Tara Haelle

The medication vibegron led to improvements in symptoms of overactive bladder and overall quality of life in men undergoing treatment for benign prostatic hyperplasia, according to findings from a phase 3 trial presented at the annual meeting of the American Urological Association (AUA) and data published in the Journal of Urology.

“Vibegron was associated with significant reductions in daily micturition and urgency episodes, as well as our secondary endpoints,” David R. Staskin, MD, an associate professor of urology at Tufts University School of Medicine in Boston, told attendees. “Symptoms really did improve compared to placebo as early as week 2.”

Vibegron is a selective beta-3 adrenergic receptor agonist approved in 2020 by the US Food and Drug Administration for the treatment of overactive bladder.

However, treating overactive bladder symptoms in patients undergoing benign prostatic hyperplasia treatment is more complex because benign prostatic hyperplasia itself can contribute to overactive bladder symptoms, said Kara Watts, MD, an associate professor of urology at Montefiore Einstein in New York City, who was not involved in the new research.

“Management of overactive bladder in this setting may require treatment of benign prostatic hyperplasia as well, but a discussion of the relationship between benign prostatic hyperplasia and overactive bladder symptoms is important,” Dr. Watts told this news organization. “Beyond consideration of treatment for benign prostatic hyperplasia — which can be in the form of medications or surgeries to reduce the size of the prostate — treatment of overactive bladder can include behavioral modification,” such as avoiding bladder irritants, timed voiding, managing constipation, and nighttime liquid restriction,” as well as “medications, percutaneous tibial nerve stimulation, and occasionally more invasive options.”

Vibegron “represents a very attractive and effective pharmaceutical management option for overactive bladder,” both in patients with and without benign prostatic hyperplasia, Dr. Watts said. “It has a favorable side-effect profile compared to other oral agents that can be prescribed for overactive bladder, such as anticholinergics, and also has the added benefit of a much lower risk of urinary retention in comparison to most other oral agents.”

Among 1104 men at least 45 years old who were undergoing treatment for benign prostatic hyperplasia and had symptoms of overactive bladder, 538 received 75 mg of vibegron and 542 received a placebo. The men in the vibegron group showed 2.04 fewer mean daily urinations at 12 weeks and 2.2 fewer at 24 weeks compared to 1.3 fewer at both 12 and 24 weeks for men in the placebo group (P < .0001), according to the researchers.

The drug also reduced urgency of urination. Mean daily episodes of urgency were 2.88 fewer at 12 weeks and 3.07 fewer at 24 weeks in the vibegron group compared to 1.93 and 2.17 fewer, respectively, in the placebo group (P < .0001).

In secondary endpoints, those taking vibegron experienced 0.22 fewer episodes of nocturia (P = .002), 0.8 fewer episodes of urgency incontinence (P = .003), a 0.9-point difference in improvement in the International Prostate Symptom Score (P < .0001), and about 15 mL more volume voided (P < .0001) compared to those receiving placebo, the researchers reported.

“The clinical significance of these findings is that vibegron represents an effective pharmacologic option for managing overactive bladder in the context of concomitant benign prostatic hyperplasia, which is a broader context than its original approval for overactive bladder alone,” Dr. Watts said.

Data from 969 patients on the overactive bladder quality-of-life questionnaire found that the symptom bother score was 6.2 points better for men in the vibegron group than those who took a placebo (P < .0001) at 12 weeks. Similarly, the total health-related quality-of-life score was 4.3 points better in the vibegron group (P < .0001). Measures of concern, coping, and sleep also improved significantly in the men taking vibegron and remained significant at 24 weeks (P < .0001).

Rates of adverse events were similar in the vibegron (45%) and placebo (39%) groups. The most common adverse event was hypertension, which occurred in 9% of the vibegron group and 8.3% of men in the placebo group.

The research was funded by Sumitomo Pharma America, Inc., which makes vibegron. Dr. Staskin is a consultant for Astellas, AzuraBio, Sumitomo Pharma America, Inc., and UroCure; is a lecturer for Astellas and Sumitomo; and holds other interests in UroCure, AzuraBio, and Quillitin Pharma. Three co-authors are Sumitomo employees; one is an investigator for Sumitomo, and another has consulted for Hologic, received research funding from Allergan/AbbVie and Uromedica, and been involved in clinical trials on behalf of Sumitomo. Dr. Watts reported no relevant financial conflicts of interest.

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

The medication vibegron led to improvements in symptoms of overactive bladder and overall quality of life in men undergoing treatment for benign prostatic hyperplasia, according to findings from a phase 3 trial presented at the annual meeting of the American Urological Association (AUA) and data published in the Journal of Urology.

“Vibegron was associated with significant reductions in daily micturition and urgency episodes, as well as our secondary endpoints,” David R. Staskin, MD, an associate professor of urology at Tufts University School of Medicine in Boston, told attendees. “Symptoms really did improve compared to placebo as early as week 2.”

Vibegron is a selective beta-3 adrenergic receptor agonist approved in 2020 by the US Food and Drug Administration for the treatment of overactive bladder.

However, treating overactive bladder symptoms in patients undergoing benign prostatic hyperplasia treatment is more complex because benign prostatic hyperplasia itself can contribute to overactive bladder symptoms, said Kara Watts, MD, an associate professor of urology at Montefiore Einstein in New York City, who was not involved in the new research.

“Management of overactive bladder in this setting may require treatment of benign prostatic hyperplasia as well, but a discussion of the relationship between benign prostatic hyperplasia and overactive bladder symptoms is important,” Dr. Watts told this news organization. “Beyond consideration of treatment for benign prostatic hyperplasia — which can be in the form of medications or surgeries to reduce the size of the prostate — treatment of overactive bladder can include behavioral modification,” such as avoiding bladder irritants, timed voiding, managing constipation, and nighttime liquid restriction,” as well as “medications, percutaneous tibial nerve stimulation, and occasionally more invasive options.”

Vibegron “represents a very attractive and effective pharmaceutical management option for overactive bladder,” both in patients with and without benign prostatic hyperplasia, Dr. Watts said. “It has a favorable side-effect profile compared to other oral agents that can be prescribed for overactive bladder, such as anticholinergics, and also has the added benefit of a much lower risk of urinary retention in comparison to most other oral agents.”

Among 1104 men at least 45 years old who were undergoing treatment for benign prostatic hyperplasia and had symptoms of overactive bladder, 538 received 75 mg of vibegron and 542 received a placebo. The men in the vibegron group showed 2.04 fewer mean daily urinations at 12 weeks and 2.2 fewer at 24 weeks compared to 1.3 fewer at both 12 and 24 weeks for men in the placebo group (P < .0001), according to the researchers.

The drug also reduced urgency of urination. Mean daily episodes of urgency were 2.88 fewer at 12 weeks and 3.07 fewer at 24 weeks in the vibegron group compared to 1.93 and 2.17 fewer, respectively, in the placebo group (P < .0001).

In secondary endpoints, those taking vibegron experienced 0.22 fewer episodes of nocturia (P = .002), 0.8 fewer episodes of urgency incontinence (P = .003), a 0.9-point difference in improvement in the International Prostate Symptom Score (P < .0001), and about 15 mL more volume voided (P < .0001) compared to those receiving placebo, the researchers reported.

“The clinical significance of these findings is that vibegron represents an effective pharmacologic option for managing overactive bladder in the context of concomitant benign prostatic hyperplasia, which is a broader context than its original approval for overactive bladder alone,” Dr. Watts said.

Data from 969 patients on the overactive bladder quality-of-life questionnaire found that the symptom bother score was 6.2 points better for men in the vibegron group than those who took a placebo (P < .0001) at 12 weeks. Similarly, the total health-related quality-of-life score was 4.3 points better in the vibegron group (P < .0001). Measures of concern, coping, and sleep also improved significantly in the men taking vibegron and remained significant at 24 weeks (P < .0001).

Rates of adverse events were similar in the vibegron (45%) and placebo (39%) groups. The most common adverse event was hypertension, which occurred in 9% of the vibegron group and 8.3% of men in the placebo group.

The research was funded by Sumitomo Pharma America, Inc., which makes vibegron. Dr. Staskin is a consultant for Astellas, AzuraBio, Sumitomo Pharma America, Inc., and UroCure; is a lecturer for Astellas and Sumitomo; and holds other interests in UroCure, AzuraBio, and Quillitin Pharma. Three co-authors are Sumitomo employees; one is an investigator for Sumitomo, and another has consulted for Hologic, received research funding from Allergan/AbbVie and Uromedica, and been involved in clinical trials on behalf of Sumitomo. Dr. Watts reported no relevant financial conflicts of interest.

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

The medication vibegron led to improvements in symptoms of overactive bladder and overall quality of life in men undergoing treatment for benign prostatic hyperplasia, according to findings from a phase 3 trial presented at the annual meeting of the American Urological Association (AUA) and data published in the Journal of Urology.

“Vibegron was associated with significant reductions in daily micturition and urgency episodes, as well as our secondary endpoints,” David R. Staskin, MD, an associate professor of urology at Tufts University School of Medicine in Boston, told attendees. “Symptoms really did improve compared to placebo as early as week 2.”

Vibegron is a selective beta-3 adrenergic receptor agonist approved in 2020 by the US Food and Drug Administration for the treatment of overactive bladder.

However, treating overactive bladder symptoms in patients undergoing benign prostatic hyperplasia treatment is more complex because benign prostatic hyperplasia itself can contribute to overactive bladder symptoms, said Kara Watts, MD, an associate professor of urology at Montefiore Einstein in New York City, who was not involved in the new research.

“Management of overactive bladder in this setting may require treatment of benign prostatic hyperplasia as well, but a discussion of the relationship between benign prostatic hyperplasia and overactive bladder symptoms is important,” Dr. Watts told this news organization. “Beyond consideration of treatment for benign prostatic hyperplasia — which can be in the form of medications or surgeries to reduce the size of the prostate — treatment of overactive bladder can include behavioral modification,” such as avoiding bladder irritants, timed voiding, managing constipation, and nighttime liquid restriction,” as well as “medications, percutaneous tibial nerve stimulation, and occasionally more invasive options.”

Vibegron “represents a very attractive and effective pharmaceutical management option for overactive bladder,” both in patients with and without benign prostatic hyperplasia, Dr. Watts said. “It has a favorable side-effect profile compared to other oral agents that can be prescribed for overactive bladder, such as anticholinergics, and also has the added benefit of a much lower risk of urinary retention in comparison to most other oral agents.”

Among 1104 men at least 45 years old who were undergoing treatment for benign prostatic hyperplasia and had symptoms of overactive bladder, 538 received 75 mg of vibegron and 542 received a placebo. The men in the vibegron group showed 2.04 fewer mean daily urinations at 12 weeks and 2.2 fewer at 24 weeks compared to 1.3 fewer at both 12 and 24 weeks for men in the placebo group (P < .0001), according to the researchers.

The drug also reduced urgency of urination. Mean daily episodes of urgency were 2.88 fewer at 12 weeks and 3.07 fewer at 24 weeks in the vibegron group compared to 1.93 and 2.17 fewer, respectively, in the placebo group (P < .0001).

In secondary endpoints, those taking vibegron experienced 0.22 fewer episodes of nocturia (P = .002), 0.8 fewer episodes of urgency incontinence (P = .003), a 0.9-point difference in improvement in the International Prostate Symptom Score (P < .0001), and about 15 mL more volume voided (P < .0001) compared to those receiving placebo, the researchers reported.

“The clinical significance of these findings is that vibegron represents an effective pharmacologic option for managing overactive bladder in the context of concomitant benign prostatic hyperplasia, which is a broader context than its original approval for overactive bladder alone,” Dr. Watts said.

Data from 969 patients on the overactive bladder quality-of-life questionnaire found that the symptom bother score was 6.2 points better for men in the vibegron group than those who took a placebo (P < .0001) at 12 weeks. Similarly, the total health-related quality-of-life score was 4.3 points better in the vibegron group (P < .0001). Measures of concern, coping, and sleep also improved significantly in the men taking vibegron and remained significant at 24 weeks (P < .0001).

Rates of adverse events were similar in the vibegron (45%) and placebo (39%) groups. The most common adverse event was hypertension, which occurred in 9% of the vibegron group and 8.3% of men in the placebo group.

The research was funded by Sumitomo Pharma America, Inc., which makes vibegron. Dr. Staskin is a consultant for Astellas, AzuraBio, Sumitomo Pharma America, Inc., and UroCure; is a lecturer for Astellas and Sumitomo; and holds other interests in UroCure, AzuraBio, and Quillitin Pharma. Three co-authors are Sumitomo employees; one is an investigator for Sumitomo, and another has consulted for Hologic, received research funding from Allergan/AbbVie and Uromedica, and been involved in clinical trials on behalf of Sumitomo. Dr. Watts reported no relevant financial conflicts of interest.

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

Sherrie Palm, a patient advocate in Mukwonago, Wisconsin, learned in her 30s that she needed to educate herself about her own health. So when she discovered a walnut-sized lump coming out of her vagina in her mid-50s, she was stunned when her primary care provider (PCP) told her it was pelvic organ prolapse (POP), where one or more organs descend into the vaginal cavity.

“I was shocked,” Ms. Palm said. After searching online and discovering how prevalent POP was, her shock turned to anger. “I was blown away that it could be this common and I’d never heard of it,” she said. “I knew within 2 weeks that I had to do something to change the status quo.”

Ms. Palm eventually founded the nonprofit Association for Pelvic Organ Prolapse Support, or APOPS, complete with a forum where women can learn about POP and support one another. She said awareness has improved substantially since her diagnosis in 2007, but “we have a long way to go” because POP and vaginal health in general are so stigmatized.

Her website notes that about half of women with incontinence do not seek help, largely because of stigma. “The status quo is that PCPs do not POP screen,” she said. ObGyns may screen but often “because the patient has asked to be screened, they say it’s not that bad, come back and see me in a year, and do your Kegels,” Ms. Palm said.

Doctors who diagnose POP agree that the issue is often off PCPs’ radar.

“Primary care doctors are really in a time crunch, so this is one of the things that may not get addressed,” Jill Rabin, MD, vice chair of education and development in obstetrics and gynecology at Northwell Health in New York, said. Dr. Rabin is also head of urogynecology at Long Island Jewish Medical Center.

Ann Nwabuebo, PT, DPT, owner and founder of Body Connect Physical Therapy in Bethesda, Maryland, said social media has been shifting the attitude that pelvic health is a taboo subject. “It’s empowering people to seek care if they’re not finding physicians who are helping.”

But social media is also a double-edged sword, said Jenny LaCross, PT, DPT, PhD, a physical therapist at MOVE PT in Monroe, Michigan, and a postdoctoral research fellow with Michigan Medicine’s Pelvic Floor Research Group. “Pelvic health in general is talked about a lot more, but there’s also a lot more misinformation,” she said.

Part of that misinformation is the idea that pelvic prolapse is solely about weakness in the pelvic floor when it can also result from a widening of natural openings within the pelvis, Dr. LaCross said. She pointed to the two definitions of pelvic organ prolapse by the International Urogynecologic Consultation and the International Continence Society, both of which have been updated in recent years.

“This is why this is challenging for primary care providers,” Dr. LaCross said. “Even urogynecologists who are the specialists that treat prolapse and incontinence have changed how they assess it and the terminology and criteria that they use.”

What hasn’t changed is the substantial negative impact POP can have on quality of life. “This is the second most common reason that women enter nursing homes,” primarily because of urinary incontinence, Dr. Rabin said. “It’s very debilitating, but a lot of it is preventable and a lot is treatable.”

Dr. Rabin estimated that three out of every five women older than 60 and one or two out of every five women younger than 60 experience POP. Prevalence studies vary widely, from nearly a quarter of women to more than half, and racial and ethnic disparities in diagnosis further complicate the statistics.

PCPs therefore have an important role to play in screening for POP. The evidence shows that “patients want their providers to bring this up,” Dr. LaCross said. “They want to talk about it, but they want the provider to ask the questions first.”
 

Causes, Risk Factors, and Symptoms

Many causes contribute to POP, with gravity, aging, childbirth, and menopause at the top of the list.

“As people get older, their pelvic muscles and connective tissue get weaker, and the nerves don’t function as well,” Dr. Rabin said. Meanwhile, the body is losing estrogen, which affects how well the muscles contract and how easily the connective tissue can tear, she said.

With menopause, when baseline estrogen is lower, the tissue integrity is not as supportive as it should be and women are going to be at an increased risk of prolapse, Dr. Nwabuebo said.

POP has a range of risk factors:

• Increasing age, as muscle mass decreases and connective tissue hardens.
• Menopause.
• Vaginal delivery with complications, such as long second-stage labor, instrument-assisted delivery, multiple vaginal lacerations, and improperly repaired episiotomy.
• Multiple vaginal deliveries.
• Birthing large babies.
• Family history of pelvic organ prolapse (genetics can play a role in POP risk).
• Previous pelvic/abdominal surgery, including cesarean delivery and hysterectomy.
• Smoking (largely because of associated coughing).
• Chronic lung conditions that cause a lot of coughing.
• Chronic constipation or irritable bowel syndrome.
• Some types of high-impact activity, such as jogging or marathon running.
• Early menopause, for younger women.
• Repetitive heavy lifting in daily activities, such as occupational lifting (though not necessarily weight lifting as an exercise).
• Higher body mass index.
• Connective tissue disorders, such as joint hypermobility syndrome or Ehlers-Danlos syndrome.

Roger Dmochowski, MD, professor of urology and surgery at Vanderbilt University Medical Center, groups POP symptoms into two groups: anatomic and functional ones. A common anatomic symptom is bulging. “They’ll describe sitting on a ball, feeling like their bladder or something’s falling out, feeling a pressure or a heaviness,” Dr. Dmochowski said.

Functional symptoms can include vaginal dryness, vaginal irritation, painful intercourse, contact of the vaginal tissues with underclothes, and associated urinary symptoms, such as stress incontinence, urge incontinence, and incomplete emptying of the bladder. Dr. Dmochowski noted that women who report urinary incontinence may be at risk for being prescribed a medication without the necessary referral to a specialist for a full gynecologic evaluation.

Two other groups of functional symptoms include bowel-related disorders – primarily fecal incontinence and ongoing constipation – and pelvic pain or discomfort.

There can also be asymptomatic cases. “A lot of women have what we call silent prolapse,” Dr. Dmochowski said. That is, “they have some degree of loss of support to the bladder, vagina, or uterus, but they’re not symptomatic.” These women may be particularly good candidates for pelvic health physical therapy.
 

Screening and Diagnosis

Because many postmenopausal women stop seeing their ob.gyn, it’s often up to their primary care physician to determine whether their patients are experiencing POP symptoms.

“Women sometimes don’t bring this up with their doctor because they think there’s not enough time, or they’ll be laughed at, or their friends told them this is normal,” Dr. Rabin said. But primary care providers are really in a unique position to be able to ask the key symptom questions.

Dr. Rabin recommends a couple of questions to cover all the bases: “Do you leak urine when you cough or sneeze or on the way to the bathroom? Do you notice a bulge coming out of the vagina, or are you bothered by pelvic pressure?”

Dr. Dmochowski offered a single question that can open the conversation to more questions: “Are you bothered by any urinary or bowel or vaginal issues that we should talk about?” He also suggests asking how bothersome the symptoms are, which can help in directing treatment or prevention options. A physical exam can reveal signs of POP as well.

Diagnosis involves a detailed history, a comprehensive physical exam, and assessment with the Pelvic Organ Prolapse Quantification (POP-Q) tool. A urogynecologist can diagnose the type of POP – such as cystocele, rectocele, enterocele, uterine prolapse, or vaginal vault prolapse – and its grade (0-4).
 

Treatment: Physical Therapy, Pessary, and Surgery

No medications can treat prolapse, though some can treat downstream effects, such as hormonal vaginal creams for vaginal dryness and irritation, and medications for urinary incontinence. However, two mistakes PCPs can make are sending someone straight to surgery or prescribing them medication for symptoms without referring them for a diagnostic evaluation, Dr. Rabin said. “You have to have a diagnosis first to know what type of prolapse is there,” she said.

Because there can be long waiting lists for a urogynecologist or urologist, PCPs should also refer their patients to a pelvic health physical therapist (PT) who can help patients begin addressing the symptoms while they await a specialist who can diagnose them.

Though PT is often thought of as preventive, it’s also a conservative first-line intervention for prolapse, Dr. Nwabuebo said. Strong evidence shows pelvic floor muscle training from pelvic health PT can reduce symptoms of prolapse and reduce the severity by one grade in those with a grade 1 or 2 prolapse. Stage 3 is trickier, where PT may or may not be able to shift the symptom presentation, Dr. Nwabeubo said, and stage 4 is usually a surgical candidate.

“If you have a grade 4 prolapse, or the tissues are really visible outside the body, physical therapy and pelvic floor muscle training is not going to elevate that tissue back up into your body, but it can sometimes help with symptoms,” Dr. LaCross said.

The PT conducts a thorough pelvic muscle assessment, discusses lifestyle, and may teach breathing and bracing strategies for lifting, for example.

“A lot of what we’re talking about with pelvic floor therapy is lifestyle modifications,” Dr. Nwabuebo said. “If I have a patient with a history of chronic constipation, it doesn’t matter how much we do pelvic floor exercises; if we don’t manage the constipation issues by addressing their nutrition, then straining when using the bathroom will keep putting pressure on the pelvic floor.”

PTs can also recommend appropriate vaginal weights and dilators to help with pelvic floor strengthening and teach patients how to use them properly.

Even if women ultimately opt for surgery, PT prior to surgery can be beneficial. Dr. Rabin cited three reasons she recommends first-line PT: It may elevate the bladder enough to reduce stress incontinence and thicken the pelvic muscles, it can improve the effectiveness of a pessary or surgery if the woman chooses one of those options, and it can quiet bladder contractions, potentially obviating the need for pharmacologic treatment for overactive bladder.

The next nonsurgical option is a pessary, a device that fits into the vagina to provide support to the tissues displaced by prolapse. There’s a wide range of pessary types: some are short-term, worn only daily, or disposable, while others can be worn longer. Some women can self-insert and remove the pessary, and others may need a clinician to do so. Dr. Dmochowski recommends patients try a pessary to see if it benefits them. About a third of women will find them comfortable enough to wear regularly, but others will feel more sensitive to the pessary’s presence, he said.

One of the newest, most innovative pessary options for women is Gynethotics, which received Food and Drug Administration (FDA) clearance in March, as the first 3D-printed, customizable pessary capable of nearly 10 million configurations based on a person’s body.

Nearly all stage 4 prolapses and most of stage 3 prolapses can be addressed only through transvaginal or transabdominal surgery.

“We tell patients, if you can get 10 years out of your operation, you’re lucky,” Dr. Dmochowski said. A major reason for the short-lived durability is the poor quality of the tissue that needs to be pulled together. Serious complications resulting from use of polypropylene mesh during prolapse surgery led the FDA to halt sales of the devices and recommend discontinuing their use. However, one type of vaginal mesh is still considered safe to use in sacral colpopexy surgery.

Three things can shorten the durability of the surgery, Dr. Dmochowski said: heavy lifting, particularly anything over 30 pounds; chronic coughing, such as in those with chronic lung conditions; and chronic constipation.

Ms. Palm tried a pessary for her grade 3 prolapse with cystocele, rectocele, and enterocele but didn’t feel she had the time to use it regularly, so she opted for surgery. After a week on the couch recovering, she took it easy for another 12 weeks. Since then, she’s dedicated much of her time to educating and supporting women with POP and combating stigma associated with it. The APOPS website that she started has become a valuable resource for PCPs to send patients to, and the forum includes more 27,000 women from around the world.

“We encourage women to share what they’re experiencing. Tell your family, tell your friends, tell the people you work with about it,” Ms. Palm said. But many still feel uncomfortable speaking up, making PCPs’ role even more important.

*This story was updated on May 14, 2024.

Sherrie Palm, a patient advocate in Mukwonago, Wisconsin, learned in her 30s that she needed to educate herself about her own health. So when she discovered a walnut-sized lump coming out of her vagina in her mid-50s, she was stunned when her primary care provider (PCP) told her it was pelvic organ prolapse (POP), where one or more organs descend into the vaginal cavity.

“I was shocked,” Ms. Palm said. After searching online and discovering how prevalent POP was, her shock turned to anger. “I was blown away that it could be this common and I’d never heard of it,” she said. “I knew within 2 weeks that I had to do something to change the status quo.”

Ms. Palm eventually founded the nonprofit Association for Pelvic Organ Prolapse Support, or APOPS, complete with a forum where women can learn about POP and support one another. She said awareness has improved substantially since her diagnosis in 2007, but “we have a long way to go” because POP and vaginal health in general are so stigmatized.

Her website notes that about half of women with incontinence do not seek help, largely because of stigma. “The status quo is that PCPs do not POP screen,” she said. ObGyns may screen but often “because the patient has asked to be screened, they say it’s not that bad, come back and see me in a year, and do your Kegels,” Ms. Palm said.

Doctors who diagnose POP agree that the issue is often off PCPs’ radar.

“Primary care doctors are really in a time crunch, so this is one of the things that may not get addressed,” Jill Rabin, MD, vice chair of education and development in obstetrics and gynecology at Northwell Health in New York, said. Dr. Rabin is also head of urogynecology at Long Island Jewish Medical Center.

Ann Nwabuebo, PT, DPT, owner and founder of Body Connect Physical Therapy in Bethesda, Maryland, said social media has been shifting the attitude that pelvic health is a taboo subject. “It’s empowering people to seek care if they’re not finding physicians who are helping.”

But social media is also a double-edged sword, said Jenny LaCross, PT, DPT, PhD, a physical therapist at MOVE PT in Monroe, Michigan, and a postdoctoral research fellow with Michigan Medicine’s Pelvic Floor Research Group. “Pelvic health in general is talked about a lot more, but there’s also a lot more misinformation,” she said.

Part of that misinformation is the idea that pelvic prolapse is solely about weakness in the pelvic floor when it can also result from a widening of natural openings within the pelvis, Dr. LaCross said. She pointed to the two definitions of pelvic organ prolapse by the International Urogynecologic Consultation and the International Continence Society, both of which have been updated in recent years.

“This is why this is challenging for primary care providers,” Dr. LaCross said. “Even urogynecologists who are the specialists that treat prolapse and incontinence have changed how they assess it and the terminology and criteria that they use.”

What hasn’t changed is the substantial negative impact POP can have on quality of life. “This is the second most common reason that women enter nursing homes,” primarily because of urinary incontinence, Dr. Rabin said. “It’s very debilitating, but a lot of it is preventable and a lot is treatable.”

Dr. Rabin estimated that three out of every five women older than 60 and one or two out of every five women younger than 60 experience POP. Prevalence studies vary widely, from nearly a quarter of women to more than half, and racial and ethnic disparities in diagnosis further complicate the statistics.

PCPs therefore have an important role to play in screening for POP. The evidence shows that “patients want their providers to bring this up,” Dr. LaCross said. “They want to talk about it, but they want the provider to ask the questions first.”
 

Causes, Risk Factors, and Symptoms

Many causes contribute to POP, with gravity, aging, childbirth, and menopause at the top of the list.

“As people get older, their pelvic muscles and connective tissue get weaker, and the nerves don’t function as well,” Dr. Rabin said. Meanwhile, the body is losing estrogen, which affects how well the muscles contract and how easily the connective tissue can tear, she said.

With menopause, when baseline estrogen is lower, the tissue integrity is not as supportive as it should be and women are going to be at an increased risk of prolapse, Dr. Nwabuebo said.

POP has a range of risk factors:

• Increasing age, as muscle mass decreases and connective tissue hardens.
• Menopause.
• Vaginal delivery with complications, such as long second-stage labor, instrument-assisted delivery, multiple vaginal lacerations, and improperly repaired episiotomy.
• Multiple vaginal deliveries.
• Birthing large babies.
• Family history of pelvic organ prolapse (genetics can play a role in POP risk).
• Previous pelvic/abdominal surgery, including cesarean delivery and hysterectomy.
• Smoking (largely because of associated coughing).
• Chronic lung conditions that cause a lot of coughing.
• Chronic constipation or irritable bowel syndrome.
• Some types of high-impact activity, such as jogging or marathon running.
• Early menopause, for younger women.
• Repetitive heavy lifting in daily activities, such as occupational lifting (though not necessarily weight lifting as an exercise).
• Higher body mass index.
• Connective tissue disorders, such as joint hypermobility syndrome or Ehlers-Danlos syndrome.

Roger Dmochowski, MD, professor of urology and surgery at Vanderbilt University Medical Center, groups POP symptoms into two groups: anatomic and functional ones. A common anatomic symptom is bulging. “They’ll describe sitting on a ball, feeling like their bladder or something’s falling out, feeling a pressure or a heaviness,” Dr. Dmochowski said.

Functional symptoms can include vaginal dryness, vaginal irritation, painful intercourse, contact of the vaginal tissues with underclothes, and associated urinary symptoms, such as stress incontinence, urge incontinence, and incomplete emptying of the bladder. Dr. Dmochowski noted that women who report urinary incontinence may be at risk for being prescribed a medication without the necessary referral to a specialist for a full gynecologic evaluation.

