 RA may improve depression-related neuropathology, including neuroinflammation and neurotransmitter imbalance, and may promote neurogenesis.

A recent meta-analysis found that adults with T2D treated with GLP-1 RA showed significant reduction in depression scale scores compared with those treated with non-GLP-1 RA antidiabetic medications.

Commenting on the study but not involved in it, psychiatrist Robert H. Dicker, MD, associate director of child and adolescent psychiatry at Northwell Zucker Hillside Hospital in Glen Oaks, New York, cautioned that these are preliminary data limited by a retrospective review, not a prospective double-blind, placebo-controlled study.

“The mechanism is unknown — is it a direct effect on weight loss with an improvement of quality of life, more positive feedback by the community, enhanced ability to exercise, and a decrease in depressive symptoms?” he asked.

Dicker suggested an alternative hypothesis: Does the GLP-1 RA have a direct effect on neurotransmitters and inflammation and, thus, an impact on mood, emotional regulation, impulse control, and suicide?

“To further answer these questions, prospective studies must be conducted. It is far too early to conclude that these medications are effective in treating mood disorders in our youth,” Dicker said. “But it is promising that these treatments do not appear to increase suicidal ideas and behavior.”

Adding another outsider’s perspective on the study, Suzanne E. Cuda, MD, FOMA, FAAP, a pediatrician who treats childhood obesity in San Antonio, said that while there was no risk for increased psychiatric disease and a suggestion that GLP-1 RAs may reduce suicidal ideation or attempts, “I don’t think this translates to a treatment for depression in adolescents. Nor does this study indicate there could be a decrease in depression due specifically to the use of GLP1Rs. If the results in this study are replicated, however, it would be reassuring to know that adolescents would not be at risk for an increase in suicidal ideation or attempts.”

This study had no external funding. Kerem reported receiving personal fees from Novo Nordisk for lectures on childhood obesity outside of the submitted work. No other disclosures were reported. Dicker and Cuda had no competing interests relevant to their comments.

A version of this article appeared on Medscape.com.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) given to adolescents with obesity was associated with a one-third decreased risk for suicidal ideation and suicide attempts compared with lifestyle intervention alone, a large international retrospective study found.

A study published in JAMA Pediatrics suggested that GLP-1 RAs such as semaglutide, liraglutide, and tirzepatide, which are widely used to treat type 2 diabetes (T2D), have a favorable psychiatric safety profile and open up potential avenues for prospective studies of psychiatric outcomes in adolescents with obesity.

Investigators Liya Kerem, MD, MSc, and Joshua Stokar, MD, of Hadassah University Medical Center in Jerusalem, Israel, reported that the reduced risk in GLP-1 RA recipients was maintained up to 3 years follow-up compared with propensity score–matched controls treated with behavioral interventions alone.

“These findings support the notion that childhood obesity does not result from lack of willpower and shed light on underlying mechanisms that can be targeted by pharmacotherapy.” Kerem and Stokar wrote.

Other research has suggested these agents have neurobiologic effects unrelated to weight loss that positively affect mood and mental health.
 

Study Details

The analysis included data from December 2019 to June 2024, drawn from 120 international healthcare organizations, mainly in the United States. A total of 4052 racially and ethnically diverse adolescents with obesity (aged 12-18 years [mean age, about 15.5 years]) being treated with an anti-obesity intervention were identified for the GLP-1 RA cohort and 50,112 for the control cohort. The arms were balanced for baseline demographic characteristics, psychiatric medications and comorbidities, and diagnoses associated with socioeconomic status and healthcare access.

Propensity score matching (PSM) resulted in 3456 participants in each of two balanced cohorts.

Before PSM, intervention patients were older (mean age, 15.5 vs 14.7 years), were more likely to be female (59% vs 49%), and had a higher body mass index (41.9 vs 33.8). They also had a higher prevalence of diabetes (40% vs 4%) and treatment with antidiabetic medications.

GLP-1 RA recipients also had a history of psychiatric diagnoses (17% vs 9% for mood disorders) and psychiatric medications (18% vs 7% for antidepressants). Previous use of non–GLP-1 RA anti-obesity medications was uncommon in the cohort overall, although more common in the GLP-1 RA cohort (2.5% vs 0.2% for phentermine).

Prescription of GLP-1 RA was associated with a 33% reduced risk for suicidal ideation or attempts over 12 months of follow-up: 1.45% vs 2.26% (hazard ratio [HR], 0.67; 95% CI, 0.47-0.95; P = .02). It was also associated with a higher rate of gastrointestinal symptoms: 6.9% vs 5.4% (HR, 1.41; 95% CI, 1.12-1.78; P = .003). There was no difference in rates of upper respiratory tract infections (URTIs), although some research suggests these agents reduce URTIs.
 

Mechanisms

The etiology of childhood obesity is complex and multifactorial, the authors wrote, and genetic predisposition to adiposity, an obesogenic environment, and a sedentary lifestyle synergistically contribute to its development. Variants in genes active in the hypothalamic appetite-regulation neurocircuitry appear to be associated with the development of childhood and adolescent obesity.

The authors noted that adolescence carries an increased risk for psychiatric disorders and suicidal ideation. “The amelioration of obesity could indirectly improve these psychiatric comorbidities,” they wrote. In addition, preclinical studies suggested that GLP-1 RA may improve depression-related neuropathology, including neuroinflammation and neurotransmitter imbalance, and may promote neurogenesis.

A recent meta-analysis found that adults with T2D treated with GLP-1 RA showed significant reduction in depression scale scores compared with those treated with non-GLP-1 RA antidiabetic medications.

