Rheumatology News

TOPLINE:

After Staphylococcus aureus bacteremia, patients with rheumatoid arthritis (RA) face nearly double the risk for osteoarticular infections compared with those without RA, with similar mortality risks in both groups.

METHODOLOGY:

• The contraction of S aureus bacteremia is linked to poor clinical outcomes in patients with RA; however, no well-sized studies have evaluated the risk for osteoarticular infections and mortality outcomes in patients with RA following S aureus bacteremia.
• This Danish nationwide cohort study aimed to explore whether the cumulative incidence of osteoarticular infections and death would be higher in patients with RA than in those without RA after contracting S aureus bacteremia.
• The study cohort included 18,274 patients with a first episode of S aureus bacteremia between 2006 and 2018, of whom 367 had been diagnosed with RA before contracting S aureus bacteremia.
• The RA cohort had more women (62%) and a higher median age of participants (73 years) than the non-RA cohort (37% women; median age of participants, 70 years).

TAKEAWAY:

• The 90-day cumulative incidence of osteoarticular infections (septic arthritis, spondylitis, osteomyelitis, psoas muscle abscess, or prosthetic joint infection) was nearly double in patients with RA compared with in those without RA (23.1% vs 12.5%; hazard ratio [HR], 1.93; 95% CI, 1.54-2.41).
• In patients with RA, the risk for osteoarticular infections increased with tumor necrosis factor inhibitor use (HR, 2.27; 95% CI, 1.29-3.98) and orthopedic implants (HR, 1.75; 95% CI, 1.08-2.85).
• Moreover, 90-day all-cause mortality was comparable in the RA (35.4%) and non-RA cohorts (33.9%).

IN PRACTICE:

“Our findings stress the need for vigilance in patients with RA who present with S aureus bacteremia to ensure timely identification and treatment of osteoarticular infections, especially in current TNFi [tumor necrosis factor inhibitor] users and patients with orthopedic implants,” the authors wrote.

SOURCE:

This study, led by Sabine S. Dieperink, MD, of the Centre of Head and Orthopaedics, Copenhagen University Rigshospitalet Glostrup, Denmark, was published online March 9 in Rheumatology (Oxford).

LIMITATIONS:

There might have been chances of misclassification of metastatic S aureus infections owing to the lack of specificity in diagnoses or procedure codes. This study relied on administrative data to record osteoarticular infections, which might have led investigators to underestimate the true cumulative incidence of osteoarticular infections. Also, some patients might have passed away before being diagnosed with osteoarticular infection owing to the high mortality.

DISCLOSURES:

This work was supported by grants from The Danish Rheumatism Association and Beckett Fonden. Some of the authors, including the lead author, declared receiving grants from various funding agencies and other sources, including pharmaceutical companies.

A version of this article appeared on Medscape.com.

TOPLINE:

After Staphylococcus aureus bacteremia, patients with rheumatoid arthritis (RA) face nearly double the risk for osteoarticular infections compared with those without RA, with similar mortality risks in both groups.

METHODOLOGY:

• The contraction of S aureus bacteremia is linked to poor clinical outcomes in patients with RA; however, no well-sized studies have evaluated the risk for osteoarticular infections and mortality outcomes in patients with RA following S aureus bacteremia.
• This Danish nationwide cohort study aimed to explore whether the cumulative incidence of osteoarticular infections and death would be higher in patients with RA than in those without RA after contracting S aureus bacteremia.
• The study cohort included 18,274 patients with a first episode of S aureus bacteremia between 2006 and 2018, of whom 367 had been diagnosed with RA before contracting S aureus bacteremia.
• The RA cohort had more women (62%) and a higher median age of participants (73 years) than the non-RA cohort (37% women; median age of participants, 70 years).

TAKEAWAY:

• The 90-day cumulative incidence of osteoarticular infections (septic arthritis, spondylitis, osteomyelitis, psoas muscle abscess, or prosthetic joint infection) was nearly double in patients with RA compared with in those without RA (23.1% vs 12.5%; hazard ratio [HR], 1.93; 95% CI, 1.54-2.41).
• In patients with RA, the risk for osteoarticular infections increased with tumor necrosis factor inhibitor use (HR, 2.27; 95% CI, 1.29-3.98) and orthopedic implants (HR, 1.75; 95% CI, 1.08-2.85).
• Moreover, 90-day all-cause mortality was comparable in the RA (35.4%) and non-RA cohorts (33.9%).

IN PRACTICE:

“Our findings stress the need for vigilance in patients with RA who present with S aureus bacteremia to ensure timely identification and treatment of osteoarticular infections, especially in current TNFi [tumor necrosis factor inhibitor] users and patients with orthopedic implants,” the authors wrote.

SOURCE:

This study, led by Sabine S. Dieperink, MD, of