Two other groups of functional symptoms include bowel-related disorders – primarily fecal incontinence and ongoing constipation – and pelvic pain or discomfort.

There can also be asymptomatic cases. “A lot of women have what we call silent prolapse,” Dr. Dmochowski said. That is, “they have some degree of loss of support to the bladder, vagina, or uterus, but they’re not symptomatic.” These women may be particularly good candidates for pelvic health physical therapy.
 

Screening and Diagnosis

Because many postmenopausal women stop seeing their ob.gyn, it’s often up to their primary care physician to determine whether their patients are experiencing POP symptoms.

“Women sometimes don’t bring this up with their doctor because they think there’s not enough time, or they’ll be laughed at, or their friends told them this is normal,” Dr. Rabin said. But primary care providers are really in a unique position to be able to ask the key symptom questions.

Dr. Rabin recommends a couple of questions to cover all the bases: “Do you leak urine when you cough or sneeze or on the way to the bathroom? Do you notice a bulge coming out of the vagina, or are you bothered by pelvic pressure?”

Dr. Dmochowski offered a single question that can open the conversation to more questions: “Are you bothered by any urinary or bowel or vaginal issues that we should talk about?” He also suggests asking how bothersome the symptoms are, which can help in directing treatment or prevention options. A physical exam can reveal signs of POP as well.

Diagnosis involves a detailed history, a comprehensive physical exam, and assessment with the Pelvic Organ Prolapse Quantification (POP-Q) tool. A urogynecologist can diagnose the type of POP – such as cystocele, rectocele, enterocele, uterine prolapse, or vaginal vault prolapse – and its grade (0-4).
 

Treatment: Physical Therapy, Pessary, and Surgery

No medications can treat prolapse, though some can treat downstream effects, such as hormonal vaginal creams for vaginal dryness and irritation, and medications for urinary incontinence. However, two mistakes PCPs can make are sending someone straight to surgery or prescribing them medication for symptoms without referring them for a diagnostic evaluation, Dr. Rabin said. “You have to have a diagnosis first to know what type of prolapse is there,” she said.

Because there can be long waiting lists for a urogynecologist or urologist, PCPs should also refer their patients to a pelvic health physical therapist (PT) who can help patients begin addressing the symptoms while they await a specialist who can diagnose them.

Though PT is often thought of as preventive, it’s also a conservative first-line intervention for prolapse, Dr. Nwabuebo said. Strong evidence shows pelvic floor muscle training from pelvic health PT can reduce symptoms of prolapse and reduce the severity by one grade in those with a grade 1 or 2 prolapse. Stage 3 is trickier, where PT may or may not be able to shift the symptom presentation, Dr. Nwabeubo said, and stage 4 is usually a surgical candidate.

“If you have a grade 4 prolapse, or the tissues are really visible outside the body, physical therapy and pelvic floor muscle training is not going to elevate that tissue back up into your body, but it can sometimes help with symptoms,” Dr. LaCross said.

The PT conducts a thorough pelvic muscle assessment, discusses lifestyle, and may teach breathing and bracing strategies for lifting, for example.

“A lot of what we’re talking about with pelvic floor therapy is lifestyle modifications,” Dr. Nwabuebo said. “If I have a patient with a history of chronic constipation, it doesn’t matter how much we do pelvic floor exercises; if we don’t manage the constipation issues by addressing their nutrition, then straining when using the bathroom will keep putting pressure on the pelvic floor.”

PTs can also recommend appropriate vaginal weights and dilators to help with pelvic floor strengthening and teach patients how to use them properly.

Even if women ultimately opt for surgery, PT prior to surgery can be beneficial. Dr. Rabin cited three reasons she recommends first-line PT: It may elevate the bladder enough to reduce stress incontinence and thicken the pelvic muscles, it can improve the effectiveness of a pessary or surgery if the woman chooses one of those options, and it can quiet bladder contractions, potentially obviating the need for pharmacologic treatment for overactive bladder.

The next nonsurgical option is a pessary, a device that fits into the vagina to provide support to the tissues displaced by prolapse. There’s a wide range of pessary types: some are short-term, worn only daily, or disposable, while others can be worn longer. Some women can self-insert and remove the pessary, and others may need a clinician to do so. Dr. Dmochowski recommends patients try a pessary to see if it benefits them. About a third of women will find them comfortable enough to wear regularly, but others will feel more sensitive to the pessary’s presence, he said.

One of the newest, most innovative pessary options for women is Gynethotics, which received Food and Drug Administration (FDA) clearance in March, as the first 3D-printed, customizable pessary capable of nearly 10 million configurations based on a person’s body.

Nearly all stage 4 prolapses and most of stage 3 prolapses can be addressed only through transvaginal or transabdominal surgery.

“We tell patients, if you can get 10 years out of your operation, you’re lucky,” Dr. Dmochowski said. A major reason for the short-lived durability is the poor quality of the tissue that needs to be pulled together. Serious complications resulting from use of polypropylene mesh during prolapse surgery led the FDA to halt sales of the devices and recommend discontinuing their use. However, one type of vaginal mesh is still considered safe to use in sacral colpopexy surgery.

Three things can shorten the durability of the surgery, Dr. Dmochowski said: heavy lifting, particularly anything over 30 pounds; chronic coughing, such as in those with chronic lung conditions; and chronic constipation.

Ms. Palm tried a pessary for her grade 3 prolapse with cystocele, rectocele, and enterocele but didn’t feel she had the time to use it regularly, so she opted for surgery. After a week on the couch recovering, she took it easy for another 12 weeks. Since then, she’s dedicated much of her time to educating and supporting women with POP and combating stigma associated with it. The APOPS website that she started has become a valuable resource for PCPs to send patients to, and the forum includes more 27,000 women from around the world.

“We encourage women to share what they’re experiencing. Tell your family, tell your friends, tell the people you work with about it,” Ms. Palm said. But many still feel uncomfortable speaking up, making PCPs’ role even more important.

*This story was updated on May 14, 2024.

Sherrie Palm, a patient advocate in Mukwonago, Wisconsin, learned in her 30s that she needed to educate herself about her own health. So when she discovered a walnut-sized lump coming out of her vagina in her mid-50s, she was stunned when her primary care provider (PCP) told her it was pelvic organ prolapse (POP), where one or more organs descend into the vaginal cavity.

“I was shocked,” Ms. Palm said. After searching online and discovering how prevalent POP was, her shock turned to anger. “I was blown away that it could be this common and I’d never heard of it,” she said. “I knew within 2 weeks that I had to do something to change the status quo.”

Ms. Palm eventually founded the nonprofit Association for Pelvic Organ Prolapse Support, or APOPS, complete with a forum where women can learn about POP and support one another. She said awareness has improved substantially since her diagnosis in 2007, but “we have a long way to go” because POP and vaginal health in general are so stigmatized.

Her website notes that about half of women with incontinence do not seek help, largely because of stigma. “The status quo is that PCPs do not POP screen,” she said. ObGyns may screen but often “because the patient has asked to be screened, they say it’s not that bad, come back and see me in a year, and do your Kegels,” Ms. Palm said.

Doctors who diagnose POP agree that the issue is often off PCPs’ radar.

“Primary care doctors are really in a time crunch, so this is one of the things that may not get addressed,” Jill Rabin, MD, vice chair of education and development in obstetrics and gynecology at Northwell Health in New York, said. Dr. Rabin is also head of urogynecology at Long Island Jewish Medical Center.

Ann Nwabuebo, PT, DPT, owner and founder of Body Connect Physical Therapy in Bethesda, Maryland, said social media has been shifting the attitude that pelvic health is a taboo subject. “It’s empowering people to seek care if they’re not finding physicians who are helping.”

But social media is also a double-edged sword, said Jenny LaCross, PT, DPT, PhD, a physical therapist at MOVE PT in Monroe, Michigan, and a postdoctoral research fellow with Michigan Medicine’s Pelvic Floor Research Group. “Pelvic health in general is talked about a lot more, but there’s also a lot more misinformation,” she said.

Part of that misinformation is the idea that pelvic prolapse is solely about weakness in the pelvic floor when it can also result from a widening of natural openings within the pelvis, Dr. LaCross said. She pointed to the two definitions of pelvic organ prolapse by the International Urogynecologic Consultation and the International Continence Society, both of which have been updated in recent years.

“This is why this is challenging for primary care providers,” Dr. LaCross said. “Even urogynecologists who are the specialists that treat prolapse and incontinence have changed how they assess it and the terminology and criteria that they use.”

What hasn’t changed is the substantial negative impact POP can have on quality of life. “This is the second most common reason that women enter nursing homes,” primarily because of urinary incontinence, Dr. Rabin said. “It’s very debilitating, but a lot of it is preventable and a lot is treatable.”

Dr. Rabin estimated that three out of every five women older than 60 and one or two out of every five women younger than 60 experience POP. Prevalence studies vary widely, from nearly a quarter of women to more than half, and racial and ethnic disparities in diagnosis further complicate the statistics.

PCPs therefore have an important role to play in screening for POP. The evidence shows that “patients want their providers to bring this up,” Dr. LaCross said. “They want to talk about it, but they want the provider to ask the questions first.”
 

Causes, Risk Factors, and Symptoms

Many causes contribute to POP, with gravity, aging, childbirth, and menopause at the top of the list.

“As people get older, their pelvic muscles and connective tissue get weaker, and the nerves don’t function as well,” Dr. Rabin said. Meanwhile, the body is losing estrogen, which affects how well the muscles contract and how easily the connective tissue can tear, she said.

With menopause, when baseline estrogen is lower, the tissue integrity is not as supportive as it should be and women are going to be at an increased risk of prolapse, Dr. Nwabuebo said.

POP has a range of risk factors:

• Increasing age, as muscle mass decreases and connective tissue hardens.
• Menopause.
• Vaginal delivery with complications, such as long second-stage labor, instrument-assisted delivery, multiple vaginal lacerations, and improperly repaired episiotomy.
• Multiple vaginal deliveries.
• Birthing large babies.
• Family history of pelvic organ prolapse (genetics can play a role in POP risk).
• Previous pelvic/abdominal surgery, including cesarean delivery and hysterectomy.
• Smoking (largely because of associated coughing).
• Chronic lung conditions that cause a lot of coughing.
• Chronic constipation or irritable bowel syndrome.
• Some types of high-impact activity, such as jogging or marathon running.
• Early menopause, for younger women.
• Repetitive heavy lifting in daily activities, such as occupational lifting (though not necessarily weight lifting as an exercise).
• Higher body mass index.
• Connective tissue disorders, such as joint hypermobility syndrome or Ehlers-Danlos syndrome.

Roger Dmochowski, MD, professor of urology and surgery at Vanderbilt University Medical Center, groups POP symptoms into two groups: anatomic and functional ones. A common anatomic symptom is bulging. “They’ll describe sitting on a ball, feeling like their bladder or something’s falling out, feeling a pressure or a heaviness,” Dr. Dmochowski said.

Functional symptoms can include vaginal dryness, vaginal irritation, painful intercourse, contact of the vaginal tissues with underclothes, and associated urinary symptoms, such as stress incontinence, urge incontinence, and incomplete emptying of the bladder. Dr. Dmochowski noted that women who report urinary incontinence may be at risk for being prescribed a medication without the necessary referral to a specialist for a full gynecologic evaluation.

Two other groups of functional symptoms include bowel-related disorders – primarily fecal incontinence and ongoing constipation – and pelvic pain or discomfort.

There can also be asymptomatic cases. “A lot of women have what we call silent prolapse,” Dr. Dmochowski said. That is, “they have some degree of loss of support to the bladder, vagina, or uterus, but they’re not symptomatic.” These women may be particularly good candidates for pelvic health physical therapy.
 

Screening and Diagnosis

Because many postmenopausal women stop seeing their ob.gyn, it’s often up to their primary care physician to determine whether their patients are experiencing POP symptoms.

“Women sometimes don’t bring this up with their doctor because they think there’s not enough time, or they’ll be laughed at, or their friends told them this is normal,” Dr. Rabin said. But primary care providers are really in a unique position to be able to ask the key symptom questions.

Dr. Rabin recommends a couple of questions to cover all the bases: “Do you leak urine when you cough or sneeze or on the way to the bathroom? Do you notice a bulge coming out of the vagina, or are you bothered by pelvic pressure?”

Dr. Dmochowski offered a single question that can open the conversation to more questions: “Are you bothered by any urinary or bowel or vaginal issues that we should talk about?” He also suggests asking how bothersome the symptoms are, which can help in directing treatment or prevention options. A physical exam can reveal signs of POP as well.

Diagnosis involves a detailed history, a comprehensive physical exam, and assessment with the Pelvic Organ Prolapse Quantification (POP-Q) tool. A urogynecologist can diagnose the type of POP – such as cystocele, rectocele, enterocele, uterine prolapse, or vaginal vault prolapse – and its grade (0-4).
 

Treatment: Physical Therapy, Pessary, and Surgery

No medications can treat prolapse, though some can treat downstream effects, such as hormonal vaginal creams for vaginal dryness and irritation, and medications for urinary incontinence. However, two mistakes PCPs can make are sending someone straight to surgery or prescribing them medication for symptoms without referring them for a diagnostic evaluation, Dr. Rabin said. “You have to have a diagnosis first to know what type of prolapse is there,” she said.

Because there can be long waiting lists for a urogynecologist or urologist, PCPs should also refer their patients to a pelvic health physical therapist (PT) who can help patients begin addressing the symptoms while they await a specialist who can diagnose them.

Though PT is often thought of as preventive, it’s also a conservative first-line intervention for prolapse, Dr. Nwabuebo said. Strong evidence shows pelvic floor muscle training from pelvic health PT can reduce symptoms of prolapse and reduce the severity by one grade in those with a grade 1 or 2 prolapse. Stage 3 is trickier, where PT may or may not be able to shift the symptom presentation, Dr. Nwabeubo said, and stage 4 is usually a surgical candidate.

“If you have a grade 4 prolapse, or the tissues are really visible outside the body, physical therapy and pelvic floor muscle training is not going to elevate that tissue back up into your body, but it can sometimes help with symptoms,” Dr. LaCross said.

The PT conducts a thorough pelvic muscle assessment, discusses lifestyle, and may teach breathing and bracing strategies for lifting, for example.

“A lot of what we’re talking about with pelvic floor therapy is lifestyle modifications,” Dr. Nwabuebo said. “If I have a patient with a history of chronic constipation, it doesn’t matter how much we do pelvic floor exercises; if we don’t manage the constipation issues by addressing their nutrition, then straining when using the bathroom will keep putting pressure on the pelvic floor.”

PTs can also recommend appropriate vaginal weights and dilators to help with pelvic floor strengthening and teach patients how to use them properly.

Even if women ultimately opt for surgery, PT prior to surgery can be beneficial. Dr. Rabin cited three reasons she recommends first-line PT: It may elevate the bladder enough to reduce stress incontinence and thicken the pelvic muscles, it can improve the effectiveness of a pessary or surgery if the woman chooses one of those options, and it can quiet bladder contractions, potentially obviating the need for pharmacologic treatment for overactive bladder.

The next nonsurgical option is a pessary, a device that fits into the vagina to provide support to the tissues displaced by prolapse. There’s a wide range of pessary types: some are short-term, worn only daily, or disposable, while others can be worn longer. Some women can self-insert and remove the pessary, and others may need a clinician to do so. Dr. Dmochowski recommends patients try a pessary to see if it benefits them. About a third of women will find them comfortable enough to wear regularly, but others will feel more sensitive to the pessary’s presence, he said.

One of the newest, most innovative pessary options for women is Gynethotics, which received Food and Drug Administration (FDA) clearance in March, as the first 3D-printed, customizable pessary capable of nearly 10 million configurations based on a person’s body.

Nearly all stage 4 prolapses and most of stage 3 prolapses can be addressed only through transvaginal or transabdominal surgery.

“We tell patients, if you can get 10 years out of your operation, you’re lucky,” Dr. Dmochowski said. A major reason for the short-lived durability is the poor quality of the tissue that needs to be pulled together. Serious complications resulting from use of polypropylene mesh during prolapse surgery led the FDA to halt sales of the devices and recommend discontinuing their use. However, one type of vaginal mesh is still considered safe to use in sacral colpopexy surgery.

Three things can shorten the durability of the surgery, Dr. Dmochowski said: heavy lifting, particularly anything over 30 pounds; chronic coughing, such as in those with chronic lung conditions; and chronic constipation.

Ms. Palm tried a pessary for her grade 3 prolapse with cystocele, rectocele, and enterocele but didn’t feel she had the time to use it regularly, so she opted for surgery. After a week on the couch recovering, she took it easy for another 12 weeks. Since then, she’s dedicated much of her time to educating and supporting women with POP and combating stigma associated with it. The APOPS website that she started has become a valuable resource for PCPs to send patients to, and the forum includes more 27,000 women from around the world.

“We encourage women to share what they’re experiencing. Tell your family, tell your friends, tell the people you work with about it,” Ms. Palm said. But many still feel uncomfortable speaking up, making PCPs’ role even more important.

*This story was updated on May 14, 2024.

A contentious scientific debate is clouding prospects for a deeper understanding of the microbiome’s role in cancer, a relatively young field of research that some believe could lead to breakthroughs in the diagnosis and treatment of the second-leading cause of death in the United States. 

Last year, the controversy heightened when experts questioned a high-profile study — a 2020 analysis claiming that the tumors of 33 different cancers had their own unique microbiomes — on whether the “signature” of these bacterial compositions could help diagnose cancer.

The incident renewed the spotlight on “tumor microbiomes” because of the bold claims of the original paper and the strongly worded refutations of those claims. The broader field has focused primarily on ways the body’s microbiome interacts with cancers and cancer treatment.

This controversy has highlighted the challenges of making headway in a field where researchers may not even have the tools yet to puzzle-out the wide-ranging implications the microbiome holds for cancer diagnosis and treatment.

But it is also part of a provocative question within that larger field: whether tumors in the body, far from the natural microbiome in the gut, have their own thriving communities of bacteria, viruses, and fungi. And, if they do, how do those tumor microbiomes affect the development and progression of the cancer and the effectiveness of cancer therapies? 
 

Cancer Controversy

The evidence is undeniable that some microbes can directly cause certain cancers and that the human gut microbiome can influence the effectiveness of certain therapies. Beyond that established science, however, the research has raised as many questions as answers about what we do and don’t know about microbiota and cancer.

The only confirmed microbiomes are on the skin and in the gut, mouth, and vagina, which are all areas with an easy direct route for bacteria to enter and grow in or on the body. A series of papers in recent years have suggested that other internal organs, and tumors within them, may have their own microbiomes. 

“Whether microbes exist in tumors of internal organs beyond body surfaces exposed to the environment is a different matter,” said Ivan Vujkovic-Cvijin, PhD, an assistant professor of biomedical sciences and gastroenterology at Cedars-Sinai Medical Center in Los Angeles, whose lab studies how human gut microbes affect inflammatory diseases. “We’ve only recently had the tools to study that question on a molecular level, and the reported results have been conflicting.” 

For example, research allegedly identified microbiota in the human placenta nearly one decade ago. But subsequent research contradicted those claims and showed that the source of the “placental microbiome” was actually contamination. Subsequent similar studies for other parts of the body faced the same scrutiny and, often, eventual debunking.

“Most likely, our immune system has undergone selective pressure to eliminate everything that crosses the gut barrier because there’s not much benefit to the body to have bacteria run amok in our internal organs,” Dr. Vujkovic-Cvijin said. “That can only disrupt the functioning of our tissues, to have an external organism living inside them.” 

The controversy that erupted last summer, surrounding research from the lab of Rob Knight, PhD, at the University of California, San Diego, centered on a slightly different but related question: Could tumors harbor their own microbiomes?

This news organization spoke with two of the authors who published a paper contesting Dr. Knight’s findings: Steven Salzberg, PhD, a professor of biomedical engineering at John Hopkins Medicine, Baltimore, Maryland, and Abraham Gihawi, PhD, a research fellow at Norwich Medical School at the University of East Anglia in the United Kingdom. 

Dr. Salzberg described two major problems with Dr. Knight’s study. 

“What they found were false positives because of contamination in the database and flaws in their methods,” Dr. Salzberg said. “I can’t prove there’s no cancer microbiome, but I can say the cancer microbiomes that they reported don’t exist because the species they were finding aren’t there.”

Dr. Knight disagrees with Dr. Salzberg’s findings, noting that Dr. Salzberg and his co-authors did not examine the publicly available databases used in his study. In a written response, he said that his team’s examination of the database revealed that less than 1% of the microbial genomes overlapped with human ones and that removing them did not change their findings.

Dr. Knight also noted that his team could still “distinguish cancer types by their microbiome” even after running their analysis without the technique that Dr. Salzberg found fault with.

Dr. Salzberg said that the database linked above is not the one Dr. Knight’s study used, however. “The primary database in their study was never made public (it’s too large, they said), and it has/had about 69,000 genomes,” Dr. Salzberg said by email. “But even if we did, this is irrelevant. He’s trying to distract from the primary errors in their study,” which Dr. Salzberg said Dr. Knight’s team has not addressed. 

The critiques Dr. Salzberg raised have been leveled at other studies investigating microbiomes specifically within tumors and independent of the body’s microbiome.

For example, a 2019 study in Nature described a fungal microbiome in pancreatic cancer that a Nature paper 4 years later directly contradicted, citing flaws that invalidated the original findings. A different 2019 study in Cell examined pancreatic tumor microbiota and patient outcomes, but it’s unclear whether the microorganisms moved from the gut to the pancreas or “constitute a durably colonized community that lives inside the tumor,” which remains a matter of debate, Dr. Vujkovic-Cvijin said.

A 2020 study in Science suggested diverse microbial communities in seven tumor types, but those findings were similarly called into question. That study stated that “bacteria were first detected in human tumors more than 100 years ago” and that “bacteria are well-known residents in human tumors,” but Dr. Salzberg considers those statements misleading. 

It’s true that bacteria and viruses have been detected in tumors because “there’s very good evidence that an acute infection caused by a very small number of viruses and bacteria can cause a tumor,” Dr. Salzberg said. Human papillomavirus, for example, can cause six different types of cancer. Inflammation and ulcers caused by Helicobacter pylori may progress to stomach cancer, and Fusobacterium nucleatum and Enterococcus faecalis have been shown to contribute to colorectal cancer. Those examples differ from a microbiome; this “a community of bacteria and possibly other microscopic bugs, like fungi, that are happily living in the tumor” the same way microbes reside in our guts, he said.

Dr. Knight said that many bacteria his team identified “have been confirmed independently in subsequent work.” He acknowledged, however, that more research is needed. 

Several of the contested studies above were among a lengthy list that Dr. Knight provided, noting that most of the disagreements “have two sides to them, and critiques from one particular group does not immediately invalidate a reported finding.” 

Yet, many of the papers Dr. Knight listed are precisely the types that skeptics like Dr. Salzberg believe are too flawed to draw reliable conclusions. 

“I think many agree that microbes may exist within tumors that are exposed to the environment, like tumors of the skin, gut, and mouth,” Dr. Vujkovic-Cvijin said. It’s less clear, however, whether tumors further from the body’s microbiome harbor any microbes or where they came from if they do. Microbial signals in organs elsewhere in the body become faint quickly, he said.
 

Underdeveloped Technology 

Though Dr. Salzberg said that the concept of a tumor microbiome is “implausible” because there’s no easy route for bacteria to reach internal organs, it’s unclear whether scientists have the technology yet to adequately answer this question. 

For one thing, samples in these types of studies are typically “ultra-low biomass samples, where the signal — the amount of microbes in the sample — is so low that it’s comparable to how much would be expected to be found in reagents and environmental contamination through processing,” Dr. Vujkovic-Cvijin explained. Many polymerases used to amplify a DNA signal, for example, are made in bacteria and may retain trace amounts identified in these studies. 

Dr. Knight agreed that low biomass is a challenge in this field but is not an unsurmountable one. 

Another challenge is that study samples, as with Dr. Knight’s work, were collected during routine surgeries without the intent to find a microbial signal. Simply using a scalpel to cut through the skin means cutting through a layer of bacteria, and surgery rooms are not designed to eliminate all bacteria. Some work has even shown there is a “hospital microbiome,” so “you can easily have that creep into your signal and mistake it for tumor-resident bacteria,” Dr. Vujkovic-Cvijin said. 

Dr. Knight asserted that the samples are taken under sterile conditions, but other researchers do not think the level of sterility necessary for completely clean samples is possible. 

“Just because it’s in your sample doesn’t mean it was in your tumor,” Dr. Gihawi said.

Even if scientists can retrieve a reliable sample without contamination, analyzing it requires comparing the genetic material to existing databases of microbial genomes. Yet, contamination and misclassification of genetic sequences can be problems in those reference genomes too, Dr. Gihawi explained.

Machine learning algorithms have a role in interpreting data, but “we need to be careful of what we use them for,” he added.

“These techniques are in their infancy, and we’re starting to chase them down, which is why we need to move microbiome research in a way that can be used clinically,” Dr. Gihawi said. 
 

Influence on Cancer Treatment Outcomes

Again, however, the question of whether microbiomes exist within tumors is only one slice of the much larger field looking at microbiomes and cancer, including its influence on cancer treatment outcomes. Although much remains to be learned, less controversy exists over the thousands of studies in the past two decades that have gradually revealed how the body’s microbiome can affect both the course of a cancer and the effectiveness of different treatments.

The growing research showing the importance of the gut microbiome in cancer treatments is not surprising given its role in immunity more broadly. Because the human immune system must recognize and defend against microbes, the microbiome helps train it, Dr. Vujkovic-Cvijin said. 

Some bacteria can escape the gut — a phenomenon called bacterial translocation — and may aid in fighting tumors. To grow large enough to be seen on imaging, tumors need to evolve several abilities, such as growing enough vascularization to receive blood flow and shutting down local immune responses.

“Any added boost, like immunotherapy, has a chance of breaking through that immune forcefield and killing the tumor cells,” Dr. Vujkovic-Cvijin said. Escaped gut bacteria may provide that boost. 

“There’s a lot of evidence that depletion of the gut microbiome impairs immunotherapy and chemotherapy. The thinking behind some of those studies is that gut microbes can cross the gut barrier and when they do, they activate the immune system,” he said. 

In mice engineered to have sterile guts, for example, the lack of bacteria results in less effective immune systems, Dr. Vujkovic-Cvijin pointed out. A host of research has shown that antibiotic exposure during and even 6 months before immunotherapy dramatically reduces survival rates. “That’s pretty convincing to me that gut microbes are important,” he said. 

Dr. Vujkovic-Cvijin cautioned that there continues to be controversy on understanding which bacteria are important for response to immunotherapy. “The field is still in its infancy in terms of understanding which bacteria are most important for these effects,” he said.

Dr. Knight suggested that escaped bacteria may be the genesis of the ones that he and other researchers believe exist in tumors. “Because tumor microbes must come from somewhere, it is to be expected that some of those microbes will be co-opted from body-site specific commensals.”

It’s also possible that metabolites released from gut bacteria escape the gut and could theoretically affect distant tumor growth, Dr. Gihawi said. The most promising avenue of research in this area is metabolites being used as biomarkers, added Dr. Gihawi, whose lab published research on a link between bacteria detected in men’s urine and a more aggressive subset of prostate cancers. But that research is not far enough along to develop lab tests for clinical use, he noted. 
 

No Consensus Yet

Even before the controversy erupted around Dr. Knight’s research, he co-founded the company Micronoma to develop cancer tests based on his microbe findings. The company has raised $17.5 million from private investors as of August 2023 and received the US Food and Drug Administration’s Breakthrough Device designation, allowing the firm to fast-track clinical trials testing the technology. The recent critiques have not changed the company’s plans. 

It’s safe to say that scientists will continue to research and debate the possibility of tumor microbiomes until a consensus emerges. 

“The field is evolving and studies testing the reproducibility of tumor-resident microbial signals are essential for developing our understanding in this area,” Dr. Vujkovic-Cvijin said.

Even if that path ultimately leads nowhere, as Dr. Salzberg expects, research into microbiomes and cancer has plenty of other directions to go.

“I’m actually quite an optimist,” Dr. Gihawi said. “I think there’s a lot of scope for some really good research here, especially in the sites where we know there is a strong microbiome, such as the gastrointestinal tract.”

A version of this article appeared on Medscape.com.

A contentious scientific debate is clouding prospects for a deeper understanding of the microbiome’s role in cancer, a relatively young field of research that some believe could lead to breakthroughs in the diagnosis and treatment of the second-leading cause of death in the United States. 

Last year, the controversy heightened when experts questioned a high-profile study — a 2020 analysis claiming that the tumors of 33 different cancers had their own unique microbiomes — on whether the “signature” of these bacterial compositions could help diagnose cancer.

The incident renewed the spotlight on “tumor microbiomes” because of the bold claims of the original paper and the strongly worded refutations of those claims. The broader field has focused primarily on ways the body’s microbiome interacts with cancers and cancer treatment.