Commenting on the study but not involved in it, psychiatrist Robert H. Dicker, MD, associate director of child and adolescent psychiatry at Northwell Zucker Hillside Hospital in Glen Oaks, New York, cautioned that these are preliminary data limited by a retrospective review, not a prospective double-blind, placebo-controlled study.

“The mechanism is unknown — is it a direct effect on weight loss with an improvement of quality of life, more positive feedback by the community, enhanced ability to exercise, and a decrease in depressive symptoms?” he asked.

Dicker suggested an alternative hypothesis: Does the GLP-1 RA have a direct effect on neurotransmitters and inflammation and, thus, an impact on mood, emotional regulation, impulse control, and suicide?

“To further answer these questions, prospective studies must be conducted. It is far too early to conclude that these medications are effective in treating mood disorders in our youth,” Dicker said. “But it is promising that these treatments do not appear to increase suicidal ideas and behavior.”

Adding another outsider’s perspective on the study, Suzanne E. Cuda, MD, FOMA, FAAP, a pediatrician who treats childhood obesity in San Antonio, said that while there was no risk for increased psychiatric disease and a suggestion that GLP-1 RAs may reduce suicidal ideation or attempts, “I don’t think this translates to a treatment for depression in adolescents. Nor does this study indicate there could be a decrease in depression due specifically to the use of GLP1Rs. If the results in this study are replicated, however, it would be reassuring to know that adolescents would not be at risk for an increase in suicidal ideation or attempts.”

This study had no external funding. Kerem reported receiving personal fees from Novo Nordisk for lectures on childhood obesity outside of the submitted work. No other disclosures were reported. Dicker and Cuda had no competing interests relevant to their comments.

A version of this article appeared on Medscape.com.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) given to adolescents with obesity was associated with a one-third decreased risk for suicidal ideation and suicide attempts compared with lifestyle intervention alone, a large international retrospective study found.

A study published in JAMA Pediatrics suggested that GLP-1 RAs such as semaglutide, liraglutide, and tirzepatide, which are widely used to treat type 2 diabetes (T2D), have a favorable psychiatric safety profile and open up potential avenues for prospective studies of psychiatric outcomes in adolescents with obesity.

Investigators Liya Kerem, MD, MSc, and Joshua Stokar, MD, of Hadassah University Medical Center in Jerusalem, Israel, reported that the reduced risk in GLP-1 RA recipients was maintained up to 3 years follow-up compared with propensity score–matched controls treated with behavioral interventions alone.

“These findings support the notion that childhood obesity does not result from lack of willpower and shed light on underlying mechanisms that can be targeted by pharmacotherapy.” Kerem and Stokar wrote.

Other research has suggested these agents have neurobiologic effects unrelated to weight loss that positively affect mood and mental health.
 

Study Details

The analysis included data from December 2019 to June 2024, drawn from 120 international healthcare organizations, mainly in the United States. A total of 4052 racially and ethnically diverse adolescents with obesity (aged 12-18 years [mean age, about 15.5 years]) being treated with an anti-obesity intervention were identified for the GLP-1 RA cohort and 50,112 for the control cohort. The arms were balanced for baseline demographic characteristics, psychiatric medications and comorbidities, and diagnoses associated with socioeconomic status and healthcare access.

Propensity score matching (PSM) resulted in 3456 participants in each of two balanced cohorts.

Before PSM, intervention patients were older (mean age, 15.5 vs 14.7 years), were more likely to be female (59% vs 49%), and had a higher body mass index (41.9 vs 33.8). They also had a higher prevalence of diabetes (40% vs 4%) and treatment with antidiabetic medications.

GLP-1 RA recipients also had a history of psychiatric diagnoses (17% vs 9% for mood disorders) and psychiatric medications (18% vs 7% for antidepressants). Previous use of non–GLP-1 RA anti-obesity medications was uncommon in the cohort overall, although more common in the GLP-1 RA cohort (2.5% vs 0.2% for phentermine).

Prescription of GLP-1 RA was associated with a 33% reduced risk for suicidal ideation or attempts over 12 months of follow-up: 1.45% vs 2.26% (hazard ratio [HR], 0.67; 95% CI, 0.47-0.95; P = .02). It was also associated with a higher rate of gastrointestinal symptoms: 6.9% vs 5.4% (HR, 1.41; 95% CI, 1.12-1.78; P = .003). There was no difference in rates of upper respiratory tract infections (URTIs), although some research suggests these agents reduce URTIs.
 

Mechanisms

The etiology of childhood obesity is complex and multifactorial, the authors wrote, and genetic predisposition to adiposity, an obesogenic environment, and a sedentary lifestyle synergistically contribute to its development. Variants in genes active in the hypothalamic appetite-regulation neurocircuitry appear to be associated with the development of childhood and adolescent obesity.

The authors noted that adolescence carries an increased risk for psychiatric disorders and suicidal ideation. “The amelioration of obesity could indirectly improve these psychiatric comorbidities,” they wrote. In addition, preclinical studies suggested that GLP-1 RA may improve depression-related neuropathology, including neuroinflammation and neurotransmitter imbalance, and may promote neurogenesis.

A recent meta-analysis found that adults with T2D treated with GLP-1 RA showed significant reduction in depression scale scores compared with those treated with non-GLP-1 RA antidiabetic medications.

Commenting on the study but not involved in it, psychiatrist Robert H. Dicker, MD, associate director of child and adolescent psychiatry at Northwell Zucker Hillside Hospital in Glen Oaks, New York, cautioned that these are preliminary data limited by a retrospective review, not a prospective double-blind, placebo-controlled study.