This controversy has highlighted the challenges of making headway in a field where researchers may not even have the tools yet to puzzle-out the wide-ranging implications the microbiome holds for cancer diagnosis and treatment.

But it is also part of a provocative question within that larger field: whether tumors in the body, far from the natural microbiome in the gut, have their own thriving communities of bacteria, viruses, and fungi. And, if they do, how do those tumor microbiomes affect the development and progression of the cancer and the effectiveness of cancer therapies? 
 

Cancer Controversy

The evidence is undeniable that some microbes can directly cause certain cancers and that the human gut microbiome can influence the effectiveness of certain therapies. Beyond that established science, however, the research has raised as many questions as answers about what we do and don’t know about microbiota and cancer.

The only confirmed microbiomes are on the skin and in the gut, mouth, and vagina, which are all areas with an easy direct route for bacteria to enter and grow in or on the body. A series of papers in recent years have suggested that other internal organs, and tumors within them, may have their own microbiomes. 

“Whether microbes exist in tumors of internal organs beyond body surfaces exposed to the environment is a different matter,” said Ivan Vujkovic-Cvijin, PhD, an assistant professor of biomedical sciences and gastroenterology at Cedars-Sinai Medical Center in Los Angeles, whose lab studies how human gut microbes affect inflammatory diseases. “We’ve only recently had the tools to study that question on a molecular level, and the reported results have been conflicting.” 

For example, research allegedly identified microbiota in the human placenta nearly one decade ago. But subsequent research contradicted those claims and showed that the source of the “placental microbiome” was actually contamination. Subsequent similar studies for other parts of the body faced the same scrutiny and, often, eventual debunking.

“Most likely, our immune system has undergone selective pressure to eliminate everything that crosses the gut barrier because there’s not much benefit to the body to have bacteria run amok in our internal organs,” Dr. Vujkovic-Cvijin said. “That can only disrupt the functioning of our tissues, to have an external organism living inside them.” 

The controversy that erupted last summer, surrounding research from the lab of Rob Knight, PhD, at the University of California, San Diego, centered on a slightly different but related question: Could tumors harbor their own microbiomes?

This news organization spoke with two of the authors who published a paper contesting Dr. Knight’s findings: Steven Salzberg, PhD, a professor of biomedical engineering at John Hopkins Medicine, Baltimore, Maryland, and Abraham Gihawi, PhD, a research fellow at Norwich Medical School at the University of East Anglia in the United Kingdom. 

Dr. Salzberg described two major problems with Dr. Knight’s study. 

“What they found were false positives because of contamination in the database and flaws in their methods,” Dr. Salzberg said. “I can’t prove there’s no cancer microbiome, but I can say the cancer microbiomes that they reported don’t exist because the species they were finding aren’t there.”

Dr. Knight disagrees with Dr. Salzberg’s findings, noting that Dr. Salzberg and his co-authors did not examine the publicly available databases used in his study. In a written response, he said that his team’s examination of the database revealed that less than 1% of the microbial genomes overlapped with human ones and that removing them did not change their findings.

Dr. Knight also noted that his team could still “distinguish cancer types by their microbiome” even after running their analysis without the technique that Dr. Salzberg found fault with.

Dr. Salzberg said that the database linked above is not the one Dr. Knight’s study used, however. “The primary database in their study was never made public (it’s too large, they said), and it has/had about 69,000 genomes,” Dr. Salzberg said by email. “But even if we did, this is irrelevant. He’s trying to distract from the primary errors in their study,” which Dr. Salzberg said Dr. Knight’s team has not addressed. 

The critiques Dr. Salzberg raised have been leveled at other studies investigating microbiomes specifically within tumors and independent of the body’s microbiome.

For example, a 2019 study in Nature described a fungal microbiome in pancreatic cancer that a Nature paper 4 years later directly contradicted, citing flaws that invalidated the original findings. A different 2019 study in Cell examined pancreatic tumor microbiota and patient outcomes, but it’s unclear whether the microorganisms moved from the gut to the pancreas or “constitute a durably colonized community that lives inside the tumor,” which remains a matter of debate, Dr. Vujkovic-Cvijin said.

A 2020 study in Science suggested diverse microbial communities in seven tumor types, but those findings were similarly called into question. That study stated that “bacteria were first detected in human tumors more than 100 years ago” and that “bacteria are well-known residents in human tumors,” but Dr. Salzberg considers those statements misleading. 

It’s true that bacteria and viruses have been detected in tumors because “there’s very good evidence that an acute infection caused by a very small number of viruses and bacteria can cause a tumor,” Dr. Salzberg said. Human papillomavirus, for example, can cause six different types of cancer. Inflammation and ulcers caused by Helicobacter pylori may progress to stomach cancer, and Fusobacterium nucleatum and Enterococcus faecalis have been shown to contribute to colorectal cancer. Those examples differ from a microbiome; this “a community of bacteria and possibly other microscopic bugs, like fungi, that are happily living in the tumor” the same way microbes reside in our guts, he said.

Dr. Knight said that many bacteria his team identified “have been confirmed independently in subsequent work.” He acknowledged, however, that more research is needed. 

Several of the contested studies above were among a lengthy list that Dr. Knight provided, noting that most of the disagreements “have two sides to them, and critiques from one particular group does not immediately invalidate a reported finding.” 

Yet, many of the papers Dr. Knight listed are precisely the types that skeptics like Dr. Salzberg believe are too flawed to draw reliable conclusions. 

“I think many agree that microbes may exist within tumors that are exposed to the environment, like tumors of the skin, gut, and mouth,” Dr. Vujkovic-Cvijin said. It’s less clear, however, whether tumors further from the body’s microbiome harbor any microbes or where they came from if they do. Microbial signals in organs elsewhere in the body become faint quickly, he said.
 

Underdeveloped Technology 

Though Dr. Salzberg said that the concept of a tumor microbiome is “implausible” because there’s no easy route for bacteria to reach internal organs, it’s unclear whether scientists have the technology yet to adequately answer this question. 

For one thing, samples in these types of studies are typically “ultra-low biomass samples, where the signal — the amount of microbes in the sample — is so low that it’s comparable to how much would be expected to be found in reagents and environmental contamination through processing,” Dr. Vujkovic-Cvijin explained. Many polymerases used to amplify a DNA signal, for example, are made in bacteria and may retain trace amounts identified in these studies. 

Dr. Knight agreed that low biomass is a challenge in this field but is not an unsurmountable one. 

Another challenge is that study samples, as with Dr. Knight’s work, were collected during routine surgeries without the intent to find a microbial signal. Simply using a scalpel to cut through the skin means cutting through a layer of bacteria, and surgery rooms are not designed to eliminate all bacteria. Some work has even shown there is a “hospital microbiome,” so “you can easily have that creep into your signal and mistake it for tumor-resident bacteria,” Dr. Vujkovic-Cvijin said. 

Dr. Knight asserted that the samples are taken under sterile conditions, but other researchers do not think the level of sterility necessary for completely clean samples is possible. 

“Just because it’s in your sample doesn’t mean it was in your tumor,” Dr. Gihawi said.

Even if scientists can retrieve a reliable sample without contamination, analyzing it requires comparing the genetic material to existing databases of microbial genomes. Yet, contamination and misclassification of genetic sequences can be problems in those reference genomes too, Dr. Gihawi explained.

Machine learning algorithms have a role in interpreting data, but “we need to be careful of what we use them for,” he added.

“These techniques are in their infancy, and we’re starting to chase them down, which is why we need to move microbiome research in a way that can be used clinically,” Dr. Gihawi said. 
 

Influence on Cancer Treatment Outcomes

Again, however, the question of whether microbiomes exist within tumors is only one slice of the much larger field looking at microbiomes and cancer, including its influence on cancer treatment outcomes. Although much remains to be learned, less controversy exists over the thousands of studies in the past two decades that have gradually revealed how the body’s microbiome can affect both the course of a cancer and the effectiveness of different treatments.

The growing research showing the importance of the gut microbiome in cancer treatments is not surprising given its role in immunity more broadly. Because the human immune system must recognize and defend against microbes, the microbiome helps train it, Dr. Vujkovic-Cvijin said. 

Some bacteria can escape the gut — a phenomenon called bacterial translocation — and may aid in fighting tumors. To grow large enough to be seen on imaging, tumors need to evolve several abilities, such as growing enough vascularization to receive blood flow and shutting down local immune responses.

“Any added boost, like immunotherapy, has a chance of breaking through that immune forcefield and killing the tumor cells,” Dr. Vujkovic-Cvijin said. Escaped gut bacteria may provide that boost. 

“There’s a lot of evidence that depletion of the gut microbiome impairs immunotherapy and chemotherapy. The thinking behind some of those studies is that gut microbes can cross the gut barrier and when they do, they activate the immune system,” he said. 

In mice engineered to have sterile guts, for example, the lack of bacteria results in less effective immune systems, Dr. Vujkovic-Cvijin pointed out. A host of research has shown that antibiotic exposure during and even 6 months before immunotherapy dramatically reduces survival rates. “That’s pretty convincing to me that gut microbes are important,” he said. 

Dr. Vujkovic-Cvijin cautioned that there continues to be controversy on understanding which bacteria are important for response to immunotherapy. “The field is still in its infancy in terms of understanding which bacteria are most important for these effects,” he said.

Dr. Knight suggested that escaped bacteria may be the genesis of the ones that he and other researchers believe exist in tumors. “Because tumor microbes must come from somewhere, it is to be expected that some of those microbes will be co-opted from body-site specific commensals.”

It’s also possible that metabolites released from gut bacteria escape the gut and could theoretically affect distant tumor growth, Dr. Gihawi said. The most promising avenue of research in this area is metabolites being used as biomarkers, added Dr. Gihawi, whose lab published research on a link between bacteria detected in men’s urine and a more aggressive subset of prostate cancers. But that research is not far enough along to develop lab tests for clinical use, he noted. 
 

No Consensus Yet

Even before the controversy erupted around Dr. Knight’s research, he co-founded the company Micronoma to develop cancer tests based on his microbe findings. The company has raised $17.5 million from private investors as of August 2023 and received the US Food and Drug Administration’s Breakthrough Device designation, allowing the firm to fast-track clinical trials testing the technology. The recent critiques have not changed the company’s plans. 

It’s safe to say that scientists will continue to research and debate the possibility of tumor microbiomes until a consensus emerges. 

“The field is evolving and studies testing the reproducibility of tumor-resident microbial signals are essential for developing our understanding in this area,” Dr. Vujkovic-Cvijin said.

Even if that path ultimately leads nowhere, as Dr. Salzberg expects, research into microbiomes and cancer has plenty of other directions to go.

“I’m actually quite an optimist,” Dr. Gihawi said. “I think there’s a lot of scope for some really good research here, especially in the sites where we know there is a strong microbiome, such as the gastrointestinal tract.”

A version of this article appeared on Medscape.com.

A contentious scientific debate is clouding prospects for a deeper understanding of the microbiome’s role in cancer, a relatively young field of research that some believe could lead to breakthroughs in the diagnosis and treatment of the second-leading cause of death in the United States. 

Last year, the controversy heightened when experts questioned a high-profile study — a 2020 analysis claiming that the tumors of 33 different cancers had their own unique microbiomes — on whether the “signature” of these bacterial compositions could help diagnose cancer.

The incident renewed the spotlight on “tumor microbiomes” because of the bold claims of the original paper and the strongly worded refutations of those claims. The broader field has focused primarily on ways the body’s microbiome interacts with cancers and cancer treatment.

This controversy has highlighted the challenges of making headway in a field where researchers may not even have the tools yet to puzzle-out the wide-ranging implications the microbiome holds for cancer diagnosis and treatment.

But it is also part of a provocative question within that larger field: whether tumors in the body, far from the natural microbiome in the gut, have their own thriving communities of bacteria, viruses, and fungi. And, if they do, how do those tumor microbiomes affect the development and progression of the cancer and the effectiveness of cancer therapies? 
 

Cancer Controversy

The evidence is undeniable that some microbes can directly cause certain cancers and that the human gut microbiome can influence the effectiveness of certain therapies. Beyond that established science, however, the research has raised as many questions as answers about what we do and don’t know about microbiota and cancer.

The only confirmed microbiomes are on the skin and in the gut, mouth, and vagina, which are all areas with an easy direct route for bacteria to enter and grow in or on the body. A series of papers in recent years have suggested that other internal organs, and tumors within them, may have their own microbiomes. 

“Whether microbes exist in tumors of internal organs beyond body surfaces exposed to the environment is a different matter,” said Ivan Vujkovic-Cvijin, PhD, an assistant professor of biomedical sciences and gastroenterology at Cedars-Sinai Medical Center in Los Angeles, whose lab studies how human gut microbes affect inflammatory diseases. “We’ve only recently had the tools to study that question on a molecular level, and the reported results have been conflicting.” 

For example, research allegedly identified microbiota in the human placenta nearly one decade ago. But subsequent research contradicted those claims and showed that the source of the “placental microbiome” was actually contamination. Subsequent similar studies for other parts of the body faced the same scrutiny and, often, eventual debunking.

“Most likely, our immune system has undergone selective pressure to eliminate everything that crosses the gut barrier because there’s not much benefit to the body to have bacteria run amok in our internal organs,” Dr. Vujkovic-Cvijin said. “That can only disrupt the functioning of our tissues, to have an external organism living inside them.” 

The controversy that erupted last summer, surrounding research from the lab of Rob Knight, PhD, at the University of California, San Diego, centered on a slightly different but related question: Could tumors harbor their own microbiomes?

This news organization spoke with two of the authors who published a paper contesting Dr. Knight’s findings: Steven Salzberg, PhD, a professor of biomedical engineering at John Hopkins Medicine, Baltimore, Maryland, and Abraham Gihawi, PhD, a research fellow at Norwich Medical School at the University of East Anglia in the United Kingdom. 

Dr. Salzberg described two major problems with Dr. Knight’s study. 

“What they found were false positives because of contamination in the database and flaws in their methods,” Dr. Salzberg said. “I can’t prove there’s no cancer microbiome, but I can say the cancer microbiomes that they reported don’t exist because the species they were finding aren’t there.”

Dr. Knight disagrees with Dr. Salzberg’s findings, noting that Dr. Salzberg and his co-authors did not examine the publicly available databases used in his study. In a written response, he said that his team’s examination of the database revealed that less than 1% of the microbial genomes overlapped with human ones and that removing them did not change their findings.

Dr. Knight also noted that his team could still “distinguish cancer types by their microbiome” even after running their analysis without the technique that Dr. Salzberg found fault with.

Dr. Salzberg said that the database linked above is not the one Dr. Knight’s study used, however. “The primary database in their study was never made public (it’s too large, they said), and it has/had about 69,000 genomes,” Dr. Salzberg said by email. “But even if we did, this is irrelevant. He’s trying to distract from the primary errors in their study,” which Dr. Salzberg said Dr. Knight’s team has not addressed. 

The critiques Dr. Salzberg raised have been leveled at other studies investigating microbiomes specifically within tumors and independent of the body’s microbiome.

For example, a 2019 study in Nature described a fungal microbiome in pancreatic cancer that a Nature paper 4 years later directly contradicted, citing flaws that invalidated the original findings. A different 2019 study in Cell examined pancreatic tumor microbiota and patient outcomes, but it’s unclear whether the microorganisms moved from the gut to the pancreas or “constitute a durably colonized community that lives inside the tumor,” which remains a matter of debate, Dr. Vujkovic-Cvijin said.

A 2020 study in Science suggested diverse microbial communities in seven tumor types, but those findings were similarly called into question. That study stated that “bacteria were first detected in human tumors more than 100 years ago” and that “bacteria are well-known residents in human tumors,” but Dr. Salzberg considers those statements misleading. 

It’s true that bacteria and viruses have been detected in tumors because “there’s very good evidence that an acute infection caused by a very small number of viruses and bacteria can cause a tumor,” Dr. Salzberg said. Human papillomavirus, for example, can cause six different types of cancer. Inflammation and ulcers caused by Helicobacter pylori may progress to stomach cancer, and Fusobacterium nucleatum and Enterococcus faecalis have been shown to contribute to colorectal cancer. Those examples differ from a microbiome; this “a community of bacteria and possibly other microscopic bugs, like fungi, that are happily living in the tumor” the same way microbes reside in our guts, he said.

Dr. Knight said that many bacteria his team identified “have been confirmed independently in subsequent work.” He acknowledged, however, that more research is needed. 

Several of the contested studies above were among a lengthy list that Dr. Knight provided, noting that most of the disagreements “have two sides to them, and critiques from one particular group does not immediately invalidate a reported finding.” 

Yet, many of the papers Dr. Knight listed are precisely the types that skeptics like Dr. Salzberg believe are too flawed to draw reliable conclusions. 

“I think many agree that microbes may exist within tumors that are exposed to the environment, like tumors of the skin, gut, and mouth,” Dr. Vujkovic-Cvijin said. It’s less clear, however, whether tumors further from the body’s microbiome harbor any microbes or where they came from if they do. Microbial signals in organs elsewhere in the body become faint quickly, he said.
 

Underdeveloped Technology 

Though Dr. Salzberg said that the concept of a tumor microbiome is “implausible” because there’s no easy route for bacteria to reach internal organs, it’s unclear whether scientists have the technology yet to adequately answer this question. 

For one thing, samples in these types of studies are typically “ultra-low biomass samples, where the signal — the amount of microbes in the sample — is so low that it’s comparable to how much would be expected to be found in reagents and environmental contamination through processing,” Dr. Vujkovic-Cvijin explained. Many polymerases used to amplify a DNA signal, for example, are made in bacteria and may retain trace amounts identified in these studies. 

Dr. Knight agreed that low biomass is a challenge in this field but is not an unsurmountable one. 

Another challenge is that study samples, as with Dr. Knight’s work, were collected during routine surgeries without the intent to find a microbial signal. Simply using a scalpel to cut through the skin means cutting through a layer of bacteria, and surgery rooms are not designed to eliminate all bacteria. Some work has even shown there is a “hospital microbiome,” so “you can easily have that creep into your signal and mistake it for tumor-resident bacteria,” Dr. Vujkovic-Cvijin said. 

Dr. Knight asserted that the samples are taken under sterile conditions, but other researchers do not think the level of sterility necessary for completely clean samples is possible. 

“Just because it’s in your sample doesn’t mean it was in your tumor,” Dr. Gihawi said.

Even if scientists can retrieve a reliable sample without contamination, analyzing it requires comparing the genetic material to existing databases of microbial genomes. Yet, contamination and misclassification of genetic sequences can be problems in those reference genomes too, Dr. Gihawi explained.

Machine learning algorithms have a role in interpreting data, but “we need to be careful of what we use them for,” he added.

“These techniques are in their infancy, and we’re starting to chase them down, which is why we need to move microbiome research in a way that can be used clinically,” Dr. Gihawi said. 
 

Influence on Cancer Treatment Outcomes

Again, however, the question of whether microbiomes exist within tumors is only one slice of the much larger field looking at microbiomes and cancer, including its influence on cancer treatment outcomes. Although much remains to be learned, less controversy exists over the thousands of studies in the past two decades that have gradually revealed how the body’s microbiome can affect both the course of a cancer and the effectiveness of different treatments.

The growing research showing the importance of the gut microbiome in cancer treatments is not surprising given its role in immunity more broadly. Because the human immune system must recognize and defend against microbes, the microbiome helps train it, Dr. Vujkovic-Cvijin said. 

Some bacteria can escape the gut — a phenomenon called bacterial translocation — and may aid in fighting tumors. To grow large enough to be seen on imaging, tumors need to evolve several abilities, such as growing enough vascularization to receive blood flow and shutting down local immune responses.

“Any added boost, like immunotherapy, has a chance of breaking through that immune forcefield and killing the tumor cells,” Dr. Vujkovic-Cvijin said. Escaped gut bacteria may provide that boost. 

“There’s a lot of evidence that depletion of the gut microbiome impairs immunotherapy and chemotherapy. The thinking behind some of those studies is that gut microbes can cross the gut barrier and when they do, they activate the immune system,” he said. 

In mice engineered to have sterile guts, for example, the lack of bacteria results in less effective immune systems, Dr. Vujkovic-Cvijin pointed out. A host of research has shown that antibiotic exposure during and even 6 months before immunotherapy dramatically reduces survival rates. “That’s pretty convincing to me that gut microbes are important,” he said. 

Dr. Vujkovic-Cvijin cautioned that there continues to be controversy on understanding which bacteria are important for response to immunotherapy. “The field is still in its infancy in terms of understanding which bacteria are most important for these effects,” he said.

Dr. Knight suggested that escaped bacteria may be the genesis of the ones that he and other researchers believe exist in tumors. “Because tumor microbes must come from somewhere, it is to be expected that some of those microbes will be co-opted from body-site specific commensals.”

It’s also possible that metabolites released from gut bacteria escape the gut and could theoretically affect distant tumor growth, Dr. Gihawi said. The most promising avenue of research in this area is metabolites being used as biomarkers, added Dr. Gihawi, whose lab published research on a link between bacteria detected in men’s urine and a more aggressive subset of prostate cancers. But that research is not far enough along to develop lab tests for clinical use, he noted. 
 

No Consensus Yet

Even before the controversy erupted around Dr. Knight’s research, he co-founded the company Micronoma to develop cancer tests based on his microbe findings. The company has raised $17.5 million from private investors as of August 2023 and received the US Food and Drug Administration’s Breakthrough Device designation, allowing the firm to fast-track clinical trials testing the technology. The recent critiques have not changed the company’s plans. 

It’s safe to say that scientists will continue to research and debate the possibility of tumor microbiomes until a consensus emerges. 

“The field is evolving and studies testing the reproducibility of tumor-resident microbial signals are essential for developing our understanding in this area,” Dr. Vujkovic-Cvijin said.

Even if that path ultimately leads nowhere, as Dr. Salzberg expects, research into microbiomes and cancer has plenty of other directions to go.

“I’m actually quite an optimist,” Dr. Gihawi said. “I think there’s a lot of scope for some really good research here, especially in the sites where we know there is a strong microbiome, such as the gastrointestinal tract.”

A version of this article appeared on Medscape.com.

CORRECTED April 7, 2024 // An earlier version of this article misstated the clinical factors of children with CNO that were significantly associated with the need for second-line treatment, as well as the scope of assessments of aspects of disease involvement and their relationship to total number of days on NSAID monotherapy and the odds of needing a second-line treatment.

Children with chronic nonbacterial osteomyelitis (CNO) who had symmetric bone lesions or multiple affected body regions were more likely to need second-line treatment than were patients without these features, according to findings presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.

CNO is an auto-inflammatory condition that results in sterile inflammatory bone lesions and most commonly affects the long bones of people who are skeletally immature. After a first-line treatment of nonsteroidal anti-inflammatory drugs (NSAIDs), second-line treatments per CARRA guidelines typically include methotrexate or sulfasalazine, tumor necrosis factor (TNF)–alpha inhibitors, and bisphosphonates.

“Since it’s common for there to be long delays before diagnosis of CNO, it is important to start an effective treatment promptly,” Katherine D. Nowicki, MD, of Children’s Hospital Colorado, Aurora, told attendees. “While we have guidance on which treatments to use, it remains unclear which patients are most likely to respond to NSAIDs and which patients will require a second-line treatment.”
 

Findings Helpful for Counseling

Melissa S. Oliver, MD, MS, assistant professor of clinical pediatrics in rheumatology at Riley Children’s Health at Indiana University Health, Indianapolis, who was not involved in the research, said the findings of this study are helpful in “counseling families and patients at that initial visit and having a lower threshold to start a second-line agent if NSAID monotherapy is not working well.”

There are no clinical trials on patients with CNO, Dr. Oliver said, so very little data exist for guiding clinicians on the best therapy to use and how long to keep patients on therapy while minimizing risk for flare when coming off therapy.

A key clinical takeaway for clinicians is being able to tell patients with unifocal disease that they may not need to be on NSAIDs for a long period and can still do well, Dr. Oliver said. For patients with multifocal disease with symmetric bone lesions or multiple regions involved with CNO, “pediatric rheumatologists should have a lower threshold to start a second-line therapy for these patients,” she said.

Oliver_Melissa_IN_web.jpg

Findings From Largest Single-Center Cohort in North America

Their topline findings revealed that patients with unifocal disease at diagnosis required 47% fewer total days of NSAID monotherapy treatment than those with multifocal disease at diagnosis, Dr. Nowicki told attendees. Having symmetric bone lesions increased the likelihood of needing a second-line therapy by 6.86 times compared with those without symmetric bone lesions, and for each additional region affected by CNO, the odds of needing a second-line therapy increased by a factor of 1.94, she said.

There were no significant differences in patient ages or sex or in mean interval from symptom onset to treatment onset across treatment groups. However, patients who received second-line treatment did have a significantly longer average time from symptom onset to diagnosis (324 days) than those who had a short course (119 days) or long course (270 days) of NSAIDs (P = .023). Mean follow-up was also significantly longer for patients with second-line treatment (3.8 years) or long-course NSAIDs (2.7 years) than for those with short-course NSAIDs (1.2 years; P < .001).

Mean erythrocyte sedimentation rate or C-reactive protein did not differ across treatment groups nor did presence of a CNO lesion on x-rays at presentation. But significantly more patients in the second-line group had a biopsy (94%) than in the long-course (74%) or short-course (69%) NSAID groups (P = .0025). They were also more likely to have one or more whole-body MRIs. Most of the patients on short-course (88%) and long-course (82%) NSAIDs did not undergo a whole-body MRI, whereas most patients (59%) on a second-line treatment underwent at least one and 24% underwent three or more MRIs (P < .001).

More patients on short-course NSAIDs had unifocal disease at diagnosis (72%) than those on long-course NSAIDs (47%) or a second-line treatment (41%; P = .015). Patients on a second-line treatment were also more likely to have symmetric involvement in the same bone (73% vs 16% short-course and 23% long-course NSAIDs) and to have more regions of the body affected (P < .001).

There were significant differences in mean days on NSAID monotherapy and number of NSAIDs trialed. Patients on a second-line treatment had a mean 441 days of NSAID monotherapy compared with 175 days for patients on short-course NSAIDs and 725 for patients on long-course NSAIDs (P < .001). Nearly all the short-course patients (94%) trialed a single NSAID, while more than half the long-course and second-line patients trialed two or more (P < .001).

None of the patients on short-course NSAIDs had complications. More patients on second-line treatments had vertebral height loss (20%) or amplified pain (14%) than long-course patients (13% and 5%, respectively; P = .02).

At the study’s end date, nearly all the patients on short-course NSAIDs were in remission (94%) compared with 71% of patients on long-course NSAIDs and only half of patients (51%) on the second-line treatment (P < .001). None of the patients on short-course NSAIDs had active disease compared with 11% of patients on long-course NSAIDs and 20% of patients on second-line treatments (P = .02).

This study included the largest single-center cohort of patients with CNO in North America, all treated at a multidisciplinary clinic with a protocolized treatment approach, but it remains limited by its retrospective nature and the missing data for 70 patients, Dr. Nowicki said. She noted that whole-body MRI was not systematically performed on all patients, so it was possible patients without a whole-body MRI had undetected asymptomatic lesions.

Despite these limitations, Dr. Oliver said retrospective studies like these can help pediatric rheumatologists get an idea of reasonable therapies to start, how long to keep patients on them, and when to escalate to the next step.

“I hope one day our CNO research will be able to tell us about which is the optimal second-line therapy for patients, such as bisphosphonates vs TNF inhibitors vs DMARDs [disease-modifying antirheumatic drugs],” Dr. Oliver said.

Dr. Nowicki and Dr. Oliver reported no disclosures. Information on study funding was not provided.

A version of this article appeared on Medscape.com .

CORRECTED April 7, 2024 // An earlier version of this article misstated the clinical factors of children with CNO that were significantly associated with the need for second-line treatment, as well as the scope of assessments of aspects of disease involvement and their relationship to total number of days on NSAID monotherapy and the odds of needing a second-line treatment.

Children with chronic nonbacterial osteomyelitis (CNO) who had symmetric bone lesions or multiple affected body regions were more likely to need second-line treatment than were patients without these features, according to findings presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.

CNO is an auto-inflammatory condition that results in sterile inflammatory bone lesions and most commonly affects the long bones of people who are skeletally immature. After a first-line treatment of nonsteroidal anti-inflammatory drugs (NSAIDs), second-line treatments per CARRA guidelines typically include methotrexate or sulfasalazine, tumor necrosis factor (TNF)–alpha inhibitors, and bisphosphonates.

“Since it’s common for there to be long delays before diagnosis of CNO, it is important to start an effective treatment promptly,” Katherine D. Nowicki, MD, of Children’s Hospital Colorado, Aurora, told attendees. “While we have guidance on which treatments to use, it remains unclear which patients are most likely to respond to NSAIDs and which patients will require a second-line treatment.”
 

Findings Helpful for Counseling

Melissa S. Oliver, MD, MS, assistant professor of clinical pediatrics in rheumatology at Riley Children’s Health at Indiana University Health, Indianapolis, who was not involved in the research, said the findings of this study are helpful in “counseling families and patients at that initial visit and having a lower threshold to start a second-line agent if NSAID monotherapy is not working well.”