“The mechanism is unknown — is it a direct effect on weight loss with an improvement of quality of life, more positive feedback by the community, enhanced ability to exercise, and a decrease in depressive symptoms?” he asked.

Dicker suggested an alternative hypothesis: Does the GLP-1 RA have a direct effect on neurotransmitters and inflammation and, thus, an impact on mood, emotional regulation, impulse control, and suicide?

“To further answer these questions, prospective studies must be conducted. It is far too early to conclude that these medications are effective in treating mood disorders in our youth,” Dicker said. “But it is promising that these treatments do not appear to increase suicidal ideas and behavior.”

Adding another outsider’s perspective on the study, Suzanne E. Cuda, MD, FOMA, FAAP, a pediatrician who treats childhood obesity in San Antonio, said that while there was no risk for increased psychiatric disease and a suggestion that GLP-1 RAs may reduce suicidal ideation or attempts, “I don’t think this translates to a treatment for depression in adolescents. Nor does this study indicate there could be a decrease in depression due specifically to the use of GLP1Rs. If the results in this study are replicated, however, it would be reassuring to know that adolescents would not be at risk for an increase in suicidal ideation or attempts.”

This study had no external funding. Kerem reported receiving personal fees from Novo Nordisk for lectures on childhood obesity outside of the submitted work. No other disclosures were reported. Dicker and Cuda had no competing interests relevant to their comments.

A version of this article appeared on Medscape.com.

More evidence suggests there is little risk in administering the live rotavirus vaccine to the babies of mothers on biologics during pregnancy for inflammatory bowel disease (IBD).

No adverse events or impairment of the immune system emerged in babies at 7 days, 1 month, and 9 months post vaccination, in findings from a small Canadian study published in Clinical Gastroenterology and Hepatology.

University of Calgary

The study found normal extended immune function testing in infants despite third-trimester maternal biologic therapy and regardless of circulating drug levels. The data provide reassurance about live rotavirus vaccination in this population and may also offer insights into the safety of other live vaccines in biologic-exposed individuals, wrote investigators led by gastroenterologist Cynthia H. Seow, MD, a professor in the Cumming School of Medicine at the University of Calgary in Alberta, Canada.

“Despite the well-established safety and effectiveness of non–live vaccination in individuals with IBD, including those on immunomodulators and biologic therapy, vaccine uptake in pregnant women with IBD and their infants remains suboptimal,” Seow said in an interview. This largely arises from maternal and physician concerns regarding transplacental transfer of IBD therapies and their impact on the safety of vaccination.

“These concerns were heightened after reports emerged of five fatal outcomes following the administration of the live Bacille Calmette-Guérin [BCG] vaccine in biologic-exposed infants. However, it had already been reported that inadvertent administration of the live oral rotavirus vaccine, a very different vaccine in terms of target and mechanism of action, in biologic-exposed individuals had not been associated with significant adverse effects,” she said.

They undertook their analysis with the hypothesis that vaccination would carry low risk, although the live oral vaccine is not currently recommended in biologic-exposed infants. “Yet rotavirus is a leading cause of severe, dehydrating diarrhea in children under the age of 5 years globally, and vaccination has led to significant reductions in hospitalizations and mortality,” Seow added.

Provision of the vaccine to anti–tumor necrosis factor (TNF)–exposed infants has been incorporated into the Canadian Public Health and Immunization guidelines, as the majority of the biologic-exposed infants were exposed to anti-TNF agents. “And with collection of further data, we expect that this will be extended to other biologic agent exposure. These data are important to pregnant women with IBD as they help to normalize their care. Pregnancy is difficult enough without having to remember exceptions to care,” Seow said.

“Before some of the studies came out, broad guidelines recommended that live vaccines should not be used in biologic-exposed infants, but this had been thought to be overly zealous and too conservative, and the risk was thought to be low,” said Elizabeth Spencer, MD, an assistant professor of pediatrics in the Division of Pediatric Gastroenterology at the Icahn School of Medicine at Mount Sinai in New York City, in an interview. Spencer was not involved in the Canadian study.

“At our center, we had some moms on biologics during pregnancy who forgot and had their babies vaccinated for rotavirus, and the babies were all fine,” she said.

The safety of this vaccine has been confirmed by several small studies and recently the PIANO Helmsley Global Consensus on Pregnancy and Inflammatory Bowel Disease, which was presented at Digestive Disease Week 2024. The consensus encompasses preconception counseling and the safety of IBD medications during pregnancy and lactation.

Icahn School of Medicine at Mount Sinai

“Another concern, however, was that giving a live GI bug like rotavirus to babies might overstimulate their immune systems and provoke IBD,” Spencer added. “While a number of population-based studies in the US and Europe showed that was not the case, at least in the general population, there was a suggestion that, down the road, vaccination might be mildly protective against IBD in some cases.”

She added the caveat that these studies were not done in mothers and their babies with IBD, who might be inherently at greater risk for IBD. “So, a question for future research would be, ‘Is immune stimulation of the gut in IBD moms and their babies a good or a bad thing for their gut?’ ”

Spencer conceded that “the data present a bit of a blurry picture, but I think it’s always better just to vaccinate according to the regular schedule. The current data say there is no added risk, but it would be nice to look specifically at risk in moms with IBD and their children.”
 

The Study

The prospective cohort study is a substudy of a larger 2023 one that included biologic use in a range of maternal illnesses, not just IBD.