There are no clinical trials on patients with CNO, Dr. Oliver said, so very little data exist for guiding clinicians on the best therapy to use and how long to keep patients on therapy while minimizing risk for flare when coming off therapy.

A key clinical takeaway for clinicians is being able to tell patients with unifocal disease that they may not need to be on NSAIDs for a long period and can still do well, Dr. Oliver said. For patients with multifocal disease with symmetric bone lesions or multiple regions involved with CNO, “pediatric rheumatologists should have a lower threshold to start a second-line therapy for these patients,” she said.

Oliver_Melissa_IN_web.jpg

Findings From Largest Single-Center Cohort in North America

Their topline findings revealed that patients with unifocal disease at diagnosis required 47% fewer total days of NSAID monotherapy treatment than those with multifocal disease at diagnosis, Dr. Nowicki told attendees. Having symmetric bone lesions increased the likelihood of needing a second-line therapy by 6.86 times compared with those without symmetric bone lesions, and for each additional region affected by CNO, the odds of needing a second-line therapy increased by a factor of 1.94, she said.

There were no significant differences in patient ages or sex or in mean interval from symptom onset to treatment onset across treatment groups. However, patients who received second-line treatment did have a significantly longer average time from symptom onset to diagnosis (324 days) than those who had a short course (119 days) or long course (270 days) of NSAIDs (P = .023). Mean follow-up was also significantly longer for patients with second-line treatment (3.8 years) or long-course NSAIDs (2.7 years) than for those with short-course NSAIDs (1.2 years; P < .001).

Mean erythrocyte sedimentation rate or C-reactive protein did not differ across treatment groups nor did presence of a CNO lesion on x-rays at presentation. But significantly more patients in the second-line group had a biopsy (94%) than in the long-course (74%) or short-course (69%) NSAID groups (P = .0025). They were also more likely to have one or more whole-body MRIs. Most of the patients on short-course (88%) and long-course (82%) NSAIDs did not undergo a whole-body MRI, whereas most patients (59%) on a second-line treatment underwent at least one and 24% underwent three or more MRIs (P < .001).

More patients on short-course NSAIDs had unifocal disease at diagnosis (72%) than those on long-course NSAIDs (47%) or a second-line treatment (41%; P = .015). Patients on a second-line treatment were also more likely to have symmetric involvement in the same bone (73% vs 16% short-course and 23% long-course NSAIDs) and to have more regions of the body affected (P < .001).

There were significant differences in mean days on NSAID monotherapy and number of NSAIDs trialed. Patients on a second-line treatment had a mean 441 days of NSAID monotherapy compared with 175 days for patients on short-course NSAIDs and 725 for patients on long-course NSAIDs (P < .001). Nearly all the short-course patients (94%) trialed a single NSAID, while more than half the long-course and second-line patients trialed two or more (P < .001).

None of the patients on short-course NSAIDs had complications. More patients on second-line treatments had vertebral height loss (20%) or amplified pain (14%) than long-course patients (13% and 5%, respectively; P = .02).

At the study’s end date, nearly all the patients on short-course NSAIDs were in remission (94%) compared with 71% of patients on long-course NSAIDs and only half of patients (51%) on the second-line treatment (P < .001). None of the patients on short-course NSAIDs had active disease compared with 11% of patients on long-course NSAIDs and 20% of patients on second-line treatments (P = .02).

This study included the largest single-center cohort of patients with CNO in North America, all treated at a multidisciplinary clinic with a protocolized treatment approach, but it remains limited by its retrospective nature and the missing data for 70 patients, Dr. Nowicki said. She noted that whole-body MRI was not systematically performed on all patients, so it was possible patients without a whole-body MRI had undetected asymptomatic lesions.

Despite these limitations, Dr. Oliver said retrospective studies like these can help pediatric rheumatologists get an idea of reasonable therapies to start, how long to keep patients on them, and when to escalate to the next step.

“I hope one day our CNO research will be able to tell us about which is the optimal second-line therapy for patients, such as bisphosphonates vs TNF inhibitors vs DMARDs [disease-modifying antirheumatic drugs],” Dr. Oliver said.

Dr. Nowicki and Dr. Oliver reported no disclosures. Information on study funding was not provided.

A version of this article appeared on Medscape.com .

CORRECTED April 7, 2024 // An earlier version of this article misstated the clinical factors of children with CNO that were significantly associated with the need for second-line treatment, as well as the scope of assessments of aspects of disease involvement and their relationship to total number of days on NSAID monotherapy and the odds of needing a second-line treatment.

Children with chronic nonbacterial osteomyelitis (CNO) who had symmetric bone lesions or multiple affected body regions were more likely to need second-line treatment than were patients without these features, according to findings presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.

CNO is an auto-inflammatory condition that results in sterile inflammatory bone lesions and most commonly affects the long bones of people who are skeletally immature. After a first-line treatment of nonsteroidal anti-inflammatory drugs (NSAIDs), second-line treatments per CARRA guidelines typically include methotrexate or sulfasalazine, tumor necrosis factor (TNF)–alpha inhibitors, and bisphosphonates.

“Since it’s common for there to be long delays before diagnosis of CNO, it is important to start an effective treatment promptly,” Katherine D. Nowicki, MD, of Children’s Hospital Colorado, Aurora, told attendees. “While we have guidance on which treatments to use, it remains unclear which patients are most likely to respond to NSAIDs and which patients will require a second-line treatment.”
 

Findings Helpful for Counseling

Melissa S. Oliver, MD, MS, assistant professor of clinical pediatrics in rheumatology at Riley Children’s Health at Indiana University Health, Indianapolis, who was not involved in the research, said the findings of this study are helpful in “counseling families and patients at that initial visit and having a lower threshold to start a second-line agent if NSAID monotherapy is not working well.”

There are no clinical trials on patients with CNO, Dr. Oliver said, so very little data exist for guiding clinicians on the best therapy to use and how long to keep patients on therapy while minimizing risk for flare when coming off therapy.

A key clinical takeaway for clinicians is being able to tell patients with unifocal disease that they may not need to be on NSAIDs for a long period and can still do well, Dr. Oliver said. For patients with multifocal disease with symmetric bone lesions or multiple regions involved with CNO, “pediatric rheumatologists should have a lower threshold to start a second-line therapy for these patients,” she said.

Oliver_Melissa_IN_web.jpg

Findings From Largest Single-Center Cohort in North America

Their topline findings revealed that patients with unifocal disease at diagnosis required 47% fewer total days of NSAID monotherapy treatment than those with multifocal disease at diagnosis, Dr. Nowicki told attendees. Having symmetric bone lesions increased the likelihood of needing a second-line therapy by 6.86 times compared with those without symmetric bone lesions, and for each additional region affected by CNO, the odds of needing a second-line therapy increased by a factor of 1.94, she said.

There were no significant differences in patient ages or sex or in mean interval from symptom onset to treatment onset across treatment groups. However, patients who received second-line treatment did have a significantly longer average time from symptom onset to diagnosis (324 days) than those who had a short course (119 days) or long course (270 days) of NSAIDs (P = .023). Mean follow-up was also significantly longer for patients with second-line treatment (3.8 years) or long-course NSAIDs (2.7 years) than for those with short-course NSAIDs (1.2 years; P < .001).

Mean erythrocyte sedimentation rate or C-reactive protein did not differ across treatment groups nor did presence of a CNO lesion on x-rays at presentation. But significantly more patients in the second-line group had a biopsy (94%) than in the long-course (74%) or short-course (69%) NSAID groups (P = .0025). They were also more likely to have one or more whole-body MRIs. Most of the patients on short-course (88%) and long-course (82%) NSAIDs did not undergo a whole-body MRI, whereas most patients (59%) on a second-line treatment underwent at least one and 24% underwent three or more MRIs (P < .001).

More patients on short-course NSAIDs had unifocal disease at diagnosis (72%) than those on long-course NSAIDs (47%) or a second-line treatment (41%; P = .015). Patients on a second-line treatment were also more likely to have symmetric involvement in the same bone (73% vs 16% short-course and 23% long-course NSAIDs) and to have more regions of the body affected (P < .001).

There were significant differences in mean days on NSAID monotherapy and number of NSAIDs trialed. Patients on a second-line treatment had a mean 441 days of NSAID monotherapy compared with 175 days for patients on short-course NSAIDs and 725 for patients on long-course NSAIDs (P < .001). Nearly all the short-course patients (94%) trialed a single NSAID, while more than half the long-course and second-line patients trialed two or more (P < .001).

None of the patients on short-course NSAIDs had complications. More patients on second-line treatments had vertebral height loss (20%) or amplified pain (14%) than long-course patients (13% and 5%, respectively; P = .02).

At the study’s end date, nearly all the patients on short-course NSAIDs were in remission (94%) compared with 71% of patients on long-course NSAIDs and only half of patients (51%) on the second-line treatment (P < .001). None of the patients on short-course NSAIDs had active disease compared with 11% of patients on long-course NSAIDs and 20% of patients on second-line treatments (P = .02).

This study included the largest single-center cohort of patients with CNO in North America, all treated at a multidisciplinary clinic with a protocolized treatment approach, but it remains limited by its retrospective nature and the missing data for 70 patients, Dr. Nowicki said. She noted that whole-body MRI was not systematically performed on all patients, so it was possible patients without a whole-body MRI had undetected asymptomatic lesions.

Despite these limitations, Dr. Oliver said retrospective studies like these can help pediatric rheumatologists get an idea of reasonable therapies to start, how long to keep patients on them, and when to escalate to the next step.

“I hope one day our CNO research will be able to tell us about which is the optimal second-line therapy for patients, such as bisphosphonates vs TNF inhibitors vs DMARDs [disease-modifying antirheumatic drugs],” Dr. Oliver said.

Dr. Nowicki and Dr. Oliver reported no disclosures. Information on study funding was not provided.

A version of this article appeared on Medscape.com .

CORRECTED April 16, 2024 // An earlier version of this article stated incorrect percentages of patients who never received any biologics during the study's 3-year period but improved rapidly or moderately.

Early initiation of biologics — within the first 2 months of symptom presentation — appears to have a significant impact on how rapidly patients with juvenile idiopathic arthritis (JIA) improve, according to findings presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.

“Our study provides evidence that early use of biologics can significantly alter the disease trajectory of patients with JIA,” Mei-Sing Ong, PhD, of Harvard Medical School, Boston, told attendees. At the same time, however, not all patients who improved rapidly during a 3-year follow-up period needed biologics, a finding that Ong said the researchers are continuing to investigate.

Marinka Twilt, MD, MScE, PhD, chair of CARRA’s JIA Research Committee and a pediatric rheumatologist and clinician scientist at Alberta Children’s Hospital in Calgary, Canada, was not involved in the research but said the continued sustained remission in patients who improved rapidly is very reassuring.

Twilt_Marinka_CANADA_web.jpg

“We always wonder if initial response will be sustained or if patients tend to flare after the initial treatment,” Dr. Twilt told this news organization. “To see the sustained response up to 3 years is fantastic.” She added that it would be enlightening to see more information about patients who rapidly improved over 3 years, including whether they were still taking a [conventional disease-modifying antirheumatic drug (DMARD)] and/or biologic.

“A new diagnosis can be overwhelming for families, and this sometimes leads to step-up therapy to not overwhelm them more with information on new drugs,” Dr. Twilt said. “This study shows that an earlier start is beneficial, and this should be discussed with families early on so there is less delay in early treatment.”

Canada and many US states currently require 3 months of conventional DMARD treatment before patients can start a biologic, Dr. Twilt said, yet “this study shows the additive benefit of using a biologic within 2 months of starting a DMARD, which hopefully will lead to insurance companies adopting this threshold.”

The STOP-JIA study is a prospective observational study that compares the effectiveness of three different treatment plans for JIA. A Step-Up cohort of 257 patients received conventional antirheumatic monotherapy initially, with a biologic added at 3 months or later as needed. The Early Combination cohort of 100 patients received conventional antirheumatic therapy with a biologic from the start. The Biologic First cohort of 43 patients began taking a biologic as a first-line therapy.

In previously reported results of the study at 12 months’ follow-up, there was no significant difference between the Step-Up and Biologic First groups, but there were significant differences between the Step-Up and Early Combination groups. Significantly more patients in the Early Combination group (58.8%) than in the Step-Up group (42.8%) had inactive disease, based on the clinical Juvenile Arthritis Disease Activity Score 10 (cJADAS-10) (P = .03). Similarly, 81% of Early Combination patients achieved the American College of Rheumatology 70% improvement criteria, compared with 62% of the Step-Up patients (P = .01).

To learn whether the timing of starting a biologic influenced the disease trajectory over time, the researchers compared subgroups of patients with similar trajectories.

“Assessing treatment outcomes at a single point in time does not give us a complete picture of the effects of treatment on disease trajectory, which is an important outcome given that JIA is characterized by a relapsing-remitting course,” Dr. Ong told attendees.

Patients were sorted in the slow, moderate, or rapid improvement trajectories. In previously reported data at 12 months’ follow-up, patients’ odds of achieving rapid improvement were 3.6 times greater if they had started a biologic within 3 months.

This study compared patients’ trajectories over 3 years in the 259 patients (65% of the original cohort) who had at least one cJADAS-10 assessment in each year of follow-up. Most patients (66.8%) were in the rapid improvement class, with 25.9% in the moderate improvement class and 7.3% in the slow improvement class.

Patients in the rapid improvement group achieved inactive disease (cJADAS-10 of 2.5 or less) within 1 year and maintained inactive disease through the second and third years. The moderate and low improvement groups both had higher disease activity at baseline, but the moderate group continued to improve in years 2 and 3, with minimal disease by year 3, on the basis of the cJADAS-10 scores of 2.5-5. The slow group continued to experience moderate disease activity during years 2 and 3.

The findings also revealed that the earlier patients began a biologic, the more likely they were to be in the rapid improvement group than the slow improvement group. Participants who started a biologic in the first month had more than five times greater odds of being in the rapid improvement group than in the slow improvement group (odds ratio [OR], 5.33; P = .017).

Those who started a biologic in the second month were also more likely to be in the rapid improvement group (OR, 2.67; P = .032). For those who began a biologic by the third month, the odds of improving rapidly were not statistically significant, though Ong noted that could have been because of the small sample size. There was also no significant difference between those who improved moderately vs slowly based on when a biologic was initiated.

It would be helpful to learn whether any of the patients in the rapid improvement group were able to stop medications or whether they all continued treatment during the 3 years of follow-up, Dr. Twilt said. “Does early treatment with biologics not only lead to early remission after initiation but also to the possibility of stopping treatment earlier and remaining in remission?” she asked.

The researchers also found that not all patients needed biologics to end up in the rapid improvement group. Among patients who never received any biologics during the 3-year period, 83% improved rapidly and 17% improved moderately. Yet the researchers identified no significant differences in demographics or clinical factors between patients who received biologics and those who did not.

“The fact that there is a group of patients in the rapid response group who never need a biologic is of great interest, as we always want to treat patients early with the medications they need, but we also want to avoid overtreating patients,” Dr. Twilt said. It’s important to find out what differentiates those patients and whether it is possible to predict which patients do not need biologics early on, she said.

Dr. Ong said the research team is working to develop machine learning methods to improve risk stratification in hopes of addressing that question.

Dr. Ong and Dr. Twilt reported no disclosures. The research was funded by CARRA and the Patient-Centered Outcomes Research Institute.
 

A version of this article appeared on Medscape.com .

CORRECTED April 16, 2024 // An earlier version of this article stated incorrect percentages of patients who never received any biologics during the study's 3-year period but improved rapidly or moderately.

Early initiation of biologics — within the first 2 months of symptom presentation — appears to have a significant impact on how rapidly patients with juvenile idiopathic arthritis (JIA) improve, according to findings presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.

“Our study provides evidence that early use of biologics can significantly alter the disease trajectory of patients with JIA,” Mei-Sing Ong, PhD, of Harvard Medical School, Boston, told attendees. At the same time, however, not all patients who improved rapidly during a 3-year follow-up period needed biologics, a finding that Ong said the researchers are continuing to investigate.

Marinka Twilt, MD, MScE, PhD, chair of CARRA’s JIA Research Committee and a pediatric rheumatologist and clinician scientist at Alberta Children’s Hospital in Calgary, Canada, was not involved in the research but said the continued sustained remission in patients who improved rapidly is very reassuring.

Twilt_Marinka_CANADA_web.jpg

“We always wonder if initial response will be sustained or if patients tend to flare after the initial treatment,” Dr. Twilt told this news organization. “To see the sustained response up to 3 years is fantastic.” She added that it would be enlightening to see more information about patients who rapidly improved over 3 years, including whether they were still taking a [conventional disease-modifying antirheumatic drug (DMARD)] and/or biologic.

“A new diagnosis can be overwhelming for families, and this sometimes leads to step-up therapy to not overwhelm them more with information on new drugs,” Dr. Twilt said. “This study shows that an earlier start is beneficial, and this should be discussed with families early on so there is less delay in early treatment.”

Canada and many US states currently require 3 months of conventional DMARD treatment before patients can start a biologic, Dr. Twilt said, yet “this study shows the additive benefit of using a biologic within 2 months of starting a DMARD, which hopefully will lead to insurance companies adopting this threshold.”

The STOP-JIA study is a prospective observational study that compares the effectiveness of three different treatment plans for JIA. A Step-Up cohort of 257 patients received conventional antirheumatic monotherapy initially, with a biologic added at 3 months or later as needed. The Early Combination cohort of 100 patients received conventional antirheumatic therapy with a biologic from the start. The Biologic First cohort of 43 patients began taking a biologic as a first-line therapy.

In previously reported results of the study at 12 months’ follow-up, there was no significant difference between the Step-Up and Biologic First groups, but there were significant differences between the Step-Up and Early Combination groups. Significantly more patients in the Early Combination group (58.8%) than in the Step-Up group (42.8%) had inactive disease, based on the clinical Juvenile Arthritis Disease Activity Score 10 (cJADAS-10) (P = .03). Similarly, 81% of Early Combination patients achieved the American College of Rheumatology 70% improvement criteria, compared with 62% of the Step-Up patients (P = .01).

To learn whether the timing of starting a biologic influenced the disease trajectory over time, the researchers compared subgroups of patients with similar trajectories.

“Assessing treatment outcomes at a single point in time does not give us a complete picture of the effects of treatment on disease trajectory, which is an important outcome given that JIA is characterized by a relapsing-remitting course,” Dr. Ong told attendees.

Patients were sorted in the slow, moderate, or rapid improvement trajectories. In previously reported data at 12 months’ follow-up, patients’ odds of achieving rapid improvement were 3.6 times greater if they had started a biologic within 3 months.

This study compared patients’ trajectories over 3 years in the 259 patients (65% of the original cohort) who had at least one cJADAS-10 assessment in each year of follow-up. Most patients (66.8%) were in the rapid improvement class, with 25.9% in the moderate improvement class and 7.3% in the slow improvement class.

Patients in the rapid improvement group achieved inactive disease (cJADAS-10 of 2.5 or less) within 1 year and maintained inactive disease through the second and third years. The moderate and low improvement groups both had higher disease activity at baseline, but the moderate group continued to improve in years 2 and 3, with minimal disease by year 3, on the basis of the cJADAS-10 scores of 2.5-5. The slow group continued to experience moderate disease activity during years 2 and 3.

The findings also revealed that the earlier patients began a biologic, the more likely they were to be in the rapid improvement group than the slow improvement group. Participants who started a biologic in the first month had more than five times greater odds of being in the rapid improvement group than in the slow improvement group (odds ratio [OR], 5.33; P = .017).

Those who started a biologic in the second month were also more likely to be in the rapid improvement group (OR, 2.67; P = .032). For those who began a biologic by the third month, the odds of improving rapidly were not statistically significant, though Ong noted that could have been because of the small sample size. There was also no significant difference between those who improved moderately vs slowly based on when a biologic was initiated.

It would be helpful to learn whether any of the patients in the rapid improvement group were able to stop medications or whether they all continued treatment during the 3 years of follow-up, Dr. Twilt said. “Does early treatment with biologics not only lead to early remission after initiation but also to the possibility of stopping treatment earlier and remaining in remission?” she asked.

The researchers also found that not all patients needed biologics to end up in the rapid improvement group. Among patients who never received any biologics during the 3-year period, 83% improved rapidly and 17% improved moderately. Yet the researchers identified no significant differences in demographics or clinical factors between patients who received biologics and those who did not.

“The fact that there is a group of patients in the rapid response group who never need a biologic is of great interest, as we always want to treat patients early with the medications they need, but we also want to avoid overtreating patients,” Dr. Twilt said. It’s important to find out what differentiates those patients and whether it is possible to predict which patients do not need biologics early on, she said.

Dr. Ong said the research team is working to develop machine learning methods to improve risk stratification in hopes of addressing that question.

Dr. Ong and Dr. Twilt reported no disclosures. The research was funded by CARRA and the Patient-Centered Outcomes Research Institute.
 

A version of this article appeared on Medscape.com .

CORRECTED April 16, 2024 // An earlier version of this article stated incorrect percentages of patients who never received any biologics during the study's 3-year period but improved rapidly or moderately.

Early initiation of biologics — within the first 2 months of symptom presentation — appears to have a significant impact on how rapidly patients with juvenile idiopathic arthritis (JIA) improve, according to findings presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.

“Our study provides evidence that early use of biologics can significantly alter the disease trajectory of patients with JIA,” Mei-Sing Ong, PhD, of Harvard Medical School, Boston, told attendees. At the same time, however, not all patients who improved rapidly during a 3-year follow-up period needed biologics, a finding that Ong said the researchers are continuing to investigate.

Marinka Twilt, MD, MScE, PhD, chair of CARRA’s JIA Research Committee and a pediatric rheumatologist and clinician scientist at Alberta Children’s Hospital in Calgary, Canada, was not involved in the research but said the continued sustained remission in patients who improved rapidly is very reassuring.

Twilt_Marinka_CANADA_web.jpg

“We always wonder if initial response will be sustained or if patients tend to flare after the initial treatment,” Dr. Twilt told this news organization. “To see the sustained response up to 3 years is fantastic.” She added that it would be enlightening to see more information about patients who rapidly improved over 3 years, including whether they were still taking a [conventional disease-modifying antirheumatic drug (DMARD)] and/or biologic.

“A new diagnosis can be overwhelming for families, and this sometimes leads to step-up therapy to not overwhelm them more with information on new drugs,” Dr. Twilt said. “This study shows that an earlier start is beneficial, and this should be discussed with families early on so there is less delay in early treatment.”

Canada and many US states currently require 3 months of conventional DMARD treatment before patients can start a biologic, Dr. Twilt said, yet “this study shows the additive benefit of using a biologic within 2 months of starting a DMARD, which hopefully will lead to insurance companies adopting this threshold.”

The STOP-JIA study is a prospective observational study that compares the effectiveness of three different treatment plans for JIA. A Step-Up cohort of 257 patients received conventional antirheumatic monotherapy initially, with a biologic added at 3 months or later as needed. The Early Combination cohort of 100 patients received conventional antirheumatic therapy with a biologic from the start. The Biologic First cohort of 43 patients began taking a biologic as a first-line therapy.

In previously reported results of the study at 12 months’ follow-up, there was no significant difference between the Step-Up and Biologic First groups, but there were significant differences between the Step-Up and Early Combination groups. Significantly more patients in the Early Combination group (58.8%) than in the Step-Up group (42.8%) had inactive disease, based on the clinical Juvenile Arthritis Disease Activity Score 10 (cJADAS-10) (P = .03). Similarly, 81% of Early Combination patients achieved the American College of Rheumatology 70% improvement criteria, compared with 62% of the Step-Up patients (P = .01).

To learn whether the timing of starting a biologic influenced the disease trajectory over time, the researchers compared subgroups of patients with similar trajectories.

“Assessing treatment outcomes at a single point in time does not give us a complete picture of the effects of treatment on disease trajectory, which is an important outcome given that JIA is characterized by a relapsing-remitting course,” Dr. Ong told attendees.

Patients were sorted in the slow, moderate, or rapid improvement trajectories. In previously reported data at 12 months’ follow-up, patients’ odds of achieving rapid improvement were 3.6 times greater if they had started a biologic within 3 months.

This study compared patients’ trajectories over 3 years in the 259 patients (65% of the original cohort) who had at least one cJADAS-10 assessment in each year of follow-up. Most patients (66.8%) were in the rapid improvement class, with 25.9% in the moderate improvement class and 7.3% in the slow improvement class.

Patients in the rapid improvement group achieved inactive disease (cJADAS-10 of 2.5 or less) within 1 year and maintained inactive disease through the second and third years. The moderate and low improvement groups both had higher disease activity at baseline, but the moderate group continued to improve in years 2 and 3, with minimal disease by year 3, on the basis of the cJADAS-10 scores of 2.5-5. The slow group continued to experience moderate disease activity during years 2 and 3.

The findings also revealed that the earlier patients began a biologic, the more likely they were to be in the rapid improvement group than the slow improvement group. Participants who started a biologic in the first month had more than five times greater odds of being in the rapid improvement group than in the slow improvement group (odds ratio [OR], 5.33; P = .017).

Those who started a biologic in the second month were also more likely to be in the rapid improvement group (OR, 2.67; P = .032). For those who began a biologic by the third month, the odds of improving rapidly were not statistically significant, though Ong noted that could have been because of the small sample size. There was also no significant difference between those who improved moderately vs slowly based on when a biologic was initiated.

It would be helpful to learn whether any of the patients in the rapid improvement group were able to stop medications or whether they all continued treatment during the 3 years of follow-up, Dr. Twilt said. “Does early treatment with biologics not only lead to early remission after initiation but also to the possibility of stopping treatment earlier and remaining in remission?” she asked.

The researchers also found that not all patients needed biologics to end up in the rapid improvement group. Among patients who never received any biologics during the 3-year period, 83% improved rapidly and 17% improved moderately. Yet the researchers identified no significant differences in demographics or clinical factors between patients who received biologics and those who did not.

“The fact that there is a group of patients in the rapid response group who never need a biologic is of great interest, as we always want to treat patients early with the medications they need, but we also want to avoid overtreating patients,” Dr. Twilt said. It’s important to find out what differentiates those patients and whether it is possible to predict which patients do not need biologics early on, she said.

Dr. Ong said the research team is working to develop machine learning methods to improve risk stratification in hopes of addressing that question.

Dr. Ong and Dr. Twilt reported no disclosures. The research was funded by CARRA and the Patient-Centered Outcomes Research Institute.
 

A version of this article appeared on Medscape.com .

The accumulation of multiple adverse social determinants of health is linked to worse disease at initial presentation and worse disease activity over time in children with rheumatologic conditions, according to findings presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.

One study revealed that cumulative factors conferring social disadvantage progressively increased the odds of active disease and functional disability in children with juvenile idiopathic arthritis (JIA). Another study similarly found that children with lupus living in neighborhoods with comparatively fewer resources for childhood opportunity had worse disease at presentation and greater disease activity over follow-up.

The findings suggest that exposure to multiple disadvantaging social variables may be linked to worse outcomes than exposure to any single factor, William Daniel Soulsby, MD, of the University of California San Francisco, told attendees in his presentation of data from the JIA study.

“Most prior studies have analyzed such determinants as independent risk factors,” Dr. Soulsby said. “However, individuals experiencing social disadvantage often face multiple social hardships that rarely act in isolation; studying these factors independently may miss underlying disparities.”

Stacy P. Ardoin, MD, MSc, professor of pediatric and adult rheumatology at Nationwide Children’s Hospital and The Ohio State University in Columbus, and vice president of CARRA, did not find the results of Soulsby’s study surprising, but she said they do “provide important confirmation of our growing understanding of the impact of social determinants of health on the outcomes of children and adolescents with chronic disease like juvenile idiopathic arthritis.” She added: “In medicine, we often think about the bench, the bedside, and the clinic, but this study tells us that if we want to improve outcomes for our patients, we also need to think about the ‘backyard,’ too.”
 

Social Disadvantage With JIA

Dr. Soulsby’s team adopted an approach similar to that of a recent National Survey of Children’s Health analysis that used a combined scoring system to calculate cumulative social disadvantage. The researchers used income level, insurance status, and education level to capture individual factors related to disadvantage and then an area deprivation index (ADI) to capture community factors. While they were unable to use any variables specific to societal factors, they included race, which is relevant at all three levels.

The cohort included 9612 patients in the CARRA Registry from July 2015 to January 2022. They included all patients who had a JIA diagnosis with onset before age 16 and at least one visit with a complete clinical Juvenile Arthritis Disease Activity Score (JADAS) score. Most of the patients (70%) were female, with an average age at enrollment of 11 and a mean time to diagnosis of 10.6 months.

Most of the patients had oligoarthritis (35.5%) or rheumatoid factor–negative polyarthritis (29.4%), followed by enthesitis-related arthritis (10.5%) and then other forms. A total of 4% of patients had a secondary rheumatologic condition. Most of the patients were White (74.9%), with 3.9% Black, 7.6% Hispanic, and 6.5% of more than one race. ADI data were missing for 17.2% of patients.