For the current study, Seow and colleagues identified 57 infants born to 52 mothers with IBD attending a pregnancy clinic at the University of Calgary in the period 2019-2023. Almost 81% of the mothers had Crohn’s disease, and the median duration of IBD was 10 years. The median gestational age at delivery was 39 weeks, and almost 60% of deliveries were vaginal. The infants had been exposed in utero to infliximab (n = 21), adalimumab (n = 19), vedolizumab (n = 10), and ustekinumab (n = 7) in the third trimester.

The 57 biologic-exposed infants underwent standardized clinical assessments, drug concentration, and immune function testing. The live oral rotavirus vaccine series was provided to 50 infants, with the first dose at a median of 13 weeks of age. Immunologic assessments validated for age were normal in all infants despite median infliximab concentrations of 6.1 μg/mL (range, 0.4-28.8 μg/mL), adalimumab concentrations of 1.7 μg/mL (range, 0.7-7.9 μg/mL), ustekinumab concentrations of 0.6 μg/mL (range, 0-1.1), and undetectable for vedolizumab at 10.7 weeks of age.

As anticipated, infant immune function was normal regardless of circulating drug levels.

The overall message, said Seow, is “healthy mum equals healthy baby. Be more concerned regarding active inflammation than active medications. In almost all circumstances, treat to target in pregnancy as you would in the nonpregnant state.” She added, however, that further studies are needed to determine the safety and optimal timing of other live vaccines, such as the BCG, in the presence of biologic therapy.

This study was funded by the Alberta Children’s Hospital Research Institute. Seow reported advisory/speaker’s fees for Janssen, AbbVie, Takeda, Pfizer, Fresenius Kabi, Bristol-Myers Squibb, Pharmascience, and Lilly, as well as funding from Alberta Children’s Hospital Research Institute, Crohn’s and Colitis Canada, the Canadian Institutes of Health Research, and Calgary Health Trust, and data safety monitoring from New South Wales Government Health, Australia. Multiple coauthors disclosed similar consulting or speaker relationships with private industry. Spencer had no competing interests with regard to her comments.

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

More evidence suggests there is little risk in administering the live rotavirus vaccine to the babies of mothers on biologics during pregnancy for inflammatory bowel disease (IBD).

No adverse events or impairment of the immune system emerged in babies at 7 days, 1 month, and 9 months post vaccination, in findings from a small Canadian study published in Clinical Gastroenterology and Hepatology.

University of Calgary

The study found normal extended immune function testing in infants despite third-trimester maternal biologic therapy and regardless of circulating drug levels. The data provide reassurance about live rotavirus vaccination in this population and may also offer insights into the safety of other live vaccines in biologic-exposed individuals, wrote investigators led by gastroenterologist Cynthia H. Seow, MD, a professor in the Cumming School of Medicine at the University of Calgary in Alberta, Canada.

“Despite the well-established safety and effectiveness of non–live vaccination in individuals with IBD, including those on immunomodulators and biologic therapy, vaccine uptake in pregnant women with IBD and their infants remains suboptimal,” Seow said in an interview. This largely arises from maternal and physician concerns regarding transplacental transfer of IBD therapies and their impact on the safety of vaccination.

“These concerns were heightened after reports emerged of five fatal outcomes following the administration of the live Bacille Calmette-Guérin [BCG] vaccine in biologic-exposed infants. However, it had already been reported that inadvertent administration of the live oral rotavirus vaccine, a very different vaccine in terms of target and mechanism of action, in biologic-exposed individuals had not been associated with significant adverse effects,” she said.

They undertook their analysis with the hypothesis that vaccination would carry low risk, although the live oral vaccine is not currently recommended in biologic-exposed infants. “Yet rotavirus is a leading cause of severe, dehydrating diarrhea in children under the age of 5 years globally, and vaccination has led to significant reductions in hospitalizations and mortality,” Seow added.

Provision of the vaccine to anti–tumor necrosis factor (TNF)–exposed infants has been incorporated into the Canadian Public Health and Immunization guidelines, as the majority of the biologic-exposed infants were exposed to anti-TNF agents. “And with collection of further data, we expect that this will be extended to other biologic agent exposure. These data are important to pregnant women with IBD as they help to normalize their care. Pregnancy is difficult enough without having to remember exceptions to care,” Seow said.

“Before some of the studies came out, broad guidelines recommended that live vaccines should not be used in biologic-exposed infants, but this had been thought to be overly zealous and too conservative, and the risk was thought to be low,” said Elizabeth Spencer, MD, an assistant professor of pediatrics in the Division of Pediatric Gastroenterology at the Icahn School of Medicine at Mount Sinai in New York City, in an interview. Spencer was not involved in the Canadian study.

“At our center, we had some moms on biologics during pregnancy who forgot and had their babies vaccinated for rotavirus, and the babies were all fine,” she said.

The safety of this vaccine has been confirmed by several small studies and recently the PIANO Helmsley Global Consensus on Pregnancy and Inflammatory Bowel Disease, which was presented at Digestive Disease Week 2024. The consensus encompasses preconception counseling and the safety of IBD medications during pregnancy and lactation.

Icahn School of Medicine at Mount Sinai

“Another concern, however, was that giving a live GI bug like rotavirus to babies might overstimulate their immune systems and provoke IBD,” Spencer added. “While a number of population-based studies in the US and Europe showed that was not the case, at least in the general population, there was a suggestion that, down the road, vaccination might be mildly protective against IBD in some cases.”

She added the caveat that these studies were not done in mothers and their babies with IBD, who might be inherently at greater risk for IBD. “So, a question for future research would be, ‘Is immune stimulation of the gut in IBD moms and their babies a good or a bad thing for their gut?’ ”

Spencer conceded that “the data present a bit of a blurry picture, but I think it’s always better just to vaccinate according to the regular schedule. The current data say there is no added risk, but it would be nice to look specifically at risk in moms with IBD and their children.”
 

The Study

The prospective cohort study is a substudy of a larger 2023 one that included biologic use in a range of maternal illnesses, not just IBD.

For the current study, Seow and colleagues identified 57 infants born to 52 mothers with IBD attending a pregnancy clinic at the University of Calgary in the period 2019-2023. Almost 81% of the mothers had Crohn’s disease, and the median duration of IBD was 10 years. The median gestational age at delivery was 39 weeks, and almost 60% of deliveries were vaginal. The infants had been exposed in utero to infliximab (n = 21), adalimumab (n = 19), vedolizumab (n = 10), and ustekinumab (n = 7) in the third trimester.

The 57 biologic-exposed infants underwent standardized clinical assessments, drug concentration, and immune function testing. The live oral rotavirus vaccine series was provided to 50 infants, with the first dose at a median of 13 weeks of age. Immunologic assessments validated for age were normal in all infants despite median infliximab concentrations of 6.1 μg/mL (range, 0.4-28.8 μg/mL), adalimumab concentrations of 1.7 μg/mL (range, 0.7-7.9 μg/mL), ustekinumab concentrations of 0.6 μg/mL (range, 0-1.1), and undetectable for vedolizumab at 10.7 weeks of age.

As anticipated, infant immune function was normal regardless of circulating drug levels.

The overall message, said Seow, is “healthy mum equals healthy baby. Be more concerned regarding active inflammation than active medications. In almost all circumstances, treat to target in pregnancy as you would in the nonpregnant state.” She added, however, that further studies are needed to determine the safety and optimal timing of other live vaccines, such as the BCG, in the presence of biologic therapy.

This study was funded by the Alberta Children’s Hospital Research Institute. Seow reported advisory/speaker’s fees for Janssen, AbbVie, Takeda, Pfizer, Fresenius Kabi, Bristol-Myers Squibb, Pharmascience, and Lilly, as well as funding from Alberta Children’s Hospital Research Institute, Crohn’s and Colitis Canada, the Canadian Institutes of Health Research, and Calgary Health Trust, and data safety monitoring from New South Wales Government Health, Australia. Multiple coauthors disclosed similar consulting or speaker relationships with private industry. Spencer had no competing interests with regard to her comments.

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

More evidence suggests there is little risk in administering the live rotavirus vaccine to the babies of mothers on biologics during pregnancy for inflammatory bowel disease (IBD).

No adverse events or impairment of the immune system emerged in babies at 7 days, 1 month, and 9 months post vaccination, in findings from a small Canadian study published in Clinical Gastroenterology and Hepatology.

University of Calgary

The study found normal extended immune function testing in infants despite third-trimester maternal biologic therapy and regardless of circulating drug levels. The data provide reassurance about live rotavirus vaccination in this population and may also offer insights into the safety of other live vaccines in biologic-exposed individuals, wrote investigators led by gastroenterologist Cynthia H. Seow, MD, a professor in the Cumming School of Medicine at the University of Calgary in Alberta, Canada.

“Despite the well-established safety and effectiveness of non–live vaccination in individuals with IBD, including those on immunomodulators and biologic therapy, vaccine uptake in pregnant women with IBD and their infants remains suboptimal,” Seow said in an interview. This largely arises from maternal and physician concerns regarding transplacental transfer of IBD therapies and their impact on the safety of vaccination.

“These concerns were heightened after reports emerged of five fatal outcomes following the administration of the live Bacille Calmette-Guérin [BCG] vaccine in biologic-exposed infants. However, it had already been reported that inadvertent administration of the live oral rotavirus vaccine, a very different vaccine in terms of target and mechanism of action, in biologic-exposed individuals had not been associated with significant adverse effects,” she said.

They undertook their analysis with the hypothesis that vaccination would carry low risk, although the live oral vaccine is not currently recommended in biologic-exposed infants. “Yet rotavirus is a leading cause of severe, dehydrating diarrhea in children under the age of 5 years globally, and vaccination has led to significant reductions in hospitalizations and mortality,” Seow added.

Provision of the vaccine to anti–tumor necrosis factor (TNF)–exposed infants has been incorporated into the Canadian Public Health and Immunization guidelines, as the majority of the biologic-exposed infants were exposed to anti-TNF agents. “And with collection of further data, we expect that this will be extended to other biologic agent exposure. These data are important to pregnant women with IBD as they help to normalize their care. Pregnancy is difficult enough without having to remember exceptions to care,” Seow said.

“Before some of the studies came out, broad guidelines recommended that live vaccines should not be used in biologic-exposed infants, but this had been thought to be overly zealous and too conservative, and the risk was thought to be low,” said Elizabeth Spencer, MD, an assistant professor of pediatrics in the Division of Pediatric Gastroenterology at the Icahn School of Medicine at Mount Sinai in New York City, in an interview. Spencer was not involved in the Canadian study.

“At our center, we had some moms on biologics during pregnancy who forgot and had their babies vaccinated for rotavirus, and the babies were all fine,” she said.

The safety of this vaccine has been confirmed by several small studies and recently the PIANO Helmsley Global Consensus on Pregnancy and Inflammatory Bowel Disease, which was presented at Digestive Disease Week 2024. The consensus encompasses preconception counseling and the safety of IBD medications during pregnancy and lactation.

Icahn School of Medicine at Mount Sinai

“Another concern, however, was that giving a live GI bug like rotavirus to babies might overstimulate their immune systems and provoke IBD,” Spencer added. “While a number of population-based studies in the US and Europe showed that was not the case, at least in the general population, there was a suggestion that, down the road, vaccination might be mildly protective against IBD in some cases.”