The researchers assigned a score to each patient that could add up to a maximum of 3. They received 1 point for an annual household income below $50,000, 1 point for having public insurance or no insurance, and 1 point for their guardian having no more than a high school education. Patients with a score of 0 comprised 60.9% of the patients, while 21.3% had a score of 1, 12.9% had a score of 2, and 4.9% had a score of 3.

Just over a quarter of the patients (26.3%) were underinsured, 19.1% were low income, and 16.4% had caregivers with a high school education or less. However, income level was unknown for 24.6% of patients, and guardians’ education level was unknown for 15.7% of patients.

The primary outcomes were the odds of active disease as based on clinical JADAS (at least a 1.1 score for oligoarticular JIA and more than 2.5 for all other subtypes) and odds of functional disability based on the Childhood Health Assessment Questionnaire (CHAQ). Adjustments were made for sex, race/ethnicity, age at enrollment, time to diagnosis, ADI, JIA category, presence of secondary rheumatologic disease, and medication (use of a conventional synthetic disease-modifying antirheumatic drug [DMARD], biologic DMARD, or small molecule drug).

Nearly half (48%) of patients had active disease during follow-up, with an average clinical JADAS score of 4 from the whole cohort. Compared with children with a cumulative disadvantage score of 0, each additional point on the clinical JADAS resulted in significantly increased odds of active disease. Those with the highest score of 3 were twice as likely to have active disease (adjusted odds ratio [aOR], 2.05; P < .001) as those with a score of 0, but those with a score of 1 (aOR, 1.36; P < .001) or 2 (aOR, 1.86; P < .001) were also more likely to have active disease. Other significant independent predictors of active arthritis included being of Black race (aOR, 1.55) or more than one race (aOR, 1.31).

Each of the scored factors also independently increased the likelihood of active disease by similar amounts: 1.69 higher odds for low household income on its own, 1.6 higher odds for public or no insurance, and 1.45 higher odds for high school education or less (all P < .001).

Similarly, odds of functional disability based on CHAQ increased significantly with each additional point. The mean CHAQ score was 0.31, and 46% of patients had functional disability during follow-up. Those with a cumulative social disadvantage score of 3 were three times as likely to have functional disability (aOR, 3.09; P < .001) as those with a score of 0. Those with a score of 1 (aOR, 1.82) or 2 (aOR, 2.81) were also more likely to have functional disability (P < .001). Again, Black individuals (aOR, 2.09) or those of mixed race (aOR, 1.78) had greater odds of functional disability (P < .001).

The independent factor most associated with increased odds of functional disability was a household income below $50,000 a year (OR, 3.03; P < .001), followed by having public or no insurance (OR, 2.57) or a caregiver with no more than a high school education (OR, 1.98). Dr. Soulsby noted that their study was limited by the missing data and may oversimplify the relationships between social determinants of health.

Overall, however, the findings revealed both the importance of social risk screening in the pediatric rheumatology clinic and the coupling of that screening with individual level support for patients, Dr. Soulsby said.

“This study did a great job of harnessing the power of the CARRA Registry,” said Dr. Ardoin, who was not involved in the research. “These findings underscore how important it is for all clinicians, including pediatric rheumatologists, to evaluate every child for social risks of poor outcomes,” she said.

One take-home message from the findings is that once pediatric rheumatologists identify social risks for poor outcomes in their patients, they can “consult with social workers and connect families with community resources in an effort to ameliorate social deprivation.”
 

Childhood Lupus and Reduced Childhood Opportunity

In a similar study looking at children with childhood-onset lupus, researchers similarly identified the way that compounding social determinants of health were linked to greater disease activity.

“We know that structural racism segregates children from historically marginalized groups into different neighborhoods with lower childhood opportunity,” Joyce C. Chang, MD, of Boston Children’s Hospital, told attendees. “When we talk about child opportunity, we’re really describing all of the resources and conditions that helped to promote healthy childhood development,” including factors related to education, physical health, the built environment, and social and economic security, she said.

Dr. Chang and her colleagues therefore assessed the relationship between a 29-indicator Child Opportunity Index for patients with childhood-onset lupus and the severity of their disease presentation and activity over time. They determined the Child Opportunity Index for different neighborhoods and assessed the amount of racial residential segregation around the three institutions involved in the study. Severity of lupus presentation was based on the need for intensive care unit admission or dialysis or a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 10 or higher. Disease activity over time was based on the SLEDAI-2K score.

The patient population included 553 patients with childhood-onset lupus from three institutions: Boston Children’s Hospital, Lurie Children’s Hospital of Chicago, and Children’s of Alabama in Birmingham, Alabama. Across the full population, 30% of the patients were Black and 30% were Hispanic, but the distribution of race and ethnicity varied by institution. Most of the Black patients, for example, were at Children’s of Alabama (59%), while 43% of the Hispanic patients were at Lurie. Across all the sites, 14% of the patients’ families preferred a non-English language as their first language, and just over half the patients (52%) had public insurance.

Dr. Chang did not have data yet from the Lurie and Alabama cohorts, so she presented preliminary data from the Boston Children’s cohort of 148 patients. In those results, children living in neighborhoods of low childhood opportunity had four times higher odds of presenting with severe disease than children living in neighborhoods of very high opportunity. Then the researchers factored in the location quotient that represented the magnitude of racial segregation in a residential area. In areas with high levels of Black vs White segregation, children were 2.5 times more likely to have a more severe initial disease presentation. However, there was not a significant difference in areas highly segregated between Hispanic and non-Hispanic residents.

After initial presentation, the data revealed a dose-dependent relationship between childhood opportunity and severity of disease activity based on SLEDAI-2K. After adjustment for insurance status, race, preferred language, age at disease onset, sex, major organ involvement, initial SLEDAI-2K score at presentation, and follow-up time, disease activity incrementally increased as childhood opportunity decreased (P < .001 for the trend).

The findings suggested that even in regions like Boston, where overall childhood opportunity is higher than the national average, “poor relative neighborhood opportunity is still associated with more severe lupus presentation, as well as higher lupus disease activity during follow-up,” Dr. Chang said. “Area-level conditions may drive inequitable outcomes at numerous points,” including initial access to subspecialty care and after establishing that care, she said.

Dr. Soulsby, Dr. Chang, and Dr. Ardoin reported having no disclosures. Dr. Soulsby’s research was funded by CARRA and the Arthritis Foundation, and Dr. Chang’s research was funded by CARRA.
 

A version of this article appeared on Medscape.com.

The accumulation of multiple adverse social determinants of health is linked to worse disease at initial presentation and worse disease activity over time in children with rheumatologic conditions, according to findings presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.

One study revealed that cumulative factors conferring social disadvantage progressively increased the odds of active disease and functional disability in children with juvenile idiopathic arthritis (JIA). Another study similarly found that children with lupus living in neighborhoods with comparatively fewer resources for childhood opportunity had worse disease at presentation and greater disease activity over follow-up.

The findings suggest that exposure to multiple disadvantaging social variables may be linked to worse outcomes than exposure to any single factor, William Daniel Soulsby, MD, of the University of California San Francisco, told attendees in his presentation of data from the JIA study.

“Most prior studies have analyzed such determinants as independent risk factors,” Dr. Soulsby said. “However, individuals experiencing social disadvantage often face multiple social hardships that rarely act in isolation; studying these factors independently may miss underlying disparities.”

Stacy P. Ardoin, MD, MSc, professor of pediatric and adult rheumatology at Nationwide Children’s Hospital and The Ohio State University in Columbus, and vice president of CARRA, did not find the results of Soulsby’s study surprising, but she said they do “provide important confirmation of our growing understanding of the impact of social determinants of health on the outcomes of children and adolescents with chronic disease like juvenile idiopathic arthritis.” She added: “In medicine, we often think about the bench, the bedside, and the clinic, but this study tells us that if we want to improve outcomes for our patients, we also need to think about the ‘backyard,’ too.”
 

Social Disadvantage With JIA

Dr. Soulsby’s team adopted an approach similar to that of a recent National Survey of Children’s Health analysis that used a combined scoring system to calculate cumulative social disadvantage. The researchers used income level, insurance status, and education level to capture individual factors related to disadvantage and then an area deprivation index (ADI) to capture community factors. While they were unable to use any variables specific to societal factors, they included race, which is relevant at all three levels.

The cohort included 9612 patients in the CARRA Registry from July 2015 to January 2022. They included all patients who had a JIA diagnosis with onset before age 16 and at least one visit with a complete clinical Juvenile Arthritis Disease Activity Score (JADAS) score. Most of the patients (70%) were female, with an average age at enrollment of 11 and a mean time to diagnosis of 10.6 months.

Most of the patients had oligoarthritis (35.5%) or rheumatoid factor–negative polyarthritis (29.4%), followed by enthesitis-related arthritis (10.5%) and then other forms. A total of 4% of patients had a secondary rheumatologic condition. Most of the patients were White (74.9%), with 3.9% Black, 7.6% Hispanic, and 6.5% of more than one race. ADI data were missing for 17.2% of patients.

The researchers assigned a score to each patient that could add up to a maximum of 3. They received 1 point for an annual household income below $50,000, 1 point for having public insurance or no insurance, and 1 point for their guardian having no more than a high school education. Patients with a score of 0 comprised 60.9% of the patients, while 21.3% had a score of 1, 12.9% had a score of 2, and 4.9% had a score of 3.

Just over a quarter of the patients (26.3%) were underinsured, 19.1% were low income, and 16.4% had caregivers with a high school education or less. However, income level was unknown for 24.6% of patients, and guardians’ education level was unknown for 15.7% of patients.

The primary outcomes were the odds of active disease as based on clinical JADAS (at least a 1.1 score for oligoarticular JIA and more than 2.5 for all other subtypes) and odds of functional disability based on the Childhood Health Assessment Questionnaire (CHAQ). Adjustments were made for sex, race/ethnicity, age at enrollment, time to diagnosis, ADI, JIA category, presence of secondary rheumatologic disease, and medication (use of a conventional synthetic disease-modifying antirheumatic drug [DMARD], biologic DMARD, or small molecule drug).

Nearly half (48%) of patients had active disease during follow-up, with an average clinical JADAS score of 4 from the whole cohort. Compared with children with a cumulative disadvantage score of 0, each additional point on the clinical JADAS resulted in significantly increased odds of active disease. Those with the highest score of 3 were twice as likely to have active disease (adjusted odds ratio [aOR], 2.05; P < .001) as those with a score of 0, but those with a score of 1 (aOR, 1.36; P < .001) or 2 (aOR, 1.86; P < .001) were also more likely to have active disease. Other significant independent predictors of active arthritis included being of Black race (aOR, 1.55) or more than one race (aOR, 1.31).

Each of the scored factors also independently increased the likelihood of active disease by similar amounts: 1.69 higher odds for low household income on its own, 1.6 higher odds for public or no insurance, and 1.45 higher odds for high school education or less (all P < .001).

Similarly, odds of functional disability based on CHAQ increased significantly with each additional point. The mean CHAQ score was 0.31, and 46% of patients had functional disability during follow-up. Those with a cumulative social disadvantage score of 3 were three times as likely to have functional disability (aOR, 3.09; P < .001) as those with a score of 0. Those with a score of 1 (aOR, 1.82) or 2 (aOR, 2.81) were also more likely to have functional disability (P < .001). Again, Black individuals (aOR, 2.09) or those of mixed race (aOR, 1.78) had greater odds of functional disability (P < .001).

The independent factor most associated with increased odds of functional disability was a household income below $50,000 a year (OR, 3.03; P < .001), followed by having public or no insurance (OR, 2.57) or a caregiver with no more than a high school education (OR, 1.98). Dr. Soulsby noted that their study was limited by the missing data and may oversimplify the relationships between social determinants of health.

Overall, however, the findings revealed both the importance of social risk screening in the pediatric rheumatology clinic and the coupling of that screening with individual level support for patients, Dr. Soulsby said.

“This study did a great job of harnessing the power of the CARRA Registry,” said Dr. Ardoin, who was not involved in the research. “These findings underscore how important it is for all clinicians, including pediatric rheumatologists, to evaluate every child for social risks of poor outcomes,” she said.

One take-home message from the findings is that once pediatric rheumatologists identify social risks for poor outcomes in their patients, they can “consult with social workers and connect families with community resources in an effort to ameliorate social deprivation.”
 

Childhood Lupus and Reduced Childhood Opportunity

In a similar study looking at children with childhood-onset lupus, researchers similarly identified the way that compounding social determinants of health were linked to greater disease activity.

“We know that structural racism segregates children from historically marginalized groups into different neighborhoods with lower childhood opportunity,” Joyce C. Chang, MD, of Boston Children’s Hospital, told attendees. “When we talk about child opportunity, we’re really describing all of the resources and conditions that helped to promote healthy childhood development,” including factors related to education, physical health, the built environment, and social and economic security, she said.

Dr. Chang and her colleagues therefore assessed the relationship between a 29-indicator Child Opportunity Index for patients with childhood-onset lupus and the severity of their disease presentation and activity over time. They determined the Child Opportunity Index for different neighborhoods and assessed the amount of racial residential segregation around the three institutions involved in the study. Severity of lupus presentation was based on the need for intensive care unit admission or dialysis or a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 10 or higher. Disease activity over time was based on the SLEDAI-2K score.

The patient population included 553 patients with childhood-onset lupus from three institutions: Boston Children’s Hospital, Lurie Children’s Hospital of Chicago, and Children’s of Alabama in Birmingham, Alabama. Across the full population, 30% of the patients were Black and 30% were Hispanic, but the distribution of race and ethnicity varied by institution. Most of the Black patients, for example, were at Children’s of Alabama (59%), while 43% of the Hispanic patients were at Lurie. Across all the sites, 14% of the patients’ families preferred a non-English language as their first language, and just over half the patients (52%) had public insurance.

Dr. Chang did not have data yet from the Lurie and Alabama cohorts, so she presented preliminary data from the Boston Children’s cohort of 148 patients. In those results, children living in neighborhoods of low childhood opportunity had four times higher odds of presenting with severe disease than children living in neighborhoods of very high opportunity. Then the researchers factored in the location quotient that represented the magnitude of racial segregation in a residential area. In areas with high levels of Black vs White segregation, children were 2.5 times more likely to have a more severe initial disease presentation. However, there was not a significant difference in areas highly segregated between Hispanic and non-Hispanic residents.

After initial presentation, the data revealed a dose-dependent relationship between childhood opportunity and severity of disease activity based on SLEDAI-2K. After adjustment for insurance status, race, preferred language, age at disease onset, sex, major organ involvement, initial SLEDAI-2K score at presentation, and follow-up time, disease activity incrementally increased as childhood opportunity decreased (P < .001 for the trend).

The findings suggested that even in regions like Boston, where overall childhood opportunity is higher than the national average, “poor relative neighborhood opportunity is still associated with more severe lupus presentation, as well as higher lupus disease activity during follow-up,” Dr. Chang said. “Area-level conditions may drive inequitable outcomes at numerous points,” including initial access to subspecialty care and after establishing that care, she said.

Dr. Soulsby, Dr. Chang, and Dr. Ardoin reported having no disclosures. Dr. Soulsby’s research was funded by CARRA and the Arthritis Foundation, and Dr. Chang’s research was funded by CARRA.
 

A version of this article appeared on Medscape.com.

The accumulation of multiple adverse social determinants of health is linked to worse disease at initial presentation and worse disease activity over time in children with rheumatologic conditions, according to findings presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.

One study revealed that cumulative factors conferring social disadvantage progressively increased the odds of active disease and functional disability in children with juvenile idiopathic arthritis (JIA). Another study similarly found that children with lupus living in neighborhoods with comparatively fewer resources for childhood opportunity had worse disease at presentation and greater disease activity over follow-up.

The findings suggest that exposure to multiple disadvantaging social variables may be linked to worse outcomes than exposure to any single factor, William Daniel Soulsby, MD, of the University of California San Francisco, told attendees in his presentation of data from the JIA study.

“Most prior studies have analyzed such determinants as independent risk factors,” Dr. Soulsby said. “However, individuals experiencing social disadvantage often face multiple social hardships that rarely act in isolation; studying these factors independently may miss underlying disparities.”

Stacy P. Ardoin, MD, MSc, professor of pediatric and adult rheumatology at Nationwide Children’s Hospital and The Ohio State University in Columbus, and vice president of CARRA, did not find the results of Soulsby’s study surprising, but she said they do “provide important confirmation of our growing understanding of the impact of social determinants of health on the outcomes of children and adolescents with chronic disease like juvenile idiopathic arthritis.” She added: “In medicine, we often think about the bench, the bedside, and the clinic, but this study tells us that if we want to improve outcomes for our patients, we also need to think about the ‘backyard,’ too.”
 

Social Disadvantage With JIA

Dr. Soulsby’s team adopted an approach similar to that of a recent National Survey of Children’s Health analysis that used a combined scoring system to calculate cumulative social disadvantage. The researchers used income level, insurance status, and education level to capture individual factors related to disadvantage and then an area deprivation index (ADI) to capture community factors. While they were unable to use any variables specific to societal factors, they included race, which is relevant at all three levels.

The cohort included 9612 patients in the CARRA Registry from July 2015 to January 2022. They included all patients who had a JIA diagnosis with onset before age 16 and at least one visit with a complete clinical Juvenile Arthritis Disease Activity Score (JADAS) score. Most of the patients (70%) were female, with an average age at enrollment of 11 and a mean time to diagnosis of 10.6 months.

Most of the patients had oligoarthritis (35.5%) or rheumatoid factor–negative polyarthritis (29.4%), followed by enthesitis-related arthritis (10.5%) and then other forms. A total of 4% of patients had a secondary rheumatologic condition. Most of the patients were White (74.9%), with 3.9% Black, 7.6% Hispanic, and 6.5% of more than one race. ADI data were missing for 17.2% of patients.

The researchers assigned a score to each patient that could add up to a maximum of 3. They received 1 point for an annual household income below $50,000, 1 point for having public insurance or no insurance, and 1 point for their guardian having no more than a high school education. Patients with a score of 0 comprised 60.9% of the patients, while 21.3% had a score of 1, 12.9% had a score of 2, and 4.9% had a score of 3.

Just over a quarter of the patients (26.3%) were underinsured, 19.1% were low income, and 16.4% had caregivers with a high school education or less. However, income level was unknown for 24.6% of patients, and guardians’ education level was unknown for 15.7% of patients.

The primary outcomes were the odds of active disease as based on clinical JADAS (at least a 1.1 score for oligoarticular JIA and more than 2.5 for all other subtypes) and odds of functional disability based on the Childhood Health Assessment Questionnaire (CHAQ). Adjustments were made for sex, race/ethnicity, age at enrollment, time to diagnosis, ADI, JIA category, presence of secondary rheumatologic disease, and medication (use of a conventional synthetic disease-modifying antirheumatic drug [DMARD], biologic DMARD, or small molecule drug).

Nearly half (48%) of patients had active disease during follow-up, with an average clinical JADAS score of 4 from the whole cohort. Compared with children with a cumulative disadvantage score of 0, each additional point on the clinical JADAS resulted in significantly increased odds of active disease. Those with the highest score of 3 were twice as likely to have active disease (adjusted odds ratio [aOR], 2.05; P < .001) as those with a score of 0, but those with a score of 1 (aOR, 1.36; P < .001) or 2 (aOR, 1.86; P < .001) were also more likely to have active disease. Other significant independent predictors of active arthritis included being of Black race (aOR, 1.55) or more than one race (aOR, 1.31).

Each of the scored factors also independently increased the likelihood of active disease by similar amounts: 1.69 higher odds for low household income on its own, 1.6 higher odds for public or no insurance, and 1.45 higher odds for high school education or less (all P < .001).

Similarly, odds of functional disability based on CHAQ increased significantly with each additional point. The mean CHAQ score was 0.31, and 46% of patients had functional disability during follow-up. Those with a cumulative social disadvantage score of 3 were three times as likely to have functional disability (aOR, 3.09; P < .001) as those with a score of 0. Those with a score of 1 (aOR, 1.82) or 2 (aOR, 2.81) were also more likely to have functional disability (P < .001). Again, Black individuals (aOR, 2.09) or those of mixed race (aOR, 1.78) had greater odds of functional disability (P < .001).

The independent factor most associated with increased odds of functional disability was a household income below $50,000 a year (OR, 3.03; P < .001), followed by having public or no insurance (OR, 2.57) or a caregiver with no more than a high school education (OR, 1.98). Dr. Soulsby noted that their study was limited by the missing data and may oversimplify the relationships between social determinants of health.

Overall, however, the findings revealed both the importance of social risk screening in the pediatric rheumatology clinic and the coupling of that screening with individual level support for patients, Dr. Soulsby said.

“This study did a great job of harnessing the power of the CARRA Registry,” said Dr. Ardoin, who was not involved in the research. “These findings underscore how important it is for all clinicians, including pediatric rheumatologists, to evaluate every child for social risks of poor outcomes,” she said.

One take-home message from the findings is that once pediatric rheumatologists identify social risks for poor outcomes in their patients, they can “consult with social workers and connect families with community resources in an effort to ameliorate social deprivation.”
 

Childhood Lupus and Reduced Childhood Opportunity

In a similar study looking at children with childhood-onset lupus, researchers similarly identified the way that compounding social determinants of health were linked to greater disease activity.

“We know that structural racism segregates children from historically marginalized groups into different neighborhoods with lower childhood opportunity,” Joyce C. Chang, MD, of Boston Children’s Hospital, told attendees. “When we talk about child opportunity, we’re really describing all of the resources and conditions that helped to promote healthy childhood development,” including factors related to education, physical health, the built environment, and social and economic security, she said.

Dr. Chang and her colleagues therefore assessed the relationship between a 29-indicator Child Opportunity Index for patients with childhood-onset lupus and the severity of their disease presentation and activity over time. They determined the Child Opportunity Index for different neighborhoods and assessed the amount of racial residential segregation around the three institutions involved in the study. Severity of lupus presentation was based on the need for intensive care unit admission or dialysis or a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 10 or higher. Disease activity over time was based on the SLEDAI-2K score.

The patient population included 553 patients with childhood-onset lupus from three institutions: Boston Children’s Hospital, Lurie Children’s Hospital of Chicago, and Children’s of Alabama in Birmingham, Alabama. Across the full population, 30% of the patients were Black and 30% were Hispanic, but the distribution of race and ethnicity varied by institution. Most of the Black patients, for example, were at Children’s of Alabama (59%), while 43% of the Hispanic patients were at Lurie. Across all the sites, 14% of the patients’ families preferred a non-English language as their first language, and just over half the patients (52%) had public insurance.

Dr. Chang did not have data yet from the Lurie and Alabama cohorts, so she presented preliminary data from the Boston Children’s cohort of 148 patients. In those results, children living in neighborhoods of low childhood opportunity had four times higher odds of presenting with severe disease than children living in neighborhoods of very high opportunity. Then the researchers factored in the location quotient that represented the magnitude of racial segregation in a residential area. In areas with high levels of Black vs White segregation, children were 2.5 times more likely to have a more severe initial disease presentation. However, there was not a significant difference in areas highly segregated between Hispanic and non-Hispanic residents.

After initial presentation, the data revealed a dose-dependent relationship between childhood opportunity and severity of disease activity based on SLEDAI-2K. After adjustment for insurance status, race, preferred language, age at disease onset, sex, major organ involvement, initial SLEDAI-2K score at presentation, and follow-up time, disease activity incrementally increased as childhood opportunity decreased (P < .001 for the trend).

The findings suggested that even in regions like Boston, where overall childhood opportunity is higher than the national average, “poor relative neighborhood opportunity is still associated with more severe lupus presentation, as well as higher lupus disease activity during follow-up,” Dr. Chang said. “Area-level conditions may drive inequitable outcomes at numerous points,” including initial access to subspecialty care and after establishing that care, she said.

Dr. Soulsby, Dr. Chang, and Dr. Ardoin reported having no disclosures. Dr. Soulsby’s research was funded by CARRA and the Arthritis Foundation, and Dr. Chang’s research was funded by CARRA.
 

A version of this article appeared on Medscape.com.

The risk of developing a new autoimmune inflammatory rheumatic disease (AIRD) is greater following a COVID-19 infection than after an influenza infection or in the general population, according to a study published March 5 in Annals of Internal Medicine. More severe COVID-19 infections were linked to a greater risk of incident rheumatic disease, but vaccination appeared protective against development of a new AIRD.

“Importantly, this study shows the value of vaccination to prevent severe disease and these types of sequelae,” Anne Davidson, MBBS, a professor in the Institute of Molecular Medicine at The Feinstein Institutes for Medical Research in Manhasset, New York, who was not involved in the study, said in an interview.

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More Robust and Rigorous Research

Past cohort studies finding an increased risk of rheumatic disease after COVID-19 “based their findings solely on comparisons between infected and uninfected groups, which could be influenced by ascertainment bias due to disparities in care, differences in health-seeking tendencies, and inherent risks among the groups,” Min Seo Kim, MD, of the Broad Institute of MIT and Harvard, Cambridge, Massachusetts, and his colleagues reported. Their study, however, required at least two claims with codes for rheumatic disease and compared patients with COVID-19 to those with flu “to adjust for the potentially heightened detection of AIRD in SARS-CoV-2–infected persons owing to their interactions with the health care system.”

Dr. Alfred Kim said the fact that they used at least two claims codes “gives a little more credence that the patients were actually experiencing some sort of autoimmune inflammatory condition as opposed to a very transient issue post COVID that just went away on its own.”

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He acknowledged that the previous research was reasonably strong, “especially in light of the fact that there has been so much work done on a molecular level demonstrating that COVID-19 is associated with a substantial increase in autoantibodies in a significant proportion of patients, so this always opened up the possibility that this could associate with some sort of autoimmune disease downstream.”

While the study is well done with a large population, “it still has limitations that might overestimate the effect,” Kevin W. Byram, MD, associate professor of medicine in rheumatology and immunology at Vanderbilt University Medical Center in Nashville, Tennessee, who was not involved in the study, said in an interview. “We certainly have seen individual cases of new rheumatic disease where COVID-19 infection is likely the trigger,” but the phenomenon is not new, he added.

“Many autoimmune diseases are spurred by a loss of tolerance that might be induced by a pathogen of some sort,” Dr. Byram said. “The study is right to point out different forms of bias that might be at play. One in particular that is important to consider in a study like this is the lack of case-level adjudication regarding the diagnosis of rheumatic disease” since the study relied on available ICD-10 codes and medication prescriptions.

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Risk Varied With Disease Severity and Vaccination Status

Among the Korean patients, 3.9% had a COVID-19 infection and 0.98% had an influenza infection. After matching, the comparison populations included 94,504 patients with COVID-19 versus 94,504 patients with flu, and 177,083 patients with COVID-19 versus 675,750 uninfected controls.

The risk of developing an AIRD at least 1 month after infection in South Korean patients with COVID-19 was 25% higher than in uninfected control participants (adjusted hazard ratio [aHR], 1.25; 95% CI, 1.18–1.31; P < .05) and 30% higher than in influenza patients (aHR, 1.3; 95% CI, 1.02–1.59; P < .05). Specifically, risk in South Korean patients with COVID-19 was significantly increased for connective tissue disease and both treated and untreated AIRD but not for inflammatory arthritis.

Among the Japanese patients, 8.2% had COVID-19 and 0.99% had flu, resulting in matched populations of 115,003 with COVID-19 versus 110,310 with flu, and 960,849 with COVID-19 versus 1,606,873 uninfected patients. The effect size was larger in Japanese patients, with a 79% increased risk for AIRD in patients with COVID-19, compared with the general population (aHR, 1.79; 95% CI, 1.77–1.82; P < .05) and a 14% increased risk, compared with patients with influenza infection (aHR, 1.14; 95% CI, 1.10–1.17; P < .05). In Japanese patients, risk was increased across all four categories, including a doubled risk for inflammatory arthritis (aHR, 2.02; 95% CI, 1.96–2.07; P < .05), compared with the general population.

The researchers had data only from the South Korean cohort to calculate risk based on vaccination status, SARS-CoV-2 variant (wild type versus Delta), and COVID-19 severity. Researchers determined a COVID-19 infection to be moderate-to-severe based on billing codes for ICU admission or requiring oxygen therapy, extracorporeal membrane oxygenation, renal replacement, or CPR.

Infection with both the original strain and the Delta variant were linked to similar increased risks for AIRD, but moderate to severe COVID-19 infections had greater risk of subsequent AIRD (aHR, 1.42; P < .05) than mild infections (aHR, 1.22; P < .05). Vaccination was linked to a lower risk of AIRD within the COVID-19 patient population: One dose was linked to a 41% reduced risk (HR, 0.59; P < .05) and two doses were linked to a 58% reduced risk (HR, 0.42; P < .05), regardless of the vaccine type, compared with unvaccinated patients with COVID-19. The apparent protective effect of vaccination was true only for patients with mild COVID-19, not those with moderate to severe infection.