She added the caveat that these studies were not done in mothers and their babies with IBD, who might be inherently at greater risk for IBD. “So, a question for future research would be, ‘Is immune stimulation of the gut in IBD moms and their babies a good or a bad thing for their gut?’ ”

Spencer conceded that “the data present a bit of a blurry picture, but I think it’s always better just to vaccinate according to the regular schedule. The current data say there is no added risk, but it would be nice to look specifically at risk in moms with IBD and their children.”
 

The Study

The prospective cohort study is a substudy of a larger 2023 one that included biologic use in a range of maternal illnesses, not just IBD.

For the current study, Seow and colleagues identified 57 infants born to 52 mothers with IBD attending a pregnancy clinic at the University of Calgary in the period 2019-2023. Almost 81% of the mothers had Crohn’s disease, and the median duration of IBD was 10 years. The median gestational age at delivery was 39 weeks, and almost 60% of deliveries were vaginal. The infants had been exposed in utero to infliximab (n = 21), adalimumab (n = 19), vedolizumab (n = 10), and ustekinumab (n = 7) in the third trimester.

The 57 biologic-exposed infants underwent standardized clinical assessments, drug concentration, and immune function testing. The live oral rotavirus vaccine series was provided to 50 infants, with the first dose at a median of 13 weeks of age. Immunologic assessments validated for age were normal in all infants despite median infliximab concentrations of 6.1 μg/mL (range, 0.4-28.8 μg/mL), adalimumab concentrations of 1.7 μg/mL (range, 0.7-7.9 μg/mL), ustekinumab concentrations of 0.6 μg/mL (range, 0-1.1), and undetectable for vedolizumab at 10.7 weeks of age.

As anticipated, infant immune function was normal regardless of circulating drug levels.

The overall message, said Seow, is “healthy mum equals healthy baby. Be more concerned regarding active inflammation than active medications. In almost all circumstances, treat to target in pregnancy as you would in the nonpregnant state.” She added, however, that further studies are needed to determine the safety and optimal timing of other live vaccines, such as the BCG, in the presence of biologic therapy.

This study was funded by the Alberta Children’s Hospital Research Institute. Seow reported advisory/speaker’s fees for Janssen, AbbVie, Takeda, Pfizer, Fresenius Kabi, Bristol-Myers Squibb, Pharmascience, and Lilly, as well as funding from Alberta Children’s Hospital Research Institute, Crohn’s and Colitis Canada, the Canadian Institutes of Health Research, and Calgary Health Trust, and data safety monitoring from New South Wales Government Health, Australia. Multiple coauthors disclosed similar consulting or speaker relationships with private industry. Spencer had no competing interests with regard to her comments.

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

The experimental monoclonal antibody tulisokibart safely induced clinical remission in a phase 2 randomized trial of moderately to severely active ulcerative colitis (UC).

In one cohort of 135 patients, the primary endpoint of clinical remission occurred in 26% of those given the novel antibody to tumor necrosis factor–like cytokine 1A (TL1A) vs 1% given placebo (95% CI, 14-37, P < .001). In a smaller cohort of 43 patients genetically pretested for likely response to the new biologic, remission after treatment was only slightly higher at 32% vs 11% (95% CI, 2-38, P = .02).

The incidence of adverse events was similar in both arms, and most events were mild.

Courtesy Icahn School of Medicine at Mount Sinai

The 12-week induction trial, conducted in 14 countries by the ARTEMIS-UC Study Group and led by Bruce E. Sands, MD, MS, AGAF, a professor of medicine at Icahn School of Medicine at Mount Sinai and system chief in the Division of Gastroenterology at Mount Sinai Health System in New York City, was published in The New England Journal of Medicine. 

“Our results suggest that important clinical benefit may be achieved through TL1A blockade in patients with UC,” Dr. Sands said in an interview, adding that this is the first rigorous study of a drug class with an entirely new mechanism of action that may be beneficial in other immune-mediated and fibrotic diseases. 

“And it is also the first prospective randomized controlled trial in IBD to incorporate a precision-medicine approach using a predictive biomarker for response in a drug development program,” he added.

Dr. Sands stressed the urgent need for new therapies since, despite the approval of multiple new classes of agents, both small molecules and biologics, “there is still a plateau of efficacy in that less than 50% of patients achieve remission at a year.”

He added that UC may progress over time owing to fibrosis of the bowel, a condition not directly or safely addressed by any existing therapies. “Identifying novel targets such as TL1A may allow us to address a different subpopulation of patients who may not respond to the targets addressed by existing therapies,” he said.

In agreement is Jason K. Hou, MD, MS, AGAF, an associate professor of medicine at Baylor College of Medicine and section chief of gastroenterology at Michael E. DeBakey VA Medical Center, both in Houston, Texas. “Although it’s a very exciting time with more options in the last few years for treating UC, even inhibitors with new agents such as JAK inhibitors and interleukin 23 antagonists, many patients have no or only a partial response,” he said in an interview. “Targeting molecules, which has been studied for decades, may offer more than a shot in the dark.” 
 

Why Target TL1A?

Genome-wide studies have shown elevated TL1A, a member of the tumor necrosis factor superfamily, in patients with inflammatory bowel disease (IBD).

“The interaction of TL1A and its ligand, death domain receptor 3, contributes to the immune-mediated inflammation and fibrosis seen in IBD through the downstream production of proinflammatory cytokines by multiple different immune cells, and the elaboration of collagen by fibroblasts,” Dr. Sands explained.