“One has to wonder whether or not these people were at much higher risk of developing autoimmune disease that just got exposed because they got COVID, so that a fraction of these would have gotten an autoimmune disease downstream,” Dr. Alfred Kim said. Regardless, one clinical implication of the findings is the reduced risk in vaccinated patients, regardless of the vaccine type, given the fact that “mRNA vaccination in particular has not been associated with any autoantibody development,” he said.

Though the correlations in the study cannot translate to causation, several mechanisms might be at play in a viral infection contributing to autoimmune risk, Dr. Davidson said. Given that viral nucleic acids also recognize self-nucleic acids, “a large load of viral nucleic acid may break tolerance,” or “viral proteins could also mimic self-proteins,” she said. “In addition, tolerance may be broken by a highly inflammatory environment associated with the release of cytokines and other inflammatory mediators.”

The association between new-onset autoimmune disease and severe COVID-19 infection suggests multiple mechanisms may be involved in excess immune stimulation, Dr. Davidson said. But she added that it’s unclear how these findings, involving the original strain and Delta variant of SARS-CoV-2, might relate to currently circulating variants.

The research was funded by the National Research Foundation of Korea, the Korea Health Industry Development Institute, and the Ministry of Food and Drug Safety of the Republic of Korea. The authors reported no relevant financial relationships with industry. Dr. Alfred Kim has sponsored research agreements with AstraZeneca, Bristol-Myers Squibb, and Novartis; receives royalties from a patent with Kypha Inc.; and has done consulting or speaking for Amgen, ANI Pharmaceuticals, Aurinia Pharmaceuticals, Exagen Diagnostics, GlaxoSmithKline, Kypha, Miltenyi Biotech, Pfizer, Rheumatology & Arthritis Learning Network, Synthekine, Techtonic Therapeutics, and UpToDate. Dr. Byram reported consulting for TenSixteen Bio. Dr. Davidson had no disclosures.

The risk of developing a new autoimmune inflammatory rheumatic disease (AIRD) is greater following a COVID-19 infection than after an influenza infection or in the general population, according to a study published March 5 in Annals of Internal Medicine. More severe COVID-19 infections were linked to a greater risk of incident rheumatic disease, but vaccination appeared protective against development of a new AIRD.

“Importantly, this study shows the value of vaccination to prevent severe disease and these types of sequelae,” Anne Davidson, MBBS, a professor in the Institute of Molecular Medicine at The Feinstein Institutes for Medical Research in Manhasset, New York, who was not involved in the study, said in an interview.

Davidson_Anne_NY_web.jpg

More Robust and Rigorous Research

Past cohort studies finding an increased risk of rheumatic disease after COVID-19 “based their findings solely on comparisons between infected and uninfected groups, which could be influenced by ascertainment bias due to disparities in care, differences in health-seeking tendencies, and inherent risks among the groups,” Min Seo Kim, MD, of the Broad Institute of MIT and Harvard, Cambridge, Massachusetts, and his colleagues reported. Their study, however, required at least two claims with codes for rheumatic disease and compared patients with COVID-19 to those with flu “to adjust for the potentially heightened detection of AIRD in SARS-CoV-2–infected persons owing to their interactions with the health care system.”

Dr. Alfred Kim said the fact that they used at least two claims codes “gives a little more credence that the patients were actually experiencing some sort of autoimmune inflammatory condition as opposed to a very transient issue post COVID that just went away on its own.”

Kim_Alfred_STLOUIS_web.jpg

He acknowledged that the previous research was reasonably strong, “especially in light of the fact that there has been so much work done on a molecular level demonstrating that COVID-19 is associated with a substantial increase in autoantibodies in a significant proportion of patients, so this always opened up the possibility that this could associate with some sort of autoimmune disease downstream.”

While the study is well done with a large population, “it still has limitations that might overestimate the effect,” Kevin W. Byram, MD, associate professor of medicine in rheumatology and immunology at Vanderbilt University Medical Center in Nashville, Tennessee, who was not involved in the study, said in an interview. “We certainly have seen individual cases of new rheumatic disease where COVID-19 infection is likely the trigger,” but the phenomenon is not new, he added.

“Many autoimmune diseases are spurred by a loss of tolerance that might be induced by a pathogen of some sort,” Dr. Byram said. “The study is right to point out different forms of bias that might be at play. One in particular that is important to consider in a study like this is the lack of case-level adjudication regarding the diagnosis of rheumatic disease” since the study relied on available ICD-10 codes and medication prescriptions.

Byram_Kevin_W_TN_web.jpg

Risk Varied With Disease Severity and Vaccination Status

Among the Korean patients, 3.9% had a COVID-19 infection and 0.98% had an influenza infection. After matching, the comparison populations included 94,504 patients with COVID-19 versus 94,504 patients with flu, and 177,083 patients with COVID-19 versus 675,750 uninfected controls.

The risk of developing an AIRD at least 1 month after infection in South Korean patients with COVID-19 was 25% higher than in uninfected control participants (adjusted hazard ratio [aHR], 1.25; 95% CI, 1.18–1.31; P < .05) and 30% higher than in influenza patients (aHR, 1.3; 95% CI, 1.02–1.59; P < .05). Specifically, risk in South Korean patients with COVID-19 was significantly increased for connective tissue disease and both treated and untreated AIRD but not for inflammatory arthritis.

Among the Japanese patients, 8.2% had COVID-19 and 0.99% had flu, resulting in matched populations of 115,003 with COVID-19 versus 110,310 with flu, and 960,849 with COVID-19 versus 1,606,873 uninfected patients. The effect size was larger in Japanese patients, with a 79% increased risk for AIRD in patients with COVID-19, compared with the general population (aHR, 1.79; 95% CI, 1.77–1.82; P < .05) and a 14% increased risk, compared with patients with influenza infection (aHR, 1.14; 95% CI, 1.10–1.17; P < .05). In Japanese patients, risk was increased across all four categories, including a doubled risk for inflammatory arthritis (aHR, 2.02; 95% CI, 1.96–2.07; P < .05), compared with the general population.

The researchers had data only from the South Korean cohort to calculate risk based on vaccination status, SARS-CoV-2 variant (wild type versus Delta), and COVID-19 severity. Researchers determined a COVID-19 infection to be moderate-to-severe based on billing codes for ICU admission or requiring oxygen therapy, extracorporeal membrane oxygenation, renal replacement, or CPR.

Infection with both the original strain and the Delta variant were linked to similar increased risks for AIRD, but moderate to severe COVID-19 infections had greater risk of subsequent AIRD (aHR, 1.42; P < .05) than mild infections (aHR, 1.22; P < .05). Vaccination was linked to a lower risk of AIRD within the COVID-19 patient population: One dose was linked to a 41% reduced risk (HR, 0.59; P < .05) and two doses were linked to a 58% reduced risk (HR, 0.42; P < .05), regardless of the vaccine type, compared with unvaccinated patients with COVID-19. The apparent protective effect of vaccination was true only for patients with mild COVID-19, not those with moderate to severe infection.

“One has to wonder whether or not these people were at much higher risk of developing autoimmune disease that just got exposed because they got COVID, so that a fraction of these would have gotten an autoimmune disease downstream,” Dr. Alfred Kim said. Regardless, one clinical implication of the findings is the reduced risk in vaccinated patients, regardless of the vaccine type, given the fact that “mRNA vaccination in particular has not been associated with any autoantibody development,” he said.

Though the correlations in the study cannot translate to causation, several mechanisms might be at play in a viral infection contributing to autoimmune risk, Dr. Davidson said. Given that viral nucleic acids also recognize self-nucleic acids, “a large load of viral nucleic acid may break tolerance,” or “viral proteins could also mimic self-proteins,” she said. “In addition, tolerance may be broken by a highly inflammatory environment associated with the release of cytokines and other inflammatory mediators.”

The association between new-onset autoimmune disease and severe COVID-19 infection suggests multiple mechanisms may be involved in excess immune stimulation, Dr. Davidson said. But she added that it’s unclear how these findings, involving the original strain and Delta variant of SARS-CoV-2, might relate to currently circulating variants.

The research was funded by the National Research Foundation of Korea, the Korea Health Industry Development Institute, and the Ministry of Food and Drug Safety of the Republic of Korea. The authors reported no relevant financial relationships with industry. Dr. Alfred Kim has sponsored research agreements with AstraZeneca, Bristol-Myers Squibb, and Novartis; receives royalties from a patent with Kypha Inc.; and has done consulting or speaking for Amgen, ANI Pharmaceuticals, Aurinia Pharmaceuticals, Exagen Diagnostics, GlaxoSmithKline, Kypha, Miltenyi Biotech, Pfizer, Rheumatology & Arthritis Learning Network, Synthekine, Techtonic Therapeutics, and UpToDate. Dr. Byram reported consulting for TenSixteen Bio. Dr. Davidson had no disclosures.

The risk of developing a new autoimmune inflammatory rheumatic disease (AIRD) is greater following a COVID-19 infection than after an influenza infection or in the general population, according to a study published March 5 in Annals of Internal Medicine. More severe COVID-19 infections were linked to a greater risk of incident rheumatic disease, but vaccination appeared protective against development of a new AIRD.

“Importantly, this study shows the value of vaccination to prevent severe disease and these types of sequelae,” Anne Davidson, MBBS, a professor in the Institute of Molecular Medicine at The Feinstein Institutes for Medical Research in Manhasset, New York, who was not involved in the study, said in an interview.

Davidson_Anne_NY_web.jpg

More Robust and Rigorous Research

Past cohort studies finding an increased risk of rheumatic disease after COVID-19 “based their findings solely on comparisons between infected and uninfected groups, which could be influenced by ascertainment bias due to disparities in care, differences in health-seeking tendencies, and inherent risks among the groups,” Min Seo Kim, MD, of the Broad Institute of MIT and Harvard, Cambridge, Massachusetts, and his colleagues reported. Their study, however, required at least two claims with codes for rheumatic disease and compared patients with COVID-19 to those with flu “to adjust for the potentially heightened detection of AIRD in SARS-CoV-2–infected persons owing to their interactions with the health care system.”

Dr. Alfred Kim said the fact that they used at least two claims codes “gives a little more credence that the patients were actually experiencing some sort of autoimmune inflammatory condition as opposed to a very transient issue post COVID that just went away on its own.”

Kim_Alfred_STLOUIS_web.jpg

He acknowledged that the previous research was reasonably strong, “especially in light of the fact that there has been so much work done on a molecular level demonstrating that COVID-19 is associated with a substantial increase in autoantibodies in a significant proportion of patients, so this always opened up the possibility that this could associate with some sort of autoimmune disease downstream.”

While the study is well done with a large population, “it still has limitations that might overestimate the effect,” Kevin W. Byram, MD, associate professor of medicine in rheumatology and immunology at Vanderbilt University Medical Center in Nashville, Tennessee, who was not involved in the study, said in an interview. “We certainly have seen individual cases of new rheumatic disease where COVID-19 infection is likely the trigger,” but the phenomenon is not new, he added.

“Many autoimmune diseases are spurred by a loss of tolerance that might be induced by a pathogen of some sort,” Dr. Byram said. “The study is right to point out different forms of bias that might be at play. One in particular that is important to consider in a study like this is the lack of case-level adjudication regarding the diagnosis of rheumatic disease” since the study relied on available ICD-10 codes and medication prescriptions.

Byram_Kevin_W_TN_web.jpg

Risk Varied With Disease Severity and Vaccination Status

Among the Korean patients, 3.9% had a COVID-19 infection and 0.98% had an influenza infection. After matching, the comparison populations included 94,504 patients with COVID-19 versus 94,504 patients with flu, and 177,083 patients with COVID-19 versus 675,750 uninfected controls.

The risk of developing an AIRD at least 1 month after infection in South Korean patients with COVID-19 was 25% higher than in uninfected control participants (adjusted hazard ratio [aHR], 1.25; 95% CI, 1.18–1.31; P < .05) and 30% higher than in influenza patients (aHR, 1.3; 95% CI, 1.02–1.59; P < .05). Specifically, risk in South Korean patients with COVID-19 was significantly increased for connective tissue disease and both treated and untreated AIRD but not for inflammatory arthritis.

Among the Japanese patients, 8.2% had COVID-19 and 0.99% had flu, resulting in matched populations of 115,003 with COVID-19 versus 110,310 with flu, and 960,849 with COVID-19 versus 1,606,873 uninfected patients. The effect size was larger in Japanese patients, with a 79% increased risk for AIRD in patients with COVID-19, compared with the general population (aHR, 1.79; 95% CI, 1.77–1.82; P < .05) and a 14% increased risk, compared with patients with influenza infection (aHR, 1.14; 95% CI, 1.10–1.17; P < .05). In Japanese patients, risk was increased across all four categories, including a doubled risk for inflammatory arthritis (aHR, 2.02; 95% CI, 1.96–2.07; P < .05), compared with the general population.

The researchers had data only from the South Korean cohort to calculate risk based on vaccination status, SARS-CoV-2 variant (wild type versus Delta), and COVID-19 severity. Researchers determined a COVID-19 infection to be moderate-to-severe based on billing codes for ICU admission or requiring oxygen therapy, extracorporeal membrane oxygenation, renal replacement, or CPR.

Infection with both the original strain and the Delta variant were linked to similar increased risks for AIRD, but moderate to severe COVID-19 infections had greater risk of subsequent AIRD (aHR, 1.42; P < .05) than mild infections (aHR, 1.22; P < .05). Vaccination was linked to a lower risk of AIRD within the COVID-19 patient population: One dose was linked to a 41% reduced risk (HR, 0.59; P < .05) and two doses were linked to a 58% reduced risk (HR, 0.42; P < .05), regardless of the vaccine type, compared with unvaccinated patients with COVID-19. The apparent protective effect of vaccination was true only for patients with mild COVID-19, not those with moderate to severe infection.

“One has to wonder whether or not these people were at much higher risk of developing autoimmune disease that just got exposed because they got COVID, so that a fraction of these would have gotten an autoimmune disease downstream,” Dr. Alfred Kim said. Regardless, one clinical implication of the findings is the reduced risk in vaccinated patients, regardless of the vaccine type, given the fact that “mRNA vaccination in particular has not been associated with any autoantibody development,” he said.

Though the correlations in the study cannot translate to causation, several mechanisms might be at play in a viral infection contributing to autoimmune risk, Dr. Davidson said. Given that viral nucleic acids also recognize self-nucleic acids, “a large load of viral nucleic acid may break tolerance,” or “viral proteins could also mimic self-proteins,” she said. “In addition, tolerance may be broken by a highly inflammatory environment associated with the release of cytokines and other inflammatory mediators.”

The association between new-onset autoimmune disease and severe COVID-19 infection suggests multiple mechanisms may be involved in excess immune stimulation, Dr. Davidson said. But she added that it’s unclear how these findings, involving the original strain and Delta variant of SARS-CoV-2, might relate to currently circulating variants.

The research was funded by the National Research Foundation of Korea, the Korea Health Industry Development Institute, and the Ministry of Food and Drug Safety of the Republic of Korea. The authors reported no relevant financial relationships with industry. Dr. Alfred Kim has sponsored research agreements with AstraZeneca, Bristol-Myers Squibb, and Novartis; receives royalties from a patent with Kypha Inc.; and has done consulting or speaking for Amgen, ANI Pharmaceuticals, Aurinia Pharmaceuticals, Exagen Diagnostics, GlaxoSmithKline, Kypha, Miltenyi Biotech, Pfizer, Rheumatology & Arthritis Learning Network, Synthekine, Techtonic Therapeutics, and UpToDate. Dr. Byram reported consulting for TenSixteen Bio. Dr. Davidson had no disclosures.

The measles outbreak in Florida, occurring just as health officials announced an official end to Philadelphia’s measles outbreak and rising global cases, has cast attention once again on concerns about vaccine hesitancy. In the midst of Florida’s surgeon general avoiding measles vaccination recommendations for parents, the American Academy of Pediatrics has updated its clinical guidance on vaccine communication.

“Disruption to routine pediatric vaccination during the COVID-19 pandemic has left many children vulnerable to vaccine-preventable diseases and more locations susceptible to outbreaks in the United States and around the world,” Sean T. O’Leary, MD, MPH, a pediatric infectious diseases specialist and associate professor of pediatrics at the University of Colorado in Aurora, and his colleagues, wrote in the new report, published in the March issue of Pediatrics. “Geographic clustering of vaccine refusal further increases the risk of communicable disease outbreaks in certain communities even when vaccination rates at a state or national level remain high overall.”

O_Leary_Sean_COLORADO_web.jpg

The authors note that disease resurgence may bolster vaccine uptake, with media coverage of recent outbreaks linked to more pro-vaccine discussions and attitudes among parents. But the evidence on that remains inconclusive, and the authors point out the slow uptake in COVID-19 vaccination as parents navigate ongoing spread of both the disease and vaccine misinformation.
 

Conflicting Evidence on Postpandemic Attitudes

It remains unclear how parent attitudes toward vaccines have shifted, if at all, since the pandemic. A study published in Pediatrics from October 2023, which Dr. O’Leary also coauthored, analyzed data from an online survey of Colorado mothers between 2018 and 2021 and found no significant difference in vaccine hesitancy during the pandemic compared with pre-pandemic.

Among 3,553 respondents, 1 in 5 (20.4%) were vaccine hesitant overall. Though parents were twice as likely to feel uncertain in trusting vaccine information after the COVID-19 vaccines were authorized (adjusted odds ratio [aOR] 2.14), they were half as likely to be unsure about hesitancy toward childhood vaccines (aOR 0.48).

Another study in Pediatrics from October 2023 found that common concerns about COVID-19 vaccines among parents included infertility, long-term effects from the vaccines, and effects on preexisting medical conditions. But even then, participants in focus groups “expressed that they would listen to their doctor for information about COVID-19 vaccines,” wrote Aubree Honcoop, MPS, of the University of Nebraska Medical Center in Omaha, and her colleagues.

“I think what we’re seeing, very importantly, is that physicians seem to be the source people rely on,” said Walter Orenstein, MD, professor of medicine and associate director of the Emory Vaccine Center at Emory University in Atlanta. “But we need to give the physicians time and incentives to spend time with families,” such as a billing code for vaccine counseling, he said.

Orenstein_Walter_Atlanta_web.jpg

Offit_Paul_Philadelphia_web.jpg

Clinical Guidance

The new report reviews previously published evidence on the spectrum of parental vaccine acceptance — from supporters and “go along to get along” parents to cautious acceptors and fence sitters to vaccine refusers — and the determinants that contribute to hesitancy. They also noted the social inequities that have played a role in vaccine uptake disparities.

“Distrust of health systems based on historic and ongoing discrimination and inequitable access to care are intertwined challenges that contribute to racial and ethnic disparities in vaccine uptake,” the authors wrote. “Although there has been progress in reducing racial, ethnic, and socioeconomic disparities in childhood vaccination coverage, the COVID-19 pandemic made clear how much work is yet to be done.”

The report also reviewed the societal, individual, payer and pediatric practice costs of vaccine refusal. The 1-year cost to taxpayers from the measles outbreak in New York City in 2018-2019, for example, was $8.4 million, excluding vaccination programs.

The report provides background information to equip pediatricians for conversations with parents about vaccines. Since safety is the top concern for vaccine hesitancy among parents, the authors advised pediatricians to be familiar with the process of vaccine testing, emergency use authorization, licensure, approval, recommendations, and safety monitoring, including the Vaccine Safety Datalink, the Vaccine Adverse Event Reporting System (VAERS), the FDA’s Biologics Effectiveness and Safety (BEST) system, and the CDC’s Clinical Immunization Safety Assessment Project (CISA).

“Because vaccines are generally given to healthy individuals to prevent disease, they are held to a higher safety standard than other medications,” the authors wrote before providing a summary of the process for physicians to reference. The report also includes information on vaccine ingredients and a chart of common misconceptions about vaccines with the corresponding facts.
 

Overcoming Hesitancy

Evidence-based strategies for increasing childhood vaccine uptake begin with a strong vaccine recommendation using a presumptive rather than participatory approach, the authors wrote. “A presumptive format is one in which the clinician asserts a position regarding vaccines using a closed-ended statement, such as ‘Sara is due for several vaccines today’ or ‘Well, we have to do some shots,’ ” the authors wrote. “This strategy is in contrast to a participatory format, in which an open-ended question is used to more explicitly invite the parent to voice an opinion, such as ‘How do you feel about vaccines today?’ ” The presumptive format and a strong recommendation are both associated with greater uptake, evidence shows.

For parents who express hesitancy, the authors provide a summary of additional evidence-based communication strategies, starting with motivational interviewing. Two other strategies they highlight include using language to re-emphasize the importance of adhering to the CDC recommended schedule — “He really needs these shots” — and bundling discussion of all recommended vaccines for a visit at once.

“Finally, clinicians can emphasize their own experiences when discussing the need for vaccination, including personal experience with vaccine-preventable diseases and the fact that they and their families are vaccinated because of their confidence in the safety and efficacy of the vaccines,” the authors wrote.

For families who refuse or delay vaccines, the authors reviewed the “ethical arguments both in favor of and against dismissal policies,” noting that nearly all pediatricians who report dismissing families who refuse vaccination are in private practice, since large systems are often unable to dismiss patients. They also point out that fewer pediatricians dismiss families for spreading out vaccines than outright refusing all vaccines.

”Dismissal of child patients of vaccine-refusing parents can be a difficult decision arrived at after considering multiple factors and documented attempts to counsel vaccine-refusing families,” they wrote. “However, if repeated attempts to help understand and address parental values and vaccine concerns fails to engender trust, move parents toward vaccine acceptance, or strengthen the therapeutic alliance, dismissal can be an acceptable option.”

Finally, the authors reminded pediatricians “that vaccine-hesitant parents are a heterogeneous group and that specific parental vaccine concerns need to be individually identified and addressed.” Working with families to discuss their questions and concerns is an opportunity to “build rapport and trust with a family,” they wrote, ”and, ultimately, protect their children from the scourge of vaccine-preventable diseases.”

The focus groups study was funded by the National Institutes of Health, and the authors reported having no disclosures. The Colorado attitudes study used no external funding, and the authors reported no disclosures. The new clinical report used no external funding, and the authors reported no disclosures. Dr. Orenstein is an uncompensated member of the Moderna Scientific Advisory Board. Dr. Offit codeveloped a licensed rotavirus vaccine, but he does not receive any royalties or own a patent for that.

The measles outbreak in Florida, occurring just as health officials announced an official end to Philadelphia’s measles outbreak and rising global cases, has cast attention once again on concerns about vaccine hesitancy. In the midst of Florida’s surgeon general avoiding measles vaccination recommendations for parents, the American Academy of Pediatrics has updated its clinical guidance on vaccine communication.

“Disruption to routine pediatric vaccination during the COVID-19 pandemic has left many children vulnerable to vaccine-preventable diseases and more locations susceptible to outbreaks in the United States and around the world,” Sean T. O’Leary, MD, MPH, a pediatric infectious diseases specialist and associate professor of pediatrics at the University of Colorado in Aurora, and his colleagues, wrote in the new report, published in the March issue of Pediatrics. “Geographic clustering of vaccine refusal further increases the risk of communicable disease outbreaks in certain communities even when vaccination rates at a state or national level remain high overall.”

O_Leary_Sean_COLORADO_web.jpg

The authors note that disease resurgence may bolster vaccine uptake, with media coverage of recent outbreaks linked to more pro-vaccine discussions and attitudes among parents. But the evidence on that remains inconclusive, and the authors point out the slow uptake in COVID-19 vaccination as parents navigate ongoing spread of both the disease and vaccine misinformation.
 

Conflicting Evidence on Postpandemic Attitudes

It remains unclear how parent attitudes toward vaccines have shifted, if at all, since the pandemic. A study published in Pediatrics from October 2023, which Dr. O’Leary also coauthored, analyzed data from an online survey of Colorado mothers between 2018 and 2021 and found no significant difference in vaccine hesitancy during the pandemic compared with pre-pandemic.

Among 3,553 respondents, 1 in 5 (20.4%) were vaccine hesitant overall. Though parents were twice as likely to feel uncertain in trusting vaccine information after the COVID-19 vaccines were authorized (adjusted odds ratio [aOR] 2.14), they were half as likely to be unsure about hesitancy toward childhood vaccines (aOR 0.48).

Another study in Pediatrics from October 2023 found that common concerns about COVID-19 vaccines among parents included infertility, long-term effects from the vaccines, and effects on preexisting medical conditions. But even then, participants in focus groups “expressed that they would listen to their doctor for information about COVID-19 vaccines,” wrote Aubree Honcoop, MPS, of the University of Nebraska Medical Center in Omaha, and her colleagues.

“I think what we’re seeing, very importantly, is that physicians seem to be the source people rely on,” said Walter Orenstein, MD, professor of medicine and associate director of the Emory Vaccine Center at Emory University in Atlanta. “But we need to give the physicians time and incentives to spend time with families,” such as a billing code for vaccine counseling, he said.

Orenstein_Walter_Atlanta_web.jpg

Offit_Paul_Philadelphia_web.jpg

Clinical Guidance

The new report reviews previously published evidence on the spectrum of parental vaccine acceptance — from supporters and “go along to get along” parents to cautious acceptors and fence sitters to vaccine refusers — and the determinants that contribute to hesitancy. They also noted the social inequities that have played a role in vaccine uptake disparities.

“Distrust of health systems based on historic and ongoing discrimination and inequitable access to care are intertwined challenges that contribute to racial and ethnic disparities in vaccine uptake,” the authors wrote. “Although there has been progress in reducing racial, ethnic, and socioeconomic disparities in childhood vaccination coverage, the COVID-19 pandemic made clear how much work is yet to be done.”

The report also reviewed the societal, individual, payer and pediatric practice costs of vaccine refusal. The 1-year cost to taxpayers from the measles outbreak in New York City in 2018-2019, for example, was $8.4 million, excluding vaccination programs.

The report provides background information to equip pediatricians for conversations with parents about vaccines. Since safety is the top concern for vaccine hesitancy among parents, the authors advised pediatricians to be familiar with the process of vaccine testing, emergency use authorization, licensure, approval, recommendations, and safety monitoring, including the Vaccine Safety Datalink, the Vaccine Adverse Event Reporting System (VAERS), the FDA’s Biologics Effectiveness and Safety (BEST) system, and the CDC’s Clinical Immunization Safety Assessment Project (CISA).

“Because vaccines are generally given to healthy individuals to prevent disease, they are held to a higher safety standard than other medications,” the authors wrote before providing a summary of the process for physicians to reference. The report also includes information on vaccine ingredients and a chart of common misconceptions about vaccines with the corresponding facts.
 

Overcoming Hesitancy

Evidence-based strategies for increasing childhood vaccine uptake begin with a strong vaccine recommendation using a presumptive rather than participatory approach, the authors wrote. “A presumptive format is one in which the clinician asserts a position regarding vaccines using a closed-ended statement, such as ‘Sara is due for several vaccines today’ or ‘Well, we have to do some shots,’ ” the authors wrote. “This strategy is in contrast to a participatory format, in which an open-ended question is used to more explicitly invite the parent to voice an opinion, such as ‘How do you feel about vaccines today?’ ” The presumptive format and a strong recommendation are both associated with greater uptake, evidence shows.

For parents who express hesitancy, the authors provide a summary of additional evidence-based communication strategies, starting with motivational interviewing. Two other strategies they highlight include using language to re-emphasize the importance of adhering to the CDC recommended schedule — “He really needs these shots” — and bundling discussion of all recommended vaccines for a visit at once.

“Finally, clinicians can emphasize their own experiences when discussing the need for vaccination, including personal experience with vaccine-preventable diseases and the fact that they and their families are vaccinated because of their confidence in the safety and efficacy of the vaccines,” the authors wrote.

For families who refuse or delay vaccines, the authors reviewed the “ethical arguments both in favor of and against dismissal policies,” noting that nearly all pediatricians who report dismissing families who refuse vaccination are in private practice, since large systems are often unable to dismiss patients. They also point out that fewer pediatricians dismiss families for spreading out vaccines than outright refusing all vaccines.

”Dismissal of child patients of vaccine-refusing parents can be a difficult decision arrived at after considering multiple factors and documented attempts to counsel vaccine-refusing families,” they wrote. “However, if repeated attempts to help understand and address parental values and vaccine concerns fails to engender trust, move parents toward vaccine acceptance, or strengthen the therapeutic alliance, dismissal can be an acceptable option.”

Finally, the authors reminded pediatricians “that vaccine-hesitant parents are a heterogeneous group and that specific parental vaccine concerns need to be individually identified and addressed.” Working with families to discuss their questions and concerns is an opportunity to “build rapport and trust with a family,” they wrote, ”and, ultimately, protect their children from the scourge of vaccine-preventable diseases.”

The focus groups study was funded by the National Institutes of Health, and the authors reported having no disclosures. The Colorado attitudes study used no external funding, and the authors reported no disclosures. The new clinical report used no external funding, and the authors reported no disclosures. Dr. Orenstein is an uncompensated member of the Moderna Scientific Advisory Board. Dr. Offit codeveloped a licensed rotavirus vaccine, but he does not receive any royalties or own a patent for that.