With the intention of targeting TL1A, his group randomly assigned patients with moderate to severe active UC who were glucocorticoid dependent or had not responded to conventional or advanced therapies, with disease extending a minimum of 15 cm from the anal verge. Across arms, the age of the mainly White, non-Hispanic participants ranged from about 37 to about 42, 35%-53% were female, and disease duration was approximately 6-8 years. 

The arms received either placebo or intravenous tulisokibart at 1000 mg on day 1 and 500 mg at weeks 2, 6, and 10. Cohort 1 included patients regardless of biomarker status for likelihood of response. Cohort 2 included only patients with a positive test for likelihood of response.

Dr. Hou was surprised that response to tulisokibart vs placebo was not greater in test-identified probable responders. “The biomarker didn’t make a huge difference, just a numerical one,” he said. “It may be that more genes are involved than the test could identify, and response is more complicated. Or perhaps the placebo response was particularly high in this small group. We need a deeper dive into why.” 
 

Earlier Application?

“This was a phase 2 study, so it’s too soon to say if tulisokibart could be used as early therapy or in severe disease,” Sands said. “However, the excellent safety profile and efficacy suggest that these populations should be explored in later studies. 

Further work is needed to validate the test to predict higher likelihood of response, he added, and recruiting for a phase 3 study is now underway.

The study was supported by Prometheus Biosciences, a subsidiary of Merck. Dr. Sands disclosed multiple ties to private companies, including research support, consulting, data safety monitoring, travel, a gift, and a stock option. Several coauthors reported, variously, research support from and/or consulting for multiple private companies. Others reported employment, variously, with Prometheus and/or Merck, Spyre Therapeutics, and Mirador Therapeutics, or patent holding for IBD drugs. Dr. Hou had no relevant competing interests to disclose but will participate in the phase 3 trial.

A version of this article appeared on Medscape.com.

The experimental monoclonal antibody tulisokibart safely induced clinical remission in a phase 2 randomized trial of moderately to severely active ulcerative colitis (UC).

In one cohort of 135 patients, the primary endpoint of clinical remission occurred in 26% of those given the novel antibody to tumor necrosis factor–like cytokine 1A (TL1A) vs 1% given placebo (95% CI, 14-37, P < .001). In a smaller cohort of 43 patients genetically pretested for likely response to the new biologic, remission after treatment was only slightly higher at 32% vs 11% (95% CI, 2-38, P = .02).

The incidence of adverse events was similar in both arms, and most events were mild.

Courtesy Icahn School of Medicine at Mount Sinai

The 12-week induction trial, conducted in 14 countries by the ARTEMIS-UC Study Group and led by Bruce E. Sands, MD, MS, AGAF, a professor of medicine at Icahn School of Medicine at Mount Sinai and system chief in the Division of Gastroenterology at Mount Sinai Health System in New York City, was published in The New England Journal of Medicine. 

“Our results suggest that important clinical benefit may be achieved through TL1A blockade in patients with UC,” Dr. Sands said in an interview, adding that this is the first rigorous study of a drug class with an entirely new mechanism of action that may be beneficial in other immune-mediated and fibrotic diseases. 

“And it is also the first prospective randomized controlled trial in IBD to incorporate a precision-medicine approach using a predictive biomarker for response in a drug development program,” he added.

Dr. Sands stressed the urgent need for new therapies since, despite the approval of multiple new classes of agents, both small molecules and biologics, “there is still a plateau of efficacy in that less than 50% of patients achieve remission at a year.”

He added that UC may progress over time owing to fibrosis of the bowel, a condition not directly or safely addressed by any existing therapies. “Identifying novel targets such as TL1A may allow us to address a different subpopulation of patients who may not respond to the targets addressed by existing therapies,” he said.

In agreement is Jason K. Hou, MD, MS, AGAF, an associate professor of medicine at Baylor College of Medicine and section chief of gastroenterology at Michael E. DeBakey VA Medical Center, both in Houston, Texas. “Although it’s a very exciting time with more options in the last few years for treating UC, even inhibitors with new agents such as JAK inhibitors and interleukin 23 antagonists, many patients have no or only a partial response,” he said in an interview. “Targeting molecules, which has been studied for decades, may offer more than a shot in the dark.” 
 

Why Target TL1A?

Genome-wide studies have shown elevated TL1A, a member of the tumor necrosis factor superfamily, in patients with inflammatory bowel disease (IBD).

“The interaction of TL1A and its ligand, death domain receptor 3, contributes to the immune-mediated inflammation and fibrosis seen in IBD through the downstream production of proinflammatory cytokines by multiple different immune cells, and the elaboration of collagen by fibroblasts,” Dr. Sands explained.

With the intention of targeting TL1A, his group randomly assigned patients with moderate to severe active UC who were glucocorticoid dependent or had not responded to conventional or advanced therapies, with disease extending a minimum of 15 cm from the anal verge. Across arms, the age of the mainly White, non-Hispanic participants ranged from about 37 to about 42, 35%-53% were female, and disease duration was approximately 6-8 years. 

The arms received either placebo or intravenous tulisokibart at 1000 mg on day 1 and 500 mg at weeks 2, 6, and 10. Cohort 1 included patients regardless of biomarker status for likelihood of response. Cohort 2 included only patients with a positive test for likelihood of response.

Dr. Hou was surprised that response to tulisokibart vs placebo was not greater in test-identified probable responders. “The biomarker didn’t make a huge difference, just a numerical one,” he said. “It may be that more genes are involved than the test could identify, and response is more complicated. Or perhaps the placebo response was particularly high in this small group. We need a deeper dive into why.” 
 