The measles outbreak in Florida, occurring just as health officials announced an official end to Philadelphia’s measles outbreak and rising global cases, has cast attention once again on concerns about vaccine hesitancy. In the midst of Florida’s surgeon general avoiding measles vaccination recommendations for parents, the American Academy of Pediatrics has updated its clinical guidance on vaccine communication.

“Disruption to routine pediatric vaccination during the COVID-19 pandemic has left many children vulnerable to vaccine-preventable diseases and more locations susceptible to outbreaks in the United States and around the world,” Sean T. O’Leary, MD, MPH, a pediatric infectious diseases specialist and associate professor of pediatrics at the University of Colorado in Aurora, and his colleagues, wrote in the new report, published in the March issue of Pediatrics. “Geographic clustering of vaccine refusal further increases the risk of communicable disease outbreaks in certain communities even when vaccination rates at a state or national level remain high overall.”

O_Leary_Sean_COLORADO_web.jpg

The authors note that disease resurgence may bolster vaccine uptake, with media coverage of recent outbreaks linked to more pro-vaccine discussions and attitudes among parents. But the evidence on that remains inconclusive, and the authors point out the slow uptake in COVID-19 vaccination as parents navigate ongoing spread of both the disease and vaccine misinformation.
 

Conflicting Evidence on Postpandemic Attitudes

It remains unclear how parent attitudes toward vaccines have shifted, if at all, since the pandemic. A study published in Pediatrics from October 2023, which Dr. O’Leary also coauthored, analyzed data from an online survey of Colorado mothers between 2018 and 2021 and found no significant difference in vaccine hesitancy during the pandemic compared with pre-pandemic.

Among 3,553 respondents, 1 in 5 (20.4%) were vaccine hesitant overall. Though parents were twice as likely to feel uncertain in trusting vaccine information after the COVID-19 vaccines were authorized (adjusted odds ratio [aOR] 2.14), they were half as likely to be unsure about hesitancy toward childhood vaccines (aOR 0.48).

Another study in Pediatrics from October 2023 found that common concerns about COVID-19 vaccines among parents included infertility, long-term effects from the vaccines, and effects on preexisting medical conditions. But even then, participants in focus groups “expressed that they would listen to their doctor for information about COVID-19 vaccines,” wrote Aubree Honcoop, MPS, of the University of Nebraska Medical Center in Omaha, and her colleagues.

“I think what we’re seeing, very importantly, is that physicians seem to be the source people rely on,” said Walter Orenstein, MD, professor of medicine and associate director of the Emory Vaccine Center at Emory University in Atlanta. “But we need to give the physicians time and incentives to spend time with families,” such as a billing code for vaccine counseling, he said.

Orenstein_Walter_Atlanta_web.jpg

Offit_Paul_Philadelphia_web.jpg

Clinical Guidance

The new report reviews previously published evidence on the spectrum of parental vaccine acceptance — from supporters and “go along to get along” parents to cautious acceptors and fence sitters to vaccine refusers — and the determinants that contribute to hesitancy. They also noted the social inequities that have played a role in vaccine uptake disparities.

“Distrust of health systems based on historic and ongoing discrimination and inequitable access to care are intertwined challenges that contribute to racial and ethnic disparities in vaccine uptake,” the authors wrote. “Although there has been progress in reducing racial, ethnic, and socioeconomic disparities in childhood vaccination coverage, the COVID-19 pandemic made clear how much work is yet to be done.”

The report also reviewed the societal, individual, payer and pediatric practice costs of vaccine refusal. The 1-year cost to taxpayers from the measles outbreak in New York City in 2018-2019, for example, was $8.4 million, excluding vaccination programs.

The report provides background information to equip pediatricians for conversations with parents about vaccines. Since safety is the top concern for vaccine hesitancy among parents, the authors advised pediatricians to be familiar with the process of vaccine testing, emergency use authorization, licensure, approval, recommendations, and safety monitoring, including the Vaccine Safety Datalink, the Vaccine Adverse Event Reporting System (VAERS), the FDA’s Biologics Effectiveness and Safety (BEST) system, and the CDC’s Clinical Immunization Safety Assessment Project (CISA).

“Because vaccines are generally given to healthy individuals to prevent disease, they are held to a higher safety standard than other medications,” the authors wrote before providing a summary of the process for physicians to reference. The report also includes information on vaccine ingredients and a chart of common misconceptions about vaccines with the corresponding facts.
 

Overcoming Hesitancy

Evidence-based strategies for increasing childhood vaccine uptake begin with a strong vaccine recommendation using a presumptive rather than participatory approach, the authors wrote. “A presumptive format is one in which the clinician asserts a position regarding vaccines using a closed-ended statement, such as ‘Sara is due for several vaccines today’ or ‘Well, we have to do some shots,’ ” the authors wrote. “This strategy is in contrast to a participatory format, in which an open-ended question is used to more explicitly invite the parent to voice an opinion, such as ‘How do you feel about vaccines today?’ ” The presumptive format and a strong recommendation are both associated with greater uptake, evidence shows.

For parents who express hesitancy, the authors provide a summary of additional evidence-based communication strategies, starting with motivational interviewing. Two other strategies they highlight include using language to re-emphasize the importance of adhering to the CDC recommended schedule — “He really needs these shots” — and bundling discussion of all recommended vaccines for a visit at once.

“Finally, clinicians can emphasize their own experiences when discussing the need for vaccination, including personal experience with vaccine-preventable diseases and the fact that they and their families are vaccinated because of their confidence in the safety and efficacy of the vaccines,” the authors wrote.

For families who refuse or delay vaccines, the authors reviewed the “ethical arguments both in favor of and against dismissal policies,” noting that nearly all pediatricians who report dismissing families who refuse vaccination are in private practice, since large systems are often unable to dismiss patients. They also point out that fewer pediatricians dismiss families for spreading out vaccines than outright refusing all vaccines.

”Dismissal of child patients of vaccine-refusing parents can be a difficult decision arrived at after considering multiple factors and documented attempts to counsel vaccine-refusing families,” they wrote. “However, if repeated attempts to help understand and address parental values and vaccine concerns fails to engender trust, move parents toward vaccine acceptance, or strengthen the therapeutic alliance, dismissal can be an acceptable option.”

Finally, the authors reminded pediatricians “that vaccine-hesitant parents are a heterogeneous group and that specific parental vaccine concerns need to be individually identified and addressed.” Working with families to discuss their questions and concerns is an opportunity to “build rapport and trust with a family,” they wrote, ”and, ultimately, protect their children from the scourge of vaccine-preventable diseases.”

The focus groups study was funded by the National Institutes of Health, and the authors reported having no disclosures. The Colorado attitudes study used no external funding, and the authors reported no disclosures. The new clinical report used no external funding, and the authors reported no disclosures. Dr. Orenstein is an uncompensated member of the Moderna Scientific Advisory Board. Dr. Offit codeveloped a licensed rotavirus vaccine, but he does not receive any royalties or own a patent for that.

The explosion of interest in glucagon-like peptide 1 receptor agonists (GLP-1 RAs), such as semaglutide and tirzepatide, has raised questions about what therapeutic effects this class of medication might have beyond their current indications for type 2 diabetes and obesity. 

Recent clinical trials have recently identified benefits from GLP-1 agents for the heart, liver, and kidneys, but the current evidence base is murkier regarding how the drugs may affect male fertility. 

Experts say the connection between GLP-1 RAs and improved male fertility makes sense biologically. For starters, overweight and obesity are strongly associated with male infertility in several overlapping ways. Obesity can disrupt hormones linked to fertility, increase the risk for defective sperm, adversely affect semen quality, and even make sexual intercourse more difficult due to obesity’s link to erectile dysfunction. As a result, GLP-1 RAs should at least in theory boost male fertility in men who take the drugs to lose weight. 

But animal studies and a handful of small trials and observational data point to the potential for GLP-1 RAs to improve male fertility in other ways.

A recent narrative review on GLP-1 RAs and male reproductive health, published in the journal Medicina in December 2023, surveyed the potential of the drugs for male infertility and offered reason for optimism. 

Hossein Sadeghi-Nejad, MD, director of urology at NYU Langone Health, New York, and a coauthor of the article, said that one reason he and his colleagues conducted their analysis was the known association between weight loss and an increase in testosterone.

“Most of the animal studies that are out there show that this class of drugs does affect testosterone levels,” Dr. Sadeghi-Nejad said; they wanted to better understand what other evidence showed about GLP-1 agonists and other fertility factors. 
 

Link Between Obesity and Fertility

The recent paper first reviews the well-established link between obesity and poorer fertility outcomes. 

“Certainly, obesity poses a significant societal problem with substantial impacts on both overall health and economic aspects,” senior author Ranjith Ramasamy, MD, associate professor of urology and director of the reproductive urology Fellowship program at the University of Miami’s Miller School of Medicine, told this news organization. “The escalating global obesity rates raise concerns, especially in the field of male infertility, where excessive body fat induces intrinsic hormonal changes leading to alterations, eventually, in semen parameters.”

The authors noted that obesity has been linked in the research to worse assisted reproductive technology (ART) outcomes and to subfecundity, taking more than 12 months to achieve pregnancy. They also referenced a systematic review that found men with obesity were more likely to have lower sperm counts and less viable sperm.

“From our standpoint, I think the key point was to raise awareness about the fact that obesity, because of the aromatization of testosterone to estradiol [from excess adipose tissue], will affect the hormonal axis and the availability of testosterone and, therefore, indirectly affects spermatogenesis,” Dr. Sadeghi-Nejad said. 

Obesity is also linked to lower levels of inhibin B, which stimulates testosterone secretion in Sertoli cells, which, when combined with the proinflammatory state of obesity, “results in a less favorable environment for sperm production,” he said. Finally, the link between obesity and poorer sexual function further inhibits fertility potential, he added. 

Until recently, the primary treatments for obesity in men experiencing fertility problems have been lifestyle modifications or surgical interventions. But the recent approval of GLP-1 RA drugs for obesity present an additional option depending on how these drugs affect other fertility parameters. 
 

Direct or Indirect Effects?

Most of the available evidence on GLP-RAs and sperm parameters comes from preclinical research. One of the few clinical trials, published last year in the Journal of Clinical Medicine, investigated the effects of liraglutide in men with metabolic hypogonadism, a body mass index between (BMI) 30 and 40, and severe erectile dysfunction. 

Among the 110 men enrolled in the study, only the 35 participants who said that they were not seeking fatherhood received liraglutide. After 4 months of treatment, these men had significantly improved semen concentration, motility, and morphology than did those wanting to conceive who received conventional fertility treatment. Erectile dysfunction was also more improved in the liraglutide group, according to the researchers. 

Though this study demonstrated the potential for liraglutide to treat metabolic hypogonadism, the men in that group also had greater weight loss and BMI reduction than the other participants. The review cited several other studies — albeit small ones — in which weight loss was associated with improvements in sperm parameters, including one randomized controlled trial in which one group lost weight with liraglutide and the other with lifestyle modifications; both groups showed increases in the concentration and number of sperm. 

One of the key questions requiring further research, then, is whether GLP-1 agents have direct effects on male fertility independent of a reduction in obesity. The randomized controlled trials comparing liraglutide and lifestyle modifications failed to find additional effects on semen in the men taking liraglutide; however, the study had only 56 participants, and results from liraglutide cannot be generalized to potential effects of semaglutide or tirzepatide, Dr. Sadeghi-Nejad said.

“Determining the relative contributions of weight loss versus direct drug actions on fertility outcomes remains challenging without robust data,” Dr. Ramasamy said. “While acknowledged that diet and physical activity positively impact fertility, confirming the synergistic role of GLP-1 receptor agonists requires evidence from well-designed randomized clinical trials.” 

Rodent studies suggest that GLP-1 RAs may independently affect testicular function because GLP-1 receptors exist in Sertoli and Leydig cells of the testes. In one study, for example, obese mice who received the GLP-1 agonist exenatide for 8 weeks had “improved sperm motility, DNA integrity, and decreased expression of pro-inflammatory cytokines,” the authors of the review reported. But the precise mechanisms aren’t well understood. 

“We know that there are GLP-1 receptors in the reproductive tract, but the extent of the downstream effect of stimulating those receptors, I don’t think we know well,” said John P. Lindsey II, MD, MEng, assistant professor of urology at University of California San Francisco Health. 

Other hormonal effects of GLP-1 agonists, such as stimulating insulin production and better regulating blood glucose levels, are better understood, said Raevti Bole, MD, a urologist at Cleveland Clinic, in Ohio, but still other effects of the drugs may not yet be identified.

“I think the really big unknown is whether these types of drugs have effects that are not hormonal on male fertility and what those effects are, and how those affect sperm,” Dr. Bole said. “For example, we know that these drugs slow gastric emptying. Is it possible that slow gastric emptying affects some of the nutrients that you absorb, and that could affect fertility?” Similarly, she said, it’s not clear whether GLP-1 agonists would have any effects on the thyroid that could then affect fertility. 
 

Effects on Offspring

Another open question about GLP-1 RAs and male fertility is their potential effects on the offspring, said Sriram Machineni, MBBS, associate professor of endocrinology at the Albert Einstein College of Medicine in New York City. The clinical trials involving the drugs for treating type 2 diabetes and obesity required both men and women to use contraception. If sperm contributing to a pregnancy are exposed to a GLP-1 agent, “we don’t know what the consequences could be,” Dr. Machineni said. “Just increasing the fertility of the man is not enough. We need to make sure it’s safe long-term for the fetus.”

Dr. Bole also pointed out the need for understanding potential effects in the fetus.

“We know that there are epigenetic changes that can happen to sperm that are influenced by the lifestyle and the physical health and environment of the parent,” Dr. Bole said. “So how could these drugs potentially affect those epigenetic changes that then potentially are passed on to the offspring? We don’t know that.” 

An ideal source for that data would be a cohort registry of people who are taking the medication and then cause a pregnancy. “They have a registry for pregnant women,” Dr. Machineni said, “but we need something similar for men.”

Dr. Sadeghi-Nejad said that he and his coauthors are working on developing a registry for men who take GLP-1 RAs that would enable long-term tracking of multiple andrologic outcomes, including fertility and sexual dysfunction. Such a registry could theoretically be useful in tracking pregnancy and offspring outcomes as well. 
 

Too Soon for Prescribing

Additional options for treating fertility in men with obesity would be welcome. Current treatments include the selective estrogen receptor modulator (SERM) clomiphene citrate and the aromatase inhibitor anastrozole. But these have their drawbacks, Dr. Sadeghi-Nejad pointed out; in the overweight population in particular, they “are not necessarily ideal,” he said.

“Although both are viable treatments for enhancing hormonal balance and semen parameters, clomiphene citrate has rare but documented side effects, including thromboembolism, gastrointestinal distress and occasional weight gain in men,” Dr. Sadeghi-Nejad and his colleagues wrote. “Furthermore, despite clomiphene citrate’s association with significant increases in sperm concentration, it is not universally effective, with a meta-analysis indicating a significant increase in sperm concentration in approximately 60% of men.” 

For men who have obesity and oligospermia but normal levels of testosterone and estradiol, “conventional pharmaceutical approaches like clomiphene may not be suitable,” the authors wrote. 

Still, GLP-1 RAs may have a role to play for this population. 

“I think it is within the wheelhouse of a reproductive urologist to consider those types of medications,” Dr. Lindsey said. For example, for a patient who has overweight or obesity, “does it make sense to think about doing clomiphene therapy, which we often do for someone who has low testosterone, in conjunction [with a GLP-1 agonist]? Maybe there’s a kind of an additive effect of having both on board.”

Dr. Ramasamy similarly noted that GLP-1 agonists cannot replace SERMs but may work “synergistically” with them.

“Despite the established popularity of GLP-1 receptor agonists, there may be some reluctance among urologists and fertility specialists to prescribe them, with some others advocating for their use to enhance semen parameters,” Dr. Ramasamy said. “However, robust scientific evidence is still lacking, necessitating caution and a wait for more substantial data.”

Even if GLP-1 RAs prove to have therapeutic benefit for fertility, considerations such as availability and cost may affect prescribing. 

“We do currently have safe and effective drugs that we use for male fertility, and those are generally nowhere near as expensive,” Dr. Bole said. “When we start talking about another drug that we can add, we have to think about the efficacy and the potential side effect but also, is this affordable for patients?” 

Eventually, once more evidence become available, all of the urologists who spoke with this news organization said that they expect discussion about the possible therapeutic utility of GLP-1 agonists to make its way into clinical guidelines.

“Obesity is such a huge impediment for fertility in the modern environment,” Dr. Machineni said. “We will have to clarify the use of these agents, so I think this will be a part of the guidelines some point, but I think we need more information.”

The research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the American Cancer Society. The review authors and other quoted physicians reported no disclosures. Dr. Machineni has consulted for Novo Nordisk and Lilly and has conducted clinical trials with semaglutide and tirzepatide for those companies. 
 

A version of this article appeared on Medscape.com.

The explosion of interest in glucagon-like peptide 1 receptor agonists (GLP-1 RAs), such as semaglutide and tirzepatide, has raised questions about what therapeutic effects this class of medication might have beyond their current indications for type 2 diabetes and obesity. 

Recent clinical trials have recently identified benefits from GLP-1 agents for the heart, liver, and kidneys, but the current evidence base is murkier regarding how the drugs may affect male fertility. 

Experts say the connection between GLP-1 RAs and improved male fertility makes sense biologically. For starters, overweight and obesity are strongly associated with male infertility in several overlapping ways. Obesity can disrupt hormones linked to fertility, increase the risk for defective sperm, adversely affect semen quality, and even make sexual intercourse more difficult due to obesity’s link to erectile dysfunction. As a result, GLP-1 RAs should at least in theory boost male fertility in men who take the drugs to lose weight. 

But animal studies and a handful of small trials and observational data point to the potential for GLP-1 RAs to improve male fertility in other ways.

A recent narrative review on GLP-1 RAs and male reproductive health, published in the journal Medicina in December 2023, surveyed the potential of the drugs for male infertility and offered reason for optimism. 

Hossein Sadeghi-Nejad, MD, director of urology at NYU Langone Health, New York, and a coauthor of the article, said that one reason he and his colleagues conducted their analysis was the known association between weight loss and an increase in testosterone.

“Most of the animal studies that are out there show that this class of drugs does affect testosterone levels,” Dr. Sadeghi-Nejad said; they wanted to better understand what other evidence showed about GLP-1 agonists and other fertility factors. 
 

Link Between Obesity and Fertility

The recent paper first reviews the well-established link between obesity and poorer fertility outcomes. 

“Certainly, obesity poses a significant societal problem with substantial impacts on both overall health and economic aspects,” senior author Ranjith Ramasamy, MD, associate professor of urology and director of the reproductive urology Fellowship program at the University of Miami’s Miller School of Medicine, told this news organization. “The escalating global obesity rates raise concerns, especially in the field of male infertility, where excessive body fat induces intrinsic hormonal changes leading to alterations, eventually, in semen parameters.”

The authors noted that obesity has been linked in the research to worse assisted reproductive technology (ART) outcomes and to subfecundity, taking more than 12 months to achieve pregnancy. They also referenced a systematic review that found men with obesity were more likely to have lower sperm counts and less viable sperm.

“From our standpoint, I think the key point was to raise awareness about the fact that obesity, because of the aromatization of testosterone to estradiol [from excess adipose tissue], will affect the hormonal axis and the availability of testosterone and, therefore, indirectly affects spermatogenesis,” Dr. Sadeghi-Nejad said. 

Obesity is also linked to lower levels of inhibin B, which stimulates testosterone secretion in Sertoli cells, which, when combined with the proinflammatory state of obesity, “results in a less favorable environment for sperm production,” he said. Finally, the link between obesity and poorer sexual function further inhibits fertility potential, he added. 

Until recently, the primary treatments for obesity in men experiencing fertility problems have been lifestyle modifications or surgical interventions. But the recent approval of GLP-1 RA drugs for obesity present an additional option depending on how these drugs affect other fertility parameters. 
 

Direct or Indirect Effects?

Most of the available evidence on GLP-RAs and sperm parameters comes from preclinical research. One of the few clinical trials, published last year in the Journal of Clinical Medicine, investigated the effects of liraglutide in men with metabolic hypogonadism, a body mass index between (BMI) 30 and 40, and severe erectile dysfunction. 

Among the 110 men enrolled in the study, only the 35 participants who said that they were not seeking fatherhood received liraglutide. After 4 months of treatment, these men had significantly improved semen concentration, motility, and morphology than did those wanting to conceive who received conventional fertility treatment. Erectile dysfunction was also more improved in the liraglutide group, according to the researchers. 

Though this study demonstrated the potential for liraglutide to treat metabolic hypogonadism, the men in that group also had greater weight loss and BMI reduction than the other participants. The review cited several other studies — albeit small ones — in which weight loss was associated with improvements in sperm parameters, including one randomized controlled trial in which one group lost weight with liraglutide and the other with lifestyle modifications; both groups showed increases in the concentration and number of sperm. 

One of the key questions requiring further research, then, is whether GLP-1 agents have direct effects on male fertility independent of a reduction in obesity. The randomized controlled trials comparing liraglutide and lifestyle modifications failed to find additional effects on semen in the men taking liraglutide; however, the study had only 56 participants, and results from liraglutide cannot be generalized to potential effects of semaglutide or tirzepatide, Dr. Sadeghi-Nejad said.

“Determining the relative contributions of weight loss versus direct drug actions on fertility outcomes remains challenging without robust data,” Dr. Ramasamy said. “While acknowledged that diet and physical activity positively impact fertility, confirming the synergistic role of GLP-1 receptor agonists requires evidence from well-designed randomized clinical trials.” 

Rodent studies suggest that GLP-1 RAs may independently affect testicular function because GLP-1 receptors exist in Sertoli and Leydig cells of the testes. In one study, for example, obese mice who received the GLP-1 agonist exenatide for 8 weeks had “improved sperm motility, DNA integrity, and decreased expression of pro-inflammatory cytokines,” the authors of the review reported. But the precise mechanisms aren’t well understood. 

“We know that there are GLP-1 receptors in the reproductive tract, but the extent of the downstream effect of stimulating those receptors, I don’t think we know well,” said John P. Lindsey II, MD, MEng, assistant professor of urology at University of California San Francisco Health. 

Other hormonal effects of GLP-1 agonists, such as stimulating insulin production and better regulating blood glucose levels, are better understood, said Raevti Bole, MD, a urologist at Cleveland Clinic, in Ohio, but still other effects of the drugs may not yet be identified.

“I think the really big unknown is whether these types of drugs have effects that are not hormonal on male fertility and what those effects are, and how those affect sperm,” Dr. Bole said. “For example, we know that these drugs slow gastric emptying. Is it possible that slow gastric emptying affects some of the nutrients that you absorb, and that could affect fertility?” Similarly, she said, it’s not clear whether GLP-1 agonists would have any effects on the thyroid that could then affect fertility. 
 

Effects on Offspring

Another open question about GLP-1 RAs and male fertility is their potential effects on the offspring, said Sriram Machineni, MBBS, associate professor of endocrinology at the Albert Einstein College of Medicine in New York City. The clinical trials involving the drugs for treating type 2 diabetes and obesity required both men and women to use contraception. If sperm contributing to a pregnancy are exposed to a GLP-1 agent, “we don’t know what the consequences could be,” Dr. Machineni said. “Just increasing the fertility of the man is not enough. We need to make sure it’s safe long-term for the fetus.”

Dr. Bole also pointed out the need for understanding potential effects in the fetus.

“We know that there are epigenetic changes that can happen to sperm that are influenced by the lifestyle and the physical health and environment of the parent,” Dr. Bole said. “So how could these drugs potentially affect those epigenetic changes that then potentially are passed on to the offspring? We don’t know that.” 

An ideal source for that data would be a cohort registry of people who are taking the medication and then cause a pregnancy. “They have a registry for pregnant women,” Dr. Machineni said, “but we need something similar for men.”

Dr. Sadeghi-Nejad said that he and his coauthors are working on developing a registry for men who take GLP-1 RAs that would enable long-term tracking of multiple andrologic outcomes, including fertility and sexual dysfunction. Such a registry could theoretically be useful in tracking pregnancy and offspring outcomes as well. 
 

Too Soon for Prescribing

Additional options for treating fertility in men with obesity would be welcome. Current treatments include the selective estrogen receptor modulator (SERM) clomiphene citrate and the aromatase inhibitor anastrozole. But these have their drawbacks, Dr. Sadeghi-Nejad pointed out; in the overweight population in particular, they “are not necessarily ideal,” he said.

“Although both are viable treatments for enhancing hormonal balance and semen parameters, clomiphene citrate has rare but documented side effects, including thromboembolism, gastrointestinal distress and occasional weight gain in men,” Dr. Sadeghi-Nejad and his colleagues wrote. “Furthermore, despite clomiphene citrate’s association with significant increases in sperm concentration, it is not universally effective, with a meta-analysis indicating a significant increase in sperm concentration in approximately 60% of men.” 

For men who have obesity and oligospermia but normal levels of testosterone and estradiol, “conventional pharmaceutical approaches like clomiphene may not be suitable,” the authors wrote. 

Still, GLP-1 RAs may have a role to play for this population. 

“I think it is within the wheelhouse of a reproductive urologist to consider those types of medications,” Dr. Lindsey said. For example, for a patient who has overweight or obesity, “does it make sense to think about doing clomiphene therapy, which we often do for someone who has low testosterone, in conjunction [with a GLP-1 agonist]? Maybe there’s a kind of an additive effect of having both on board.”

Dr. Ramasamy similarly noted that GLP-1 agonists cannot replace SERMs but may work “synergistically” with them.

“Despite the established popularity of GLP-1 receptor agonists, there may be some reluctance among urologists and fertility specialists to prescribe them, with some others advocating for their use to enhance semen parameters,” Dr. Ramasamy said. “However, robust scientific evidence is still lacking, necessitating caution and a wait for more substantial data.”

Even if GLP-1 RAs prove to have therapeutic benefit for fertility, considerations such as availability and cost may affect prescribing. 

“We do currently have safe and effective drugs that we use for male fertility, and those are generally nowhere near as expensive,” Dr. Bole said. “When we start talking about another drug that we can add, we have to think about the efficacy and the potential side effect but also, is this affordable for patients?” 

Eventually, once more evidence become available, all of the urologists who spoke with this news organization said that they expect discussion about the possible therapeutic utility of GLP-1 agonists to make its way into clinical guidelines.

“Obesity is such a huge impediment for fertility in the modern environment,” Dr. Machineni said. “We will have to clarify the use of these agents, so I think this will be a part of the guidelines some point, but I think we need more information.”

The research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the American Cancer Society. The review authors and other quoted physicians reported no disclosures. Dr. Machineni has consulted for Novo Nordisk and Lilly and has conducted clinical trials with semaglutide and tirzepatide for those companies. 
 

A version of this article appeared on Medscape.com.

The explosion of interest in glucagon-like peptide 1 receptor agonists (GLP-1 RAs), such as semaglutide and tirzepatide, has raised questions about what therapeutic effects this class of medication might have beyond their current indications for type 2 diabetes and obesity. 

Recent clinical trials have recently identified benefits from GLP-1 agents for the heart, liver, and kidneys, but the current evidence base is murkier regarding how the drugs may affect male fertility. 

Experts say the connection between GLP-1 RAs and improved male fertility makes sense biologically. For starters, overweight and obesity are strongly associated with male infertility in several overlapping ways. Obesity can disrupt hormones linked to fertility, increase the risk for defective sperm, adversely affect semen quality, and even make sexual intercourse more difficult due to obesity’s link to erectile dysfunction. As a result, GLP-1 RAs should at least in theory boost male fertility in men who take the drugs to lose weight. 

But animal studies and a handful of small trials and observational data point to the potential for GLP-1 RAs to improve male fertility in other ways.

A recent narrative review on GLP-1 RAs and male reproductive health, published in the journal Medicina in December 2023, surveyed the potential of the drugs for male infertility and offered reason for optimism. 

Hossein Sadeghi-Nejad, MD, director of urology at NYU Langone Health, New York, and a coauthor of the article, said that one reason he and his colleagues conducted their analysis was the known association between weight loss and an increase in testosterone.

“Most of the animal studies that are out there show that this class of drugs does affect testosterone levels,” Dr. Sadeghi-Nejad said; they wanted to better understand what other evidence showed about GLP-1 agonists and other fertility factors. 
 

Link Between Obesity and Fertility

The recent paper first reviews the well-established link between obesity and poorer fertility outcomes. 

“Certainly, obesity poses a significant societal problem with substantial impacts on both overall health and economic aspects,” senior author Ranjith Ramasamy, MD, associate professor of urology and director of the reproductive urology Fellowship program at the University of Miami’s Miller School of Medicine, told this news organization. “The escalating global obesity rates raise concerns, especially in the field of male infertility, where excessive body fat induces intrinsic hormonal changes leading to alterations, eventually, in semen parameters.”

The authors noted that obesity has been linked in the research to worse assisted reproductive technology (ART) outcomes and to subfecundity, taking more than 12 months to achieve pregnancy. They also referenced a systematic review that found men with obesity were more likely to have lower sperm counts and less viable sperm.

“From our standpoint, I think the key point was to raise awareness about the fact that obesity, because of the aromatization of testosterone to estradiol [from excess adipose tissue], will affect the hormonal axis and the availability of testosterone and, therefore, indirectly affects spermatogenesis,” Dr. Sadeghi-Nejad said. 

Obesity is also linked to lower levels of inhibin B, which stimulates testosterone secretion in Sertoli cells, which, when combined with the proinflammatory state of obesity, “results in a less favorable environment for sperm production,” he said. Finally, the link between obesity and poorer sexual function further inhibits fertility potential, he added. 

Until recently, the primary treatments for obesity in men experiencing fertility problems have been lifestyle modifications or surgical interventions. But the recent approval of GLP-1 RA drugs for obesity present an additional option depending on how these drugs affect other fertility parameters. 
 

Direct or Indirect Effects?

Most of the available evidence on GLP-RAs and sperm parameters comes from preclinical research. One of the few clinical trials, published last year in the Journal of Clinical Medicine, investigated the effects of liraglutide in men with metabolic hypogonadism, a body mass index between (BMI) 30 and 40, and severe erectile dysfunction. 

Among the 110 men enrolled in the study, only the 35 participants who said that they were not seeking fatherhood received liraglutide. After 4 months of treatment, these men had significantly improved semen concentration, motility, and morphology than did those wanting to conceive who received conventional fertility treatment. Erectile dysfunction was also more improved in the liraglutide group, according to the researchers. 

Though this study demonstrated the potential for liraglutide to treat metabolic hypogonadism, the men in that group also had greater weight loss and BMI reduction than the other participants. The review cited several other studies — albeit small ones — in which weight loss was associated with improvements in sperm parameters, including one randomized controlled trial in which one group lost weight with liraglutide and the other with lifestyle modifications; both groups showed increases in the concentration and number of sperm. 

One of the key questions requiring further research, then, is whether GLP-1 agents have direct effects on male fertility independent of a reduction in obesity. The randomized controlled trials comparing liraglutide and lifestyle modifications failed to find additional effects on semen in the men taking liraglutide; however, the study had only 56 participants, and results from liraglutide cannot be generalized to potential effects of semaglutide or tirzepatide, Dr. Sadeghi-Nejad said.

“Determining the relative contributions of weight loss versus direct drug actions on fertility outcomes remains challenging without robust data,” Dr. Ramasamy said. “While acknowledged that diet and physical activity positively impact fertility, confirming the synergistic role of GLP-1 receptor agonists requires evidence from well-designed randomized clinical trials.” 

Rodent studies suggest that GLP-1 RAs may independently affect testicular function because GLP-1 receptors exist in Sertoli and Leydig cells of the testes. In one study, for example, obese mice who received the GLP-1 agonist exenatide for 8 weeks had “improved sperm motility, DNA integrity, and decreased expression of pro-inflammatory cytokines,” the authors of the review reported. But the precise mechanisms aren’t well understood. 

“We know that there are GLP-1 receptors in the reproductive tract, but the extent of the downstream effect of stimulating those receptors, I don’t think we know well,” said John P. Lindsey II, MD, MEng, assistant professor of urology at University of California San Francisco Health. 

Other hormonal effects of GLP-1 agonists, such as stimulating insulin production and better regulating blood glucose levels, are better understood, said Raevti Bole, MD, a urologist at Cleveland Clinic, in Ohio, but still other effects of the drugs may not yet be identified.

“I think the really big unknown is whether these types of drugs have effects that are not hormonal on male fertility and what those effects are, and how those affect sperm,” Dr. Bole said. “For example, we know that these drugs slow gastric emptying. Is it possible that slow gastric emptying affects some of the nutrients that you absorb, and that could affect fertility?” Similarly, she said, it’s not clear whether GLP-1 agonists would have any effects on the thyroid that could then affect fertility. 
 

Effects on Offspring

Another open question about GLP-1 RAs and male fertility is their potential effects on the offspring, said Sriram Machineni, MBBS, associate professor of endocrinology at the Albert Einstein College of Medicine in New York City. The clinical trials involving the drugs for treating type 2 diabetes and obesity required both men and women to use contraception. If sperm contributing to a pregnancy are exposed to a GLP-1 agent, “we don’t know what the consequences could be,” Dr. Machineni said. “Just increasing the fertility of the man is not enough. We need to make sure it’s safe long-term for the fetus.”

Dr. Bole also pointed out the need for understanding potential effects in the fetus.

“We know that there are epigenetic changes that can happen to sperm that are influenced by the lifestyle and the physical health and environment of the parent,” Dr. Bole said. “So how could these drugs potentially affect those epigenetic changes that then potentially are passed on to the offspring? We don’t know that.” 

An ideal source for that data would be a cohort registry of people who are taking the medication and then cause a pregnancy. “They have a registry for pregnant women,” Dr. Machineni said, “but we need something similar for men.”

Dr. Sadeghi-Nejad said that he and his coauthors are working on developing a registry for men who take GLP-1 RAs that would enable long-term tracking of multiple andrologic outcomes, including fertility and sexual dysfunction. Such a registry could theoretically be useful in tracking pregnancy and offspring outcomes as well. 
 

Too Soon for Prescribing

Additional options for treating fertility in men with obesity would be welcome. Current treatments include the selective estrogen receptor modulator (SERM) clomiphene citrate and the aromatase inhibitor anastrozole. But these have their drawbacks, Dr. Sadeghi-Nejad pointed out; in the overweight population in particular, they “are not necessarily ideal,” he said.

“Although both are viable treatments for enhancing hormonal balance and semen parameters, clomiphene citrate has rare but documented side effects, including thromboembolism, gastrointestinal distress and occasional weight gain in men,” Dr. Sadeghi-Nejad and his colleagues wrote. “Furthermore, despite clomiphene citrate’s association with significant increases in sperm concentration, it is not universally effective, with a meta-analysis indicating a significant increase in sperm concentration in approximately 60% of men.” 

For men who have obesity and oligospermia but normal levels of testosterone and estradiol, “conventional pharmaceutical approaches like clomiphene may not be suitable,” the authors wrote. 

Still, GLP-1 RAs may have a role to play for this population. 

“I think it is within the wheelhouse of a reproductive urologist to consider those types of medications,” Dr. Lindsey said. For example, for a patient who has overweight or obesity, “does it make sense to think about doing clomiphene therapy, which we often do for someone who has low testosterone, in conjunction [with a GLP-1 agonist]? Maybe there’s a kind of an additive effect of having both on board.”

Dr. Ramasamy similarly noted that GLP-1 agonists cannot replace SERMs but may work “synergistically” with them.

“Despite the established popularity of GLP-1 receptor agonists, there may be some reluctance among urologists and fertility specialists to prescribe them, with some others advocating for their use to enhance semen parameters,” Dr. Ramasamy said. “However, robust scientific evidence is still lacking, necessitating caution and a wait for more substantial data.”

Even if GLP-1 RAs prove to have therapeutic benefit for fertility, considerations such as availability and cost may affect prescribing. 

“We do currently have safe and effective drugs that we use for male fertility, and those are generally nowhere near as expensive,” Dr. Bole said. “When we start talking about another drug that we can add, we have to think about the efficacy and the potential side effect but also, is this affordable for patients?” 

Eventually, once more evidence become available, all of the urologists who spoke with this news organization said that they expect discussion about the possible therapeutic utility of GLP-1 agonists to make its way into clinical guidelines.

“Obesity is such a huge impediment for fertility in the modern environment,” Dr. Machineni said. “We will have to clarify the use of these agents, so I think this will be a part of the guidelines some point, but I think we need more information.”

The research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the American Cancer Society. The review authors and other quoted physicians reported no disclosures. Dr. Machineni has consulted for Novo Nordisk and Lilly and has conducted clinical trials with semaglutide and tirzepatide for those companies. 
 

A version of this article appeared on Medscape.com.

Patients with Cushing disease have an increased risk for new-onset autoimmune disease in the 3 years after surgical remission, according to a new retrospective study published on February 20 in Annals of Internal Medicine.

Outcomes for patients with Cushing disease were compared against those with nonfunctioning pituitary adenomas (NFPAs). New-onset autoimmune disease occurred in 10.4% with Cushing disease and 1.6% among patients with NFPA (hazard ratio, 7.80; 95% CI, 2.88-21.10).

“Understanding and recognizing new and recurrent autoimmune disease in this setting is important to avoid misclassifying such patients with glucocorticoid withdrawal syndrome, which could result in failure to treat underlying autoimmune disease, as well as erroneous diagnosis of steroid withdrawal cases,” wrote Dennis Delasi Nyanyo of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.

Given the general population’s annual incidence of major autoimmune diseases, estimated at about 100 cases per 100,000 people, and the 3-year incidence of 10.4% found in this study’s cohort, “our findings suggest that Cushing disease remission may trigger development of autoimmune disease,” the authors wrote.
 

Monitor Patients With Family History of Autoimmune Disease?

The study results were not necessarily surprising to Anthony P. Heaney, MD, PhD, an endocrinologist and professor of medicine at the University of California, Los Angeles, because past research has raised similar questions. The authors’ suggestion that the rapid postsurgical drop in cortisol that occurs as a result of treating Cushing disease becomes some sort of autoimmune trigger is interesting but remains speculative, Dr. Heaney pointed out.

If future evidence supports that possibility, “it would suggest, in terms of managing those patients in the postoperative setting, that there may be some merit to giving them higher concentrations of glucocorticoids for a short period of time,” Dr. Heaney said, thereby bringing their levels down more gradually rather than taking them off a cliff, in a sense. Or, if more evidence bears out the authors’ hypothesis, another approach might be treating patients with medicine to bring down the cortisol before surgery, though there are challenges to that approach, Dr. Heaney said.

At the same time, those who developed new autoimmune disease remain a small subset of patients with Cushing disease, so such approaches may become only potentially appropriate to consider in patients with risk factors, such as a family history of autoimmune disease.

The researchers conducted a retrospective chart review of adult patients who underwent transsphenoidal surgery for either Cushing disease or NFPA at Massachusetts General Hospital between 2005 and 2019.

The study involved 194 patients with Cushing disease who had postsurgical remission and at least one follow-up visit with a pituitary expert and 92 patients with NFPA who were matched to patients with Cushing disease based on age and sex. The authors regarded autoimmune disease diagnosed within 36 months of the surgery to be temporally associated with Cushing disease remission. Among the autoimmune diseases considered were “rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, psoriasis, vitiligo, autoimmune neuropathy, multiple sclerosis, myasthenia gravis, and ulcerative colitis.”

Patients differed in average body mass index and tumor size, but family history of autoimmune disease was similar in both groups. Average BMI was 34.5 in the Cushing group and 29.5 in the NFPA group. Average tumor size was 5.7 mm in the Cushing group and 21.3 mm in the NFPA group.

Before surgery, 2.9% of patients with Cushing disease and 15.4% of patients with NFPA had central hypothyroidism, and 8% in the Cushing group and 56.8% in the NFPA group had hyperprolactinemia. Central adrenal insufficiency occurred in 11% with NFPA and in all with Cushing disease, by definition.

After surgery, 93.8% in the Cushing group and 16.5% in the NFPA group had adrenal insufficiency. In addition, patients with Cushing disease had lower postsurgical nadir serum cortisol levels (63.8 nmol/L) than those with NFPA (282.3 nmol/L).

Of the 17 patients with Cushing disease — all women — who developed autoimmune disease within 3 years, 6 had a personal history of autoimmune disease and 7 had a family history of it. In addition, 41.2% of them had adrenal insufficiency when they developed the new autoimmune disease. Among the diseases were six autoimmune thyroiditis cases, three Sjögren syndrome cases, and two autoimmune seronegative spondyloarthropathy.

Dr. Heaney said he found it interesting that more than half of the new autoimmune diseases in patients with Cushing disease were related to the thyroid. “In this kind of setting, where you have a patient who has been producing too much steroid over a period of time and then you take that away, it’s almost like you release a brake on the TSH [thyroid-stimulating hormone],” Dr. Heaney said. “So, there’s probably some rebound in TSH that occurs, and that could be driving the thyroiditis, to some extent, that we see in these patients.”

Only one patient with NFPA developed new-onset autoimmune disease, a woman who developed Graves disease 22 months after surgery. When the researchers excluded patients in both groups with central hypothyroidism, new-onset autoimmune disease was still significantly higher (11.4%) in the Cushing group than in the NFPA group (1.9%; HR, 7.02; 95% CI, 2.54-19.39).
 

Could Postoperative Adrenal Insufficiency Contribute to Risk?

Within the Cushing cohort, those who developed autoimmune disease had a lower BMI (31.8 vs 34.8) and larger tumor size (7.2 vs 5.6 mm) than those who didn’t develop new autoimmune disease. Patients who developed autoimmune disease also had a lower baseline urine free cortisol ratio (2.7 vs 6.3) before surgery and more family history of autoimmune disease (41.2% vs 20.9%) than those who didn’t develop one.

“The higher prevalence of adrenal insufficiency and the lower nadir serum cortisol levels in the Cushing disease group suggest that the postoperative adrenal insufficiency in the Cushing disease group might have contributed to autoimmune disease pathogenesis,” the authors wrote. “This finding is clinically significant because cortisol plays a pivotal role in modulating the immune system.”

Most postoperative management among patients with Cushing disease was similar, with all but one patient receiving 0.5 or 1 mg daily dexamethasone within the first week after surgery. (The one outlier received 5 mg daily prednisone.) However, fewer patients who developed autoimmune disease (17.6%) received supraphysiologic doses of glucocorticoid — equivalent to at least 25 mg hydrocortisone — compared with patients who didn’t develop autoimmune disease (41.8%).

“Although the daily average hydrocortisone equivalent replacement doses within the first month and during long-term follow-up were within the physiologic range in both subgroups, patients with Cushing disease who had autoimmune disease received slightly lower doses of glucocorticoid replacement within the first month after surgery,” the authors reported. “The immediate postoperative period might be a critical window where supraphysiologic glucocorticoids seem to be protective with regard to development of autoimmune disease,” they wrote, though they acknowledged the study’s retrospective design as a limitation in drawing that conclusion.

At the least, they suggested that new symptoms in patients with Cushing disease, particularly those with a family history of autoimmune disease, should prompt investigation of potential autoimmune disease.

Recordati Rare Diseases funded the study. The research was also conducted with support from Harvard Catalyst (the Harvard Clinical and Translational Science Center) as well as financial contributions from Harvard University and its affiliated academic healthcare centers. One author reported holding stocks in Pfizer and Amgen, and another reported receiving consulting fees from Corcept. Dr. Heaney reported receiving institutional grants for trials from Corcept, Ascendis, Crinetics, and Sparrow Pharm; serving on the advisory board for Xeris, Recordati, Corcept, Novo Nordisk, Lundbeck, and Crinetics; and serving as a speaker for Chiesi, Novo Nordisk, and Corcept.
 

A version of this article appeared on Medscape.com.

Patients with Cushing disease have an increased risk for new-onset autoimmune disease in the 3 years after surgical remission, according to a new retrospective study published on February 20 in Annals of Internal Medicine.

Outcomes for patients with Cushing disease were compared against those with nonfunctioning pituitary adenomas (NFPAs). New-onset autoimmune disease occurred in 10.4% with Cushing disease and 1.6% among patients with NFPA (hazard ratio, 7.80; 95% CI, 2.88-21.10).

“Understanding and recognizing new and recurrent autoimmune disease in this setting is important to avoid misclassifying such patients with glucocorticoid withdrawal syndrome, which could result in failure to treat underlying autoimmune disease, as well as erroneous diagnosis of steroid withdrawal cases,” wrote Dennis Delasi Nyanyo of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.

Given the general population’s annual incidence of major autoimmune diseases, estimated at about 100 cases per 100,000 people, and the 3-year incidence of 10.4% found in this study’s cohort, “our findings suggest that Cushing disease remission may trigger development of autoimmune disease,” the authors wrote.
 

Monitor Patients With Family History of Autoimmune Disease?

The study results were not necessarily surprising to Anthony P. Heaney, MD, PhD, an endocrinologist and professor of medicine at the University of California, Los Angeles, because past research has raised similar questions. The authors’ suggestion that the rapid postsurgical drop in cortisol that occurs as a result of treating Cushing disease becomes some sort of autoimmune trigger is interesting but remains speculative, Dr. Heaney pointed out.

If future evidence supports that possibility, “it would suggest, in terms of managing those patients in the postoperative setting, that there may be some merit to giving them higher concentrations of glucocorticoids for a short period of time,” Dr. Heaney said, thereby bringing their levels down more gradually rather than taking them off a cliff, in a sense. Or, if more evidence bears out the authors’ hypothesis, another approach might be treating patients with medicine to bring down the cortisol before surgery, though there are challenges to that approach, Dr. Heaney said.

At the same time, those who developed new autoimmune disease remain a small subset of patients with Cushing disease, so such approaches may become only potentially appropriate to consider in patients with risk factors, such as a family history of autoimmune disease.

The researchers conducted a retrospective chart review of adult patients who underwent transsphenoidal surgery for either Cushing disease or NFPA at Massachusetts General Hospital between 2005 and 2019.

The study involved 194 patients with Cushing disease who had postsurgical remission and at least one follow-up visit with a pituitary expert and 92 patients with NFPA who were matched to patients with Cushing disease based on age and sex. The authors regarded autoimmune disease diagnosed within 36 months of the surgery to be temporally associated with Cushing disease remission. Among the autoimmune diseases considered were “rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, psoriasis, vitiligo, autoimmune neuropathy, multiple sclerosis, myasthenia gravis, and ulcerative colitis.”

Patients differed in average body mass index and tumor size, but family history of autoimmune disease was similar in both groups. Average BMI was 34.5 in the Cushing group and 29.5 in the NFPA group. Average tumor size was 5.7 mm in the Cushing group and 21.3 mm in the NFPA group.

Before surgery, 2.9% of patients with Cushing disease and 15.4% of patients with NFPA had central hypothyroidism, and 8% in the Cushing group and 56.8% in the NFPA group had hyperprolactinemia. Central adrenal insufficiency occurred in 11% with NFPA and in all with Cushing disease, by definition.

After surgery, 93.8% in the Cushing group and 16.5% in the NFPA group had adrenal insufficiency. In addition, patients with Cushing disease had lower postsurgical nadir serum cortisol levels (63.8 nmol/L) than those with NFPA (282.3 nmol/L).

Of the 17 patients with Cushing disease — all women — who developed autoimmune disease within 3 years, 6 had a personal history of autoimmune disease and 7 had a family history of it. In addition, 41.2% of them had adrenal insufficiency when they developed the new autoimmune disease. Among the diseases were six autoimmune thyroiditis cases, three Sjögren syndrome cases, and two autoimmune seronegative spondyloarthropathy.

Dr. Heaney said he found it interesting that more than half of the new autoimmune diseases in patients with Cushing disease were related to the thyroid. “In this kind of setting, where you have a patient who has been producing too much steroid over a period of time and then you take that away, it’s almost like you release a brake on the TSH [thyroid-stimulating hormone],” Dr. Heaney said. “So, there’s probably some rebound in TSH that occurs, and that could be driving the thyroiditis, to some extent, that we see in these patients.”

Only one patient with NFPA developed new-onset autoimmune disease, a woman who developed Graves disease 22 months after surgery. When the researchers excluded patients in both groups with central hypothyroidism, new-onset autoimmune disease was still significantly higher (11.4%) in the Cushing group than in the NFPA group (1.9%; HR, 7.02; 95% CI, 2.54-19.39).
 

Could Postoperative Adrenal Insufficiency Contribute to Risk?

Within the Cushing cohort, those who developed autoimmune disease had a lower BMI (31.8 vs 34.8) and larger tumor size (7.2 vs 5.6 mm) than those who didn’t develop new autoimmune disease. Patients who developed autoimmune disease also had a lower baseline urine free cortisol ratio (2.7 vs 6.3) before surgery and more family history of autoimmune disease (41.2% vs 20.9%) than those who didn’t develop one.

“The higher prevalence of adrenal insufficiency and the lower nadir serum cortisol levels in the Cushing disease group suggest that the postoperative adrenal insufficiency in the Cushing disease group might have contributed to autoimmune disease pathogenesis,” the authors wrote. “This finding is clinically significant because cortisol plays a pivotal role in modulating the immune system.”

Most postoperative management among patients with Cushing disease was similar, with all but one patient receiving 0.5 or 1 mg daily dexamethasone within the first week after surgery. (The one outlier received 5 mg daily prednisone.) However, fewer patients who developed autoimmune disease (17.6%) received supraphysiologic doses of glucocorticoid — equivalent to at least 25 mg hydrocortisone — compared with patients who didn’t develop autoimmune disease (41.8%).

“Although the daily average hydrocortisone equivalent replacement doses within the first month and during long-term follow-up were within the physiologic range in both subgroups, patients with Cushing disease who had autoimmune disease received slightly lower doses of glucocorticoid replacement within the first month after surgery,” the authors reported. “The immediate postoperative period might be a critical window where supraphysiologic glucocorticoids seem to be protective with regard to development of autoimmune disease,” they wrote, though they acknowledged the study’s retrospective design as a limitation in drawing that conclusion.

At the least, they suggested that new symptoms in patients with Cushing disease, particularly those with a family history of autoimmune disease, should prompt investigation of potential autoimmune disease.

Recordati Rare Diseases funded the study. The research was also conducted with support from Harvard Catalyst (the Harvard Clinical and Translational Science Center) as well as financial contributions from Harvard University and its affiliated academic healthcare centers. One author reported holding stocks in Pfizer and Amgen, and another reported receiving consulting fees from Corcept. Dr. Heaney reported receiving institutional grants for trials from Corcept, Ascendis, Crinetics, and Sparrow Pharm; serving on the advisory board for Xeris, Recordati, Corcept, Novo Nordisk, Lundbeck, and Crinetics; and serving as a speaker for Chiesi, Novo Nordisk, and Corcept.
 

A version of this article appeared on Medscape.com.

Patients with Cushing disease have an increased risk for new-onset autoimmune disease in the 3 years after surgical remission, according to a new retrospective study published on February 20 in Annals of Internal Medicine.

Outcomes for patients with Cushing disease were compared against those with nonfunctioning pituitary adenomas (NFPAs). New-onset autoimmune disease occurred in 10.4% with Cushing disease and 1.6% among patients with NFPA (hazard ratio, 7.80; 95% CI, 2.88-21.10).

“Understanding and recognizing new and recurrent autoimmune disease in this setting is important to avoid misclassifying such patients with glucocorticoid withdrawal syndrome, which could result in failure to treat underlying autoimmune disease, as well as erroneous diagnosis of steroid withdrawal cases,” wrote Dennis Delasi Nyanyo of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.

Given the general population’s annual incidence of major autoimmune diseases, estimated at about 100 cases per 100,000 people, and the 3-year incidence of 10.4% found in this study’s cohort, “our findings suggest that Cushing disease remission may trigger development of autoimmune disease,” the authors wrote.
 

Monitor Patients With Family History of Autoimmune Disease?

The study results were not necessarily surprising to Anthony P. Heaney, MD, PhD, an endocrinologist and professor of medicine at the University of California, Los Angeles, because past research has raised similar questions. The authors’ suggestion that the rapid postsurgical drop in cortisol that occurs as a result of treating Cushing disease becomes some sort of autoimmune trigger is interesting but remains speculative, Dr. Heaney pointed out.

If future evidence supports that possibility, “it would suggest, in terms of managing those patients in the postoperative setting, that there may be some merit to giving them higher concentrations of glucocorticoids for a short period of time,” Dr. Heaney said, thereby bringing their levels down more gradually rather than taking them off a cliff, in a sense. Or, if more evidence bears out the authors’ hypothesis, another approach might be treating patients with medicine to bring down the cortisol before surgery, though there are challenges to that approach, Dr. Heaney said.

At the same time, those who developed new autoimmune disease remain a small subset of patients with Cushing disease, so such approaches may become only potentially appropriate to consider in patients with risk factors, such as a family history of autoimmune disease.

The researchers conducted a retrospective chart review of adult patients who underwent transsphenoidal surgery for either Cushing disease or NFPA at Massachusetts General Hospital between 2005 and 2019.

The study involved 194 patients with Cushing disease who had postsurgical remission and at least one follow-up visit with a pituitary expert and 92 patients with NFPA who were matched to patients with Cushing disease based on age and sex. The authors regarded autoimmune disease diagnosed within 36 months of the surgery to be temporally associated with Cushing disease remission. Among the autoimmune diseases considered were “rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, psoriasis, vitiligo, autoimmune neuropathy, multiple sclerosis, myasthenia gravis, and ulcerative colitis.”

Patients differed in average body mass index and tumor size, but family history of autoimmune disease was similar in both groups. Average BMI was 34.5 in the Cushing group and 29.5 in the NFPA group. Average tumor size was 5.7 mm in the Cushing group and 21.3 mm in the NFPA group.

Before surgery, 2.9% of patients with Cushing disease and 15.4% of patients with NFPA had central hypothyroidism, and 8% in the Cushing group and 56.8% in the NFPA group had hyperprolactinemia. Central adrenal insufficiency occurred in 11% with NFPA and in all with Cushing disease, by definition.

After surgery, 93.8% in the Cushing group and 16.5% in the NFPA group had adrenal insufficiency. In addition, patients with Cushing disease had lower postsurgical nadir serum cortisol levels (63.8 nmol/L) than those with NFPA (282.3 nmol/L).

Of the 17 patients with Cushing disease — all women — who developed autoimmune disease within 3 years, 6 had a personal history of autoimmune disease and 7 had a family history of it. In addition, 41.2% of them had adrenal insufficiency when they developed the new autoimmune disease. Among the diseases were six autoimmune thyroiditis cases, three Sjögren syndrome cases, and two autoimmune seronegative spondyloarthropathy.

Dr. Heaney said he found it interesting that more than half of the new autoimmune diseases in patients with Cushing disease were related to the thyroid. “In this kind of setting, where you have a patient who has been producing too much steroid over a period of time and then you take that away, it’s almost like you release a brake on the TSH [thyroid-stimulating hormone],” Dr. Heaney said. “So, there’s probably some rebound in TSH that occurs, and that could be driving the thyroiditis, to some extent, that we see in these patients.”

Only one patient with NFPA developed new-onset autoimmune disease, a woman who developed Graves disease 22 months after surgery. When the researchers excluded patients in both groups with central hypothyroidism, new-onset autoimmune disease was still significantly higher (11.4%) in the Cushing group than in the NFPA group (1.9%; HR, 7.02; 95% CI, 2.54-19.39).
 

Could Postoperative Adrenal Insufficiency Contribute to Risk?

Within the Cushing cohort, those who developed autoimmune disease had a lower BMI (31.8 vs 34.8) and larger tumor size (7.2 vs 5.6 mm) than those who didn’t develop new autoimmune disease. Patients who developed autoimmune disease also had a lower baseline urine free cortisol ratio (2.7 vs 6.3) before surgery and more family history of autoimmune disease (41.2% vs 20.9%) than those who didn’t develop one.

“The higher prevalence of adrenal insufficiency and the lower nadir serum cortisol levels in the Cushing disease group suggest that the postoperative adrenal insufficiency in the Cushing disease group might have contributed to autoimmune disease pathogenesis,” the authors wrote. “This finding is clinically significant because cortisol plays a pivotal role in modulating the immune system.”

Most postoperative management among patients with Cushing disease was similar, with all but one patient receiving 0.5 or 1 mg daily dexamethasone within the first week after surgery. (The one outlier received 5 mg daily prednisone.) However, fewer patients who developed autoimmune disease (17.6%) received supraphysiologic doses of glucocorticoid — equivalent to at least 25 mg hydrocortisone — compared with patients who didn’t develop autoimmune disease (41.8%).

“Although the daily average hydrocortisone equivalent replacement doses within the first month and during long-term follow-up were within the physiologic range in both subgroups, patients with Cushing disease who had autoimmune disease received slightly lower doses of glucocorticoid replacement within the first month after surgery,” the authors reported. “The immediate postoperative period might be a critical window where supraphysiologic glucocorticoids seem to be protective with regard to development of autoimmune disease,” they wrote, though they acknowledged the study’s retrospective design as a limitation in drawing that conclusion.

At the least, they suggested that new symptoms in patients with Cushing disease, particularly those with a family history of autoimmune disease, should prompt investigation of potential autoimmune disease.

Recordati Rare Diseases funded the study. The research was also conducted with support from Harvard Catalyst (the Harvard Clinical and Translational Science Center) as well as financial contributions from Harvard University and its affiliated academic healthcare centers. One author reported holding stocks in Pfizer and Amgen, and another reported receiving consulting fees from Corcept. Dr. Heaney reported receiving institutional grants for trials from Corcept, Ascendis, Crinetics, and Sparrow Pharm; serving on the advisory board for Xeris, Recordati, Corcept, Novo Nordisk, Lundbeck, and Crinetics; and serving as a speaker for Chiesi, Novo Nordisk, and Corcept.
 

A version of this article appeared on Medscape.com.