Earlier Application?

“This was a phase 2 study, so it’s too soon to say if tulisokibart could be used as early therapy or in severe disease,” Sands said. “However, the excellent safety profile and efficacy suggest that these populations should be explored in later studies. 

Further work is needed to validate the test to predict higher likelihood of response, he added, and recruiting for a phase 3 study is now underway.

The study was supported by Prometheus Biosciences, a subsidiary of Merck. Dr. Sands disclosed multiple ties to private companies, including research support, consulting, data safety monitoring, travel, a gift, and a stock option. Several coauthors reported, variously, research support from and/or consulting for multiple private companies. Others reported employment, variously, with Prometheus and/or Merck, Spyre Therapeutics, and Mirador Therapeutics, or patent holding for IBD drugs. Dr. Hou had no relevant competing interests to disclose but will participate in the phase 3 trial.

A version of this article appeared on Medscape.com.

The experimental monoclonal antibody tulisokibart safely induced clinical remission in a phase 2 randomized trial of moderately to severely active ulcerative colitis (UC).

In one cohort of 135 patients, the primary endpoint of clinical remission occurred in 26% of those given the novel antibody to tumor necrosis factor–like cytokine 1A (TL1A) vs 1% given placebo (95% CI, 14-37, P < .001). In a smaller cohort of 43 patients genetically pretested for likely response to the new biologic, remission after treatment was only slightly higher at 32% vs 11% (95% CI, 2-38, P = .02).

The incidence of adverse events was similar in both arms, and most events were mild.

Courtesy Icahn School of Medicine at Mount Sinai

The 12-week induction trial, conducted in 14 countries by the ARTEMIS-UC Study Group and led by Bruce E. Sands, MD, MS, AGAF, a professor of medicine at Icahn School of Medicine at Mount Sinai and system chief in the Division of Gastroenterology at Mount Sinai Health System in New York City, was published in The New England Journal of Medicine. 

“Our results suggest that important clinical benefit may be achieved through TL1A blockade in patients with UC,” Dr. Sands said in an interview, adding that this is the first rigorous study of a drug class with an entirely new mechanism of action that may be beneficial in other immune-mediated and fibrotic diseases. 

“And it is also the first prospective randomized controlled trial in IBD to incorporate a precision-medicine approach using a predictive biomarker for response in a drug development program,” he added.

Dr. Sands stressed the urgent need for new therapies since, despite the approval of multiple new classes of agents, both small molecules and biologics, “there is still a plateau of efficacy in that less than 50% of patients achieve remission at a year.”

He added that UC may progress over time owing to fibrosis of the bowel, a condition not directly or safely addressed by any existing therapies. “Identifying novel targets such as TL1A may allow us to address a different subpopulation of patients who may not respond to the targets addressed by existing therapies,” he said.

In agreement is Jason K. Hou, MD, MS, AGAF, an associate professor of medicine at Baylor College of Medicine and section chief of gastroenterology at Michael E. DeBakey VA Medical Center, both in Houston, Texas. “Although it’s a very exciting time with more options in the last few years for treating UC, even inhibitors with new agents such as JAK inhibitors and interleukin 23 antagonists, many patients have no or only a partial response,” he said in an interview. “Targeting molecules, which has been studied for decades, may offer more than a shot in the dark.” 
 

Why Target TL1A?

Genome-wide studies have shown elevated TL1A, a member of the tumor necrosis factor superfamily, in patients with inflammatory bowel disease (IBD).

“The interaction of TL1A and its ligand, death domain receptor 3, contributes to the immune-mediated inflammation and fibrosis seen in IBD through the downstream production of proinflammatory cytokines by multiple different immune cells, and the elaboration of collagen by fibroblasts,” Dr. Sands explained.

With the intention of targeting TL1A, his group randomly assigned patients with moderate to severe active UC who were glucocorticoid dependent or had not responded to conventional or advanced therapies, with disease extending a minimum of 15 cm from the anal verge. Across arms, the age of the mainly White, non-Hispanic participants ranged from about 37 to about 42, 35%-53% were female, and disease duration was approximately 6-8 years. 

The arms received either placebo or intravenous tulisokibart at 1000 mg on day 1 and 500 mg at weeks 2, 6, and 10. Cohort 1 included patients regardless of biomarker status for likelihood of response. Cohort 2 included only patients with a positive test for likelihood of response.

Dr. Hou was surprised that response to tulisokibart vs placebo was not greater in test-identified probable responders. “The biomarker didn’t make a huge difference, just a numerical one,” he said. “It may be that more genes are involved than the test could identify, and response is more complicated. Or perhaps the placebo response was particularly high in this small group. We need a deeper dive into why.” 
 

Earlier Application?

“This was a phase 2 study, so it’s too soon to say if tulisokibart could be used as early therapy or in severe disease,” Sands said. “However, the excellent safety profile and efficacy suggest that these populations should be explored in later studies. 

Further work is needed to validate the test to predict higher likelihood of response, he added, and recruiting for a phase 3 study is now underway.

The study was supported by Prometheus Biosciences, a subsidiary of Merck. Dr. Sands disclosed multiple ties to private companies, including research support, consulting, data safety monitoring, travel, a gift, and a stock option. Several coauthors reported, variously, research support from and/or consulting for multiple private companies. Others reported employment, variously, with Prometheus and/or Merck, Spyre Therapeutics, and Mirador Therapeutics, or patent holding for IBD drugs. Dr. Hou had no relevant competing interests to disclose but will participate in the phase 3 trial.

A version of this article appeared on Medscape.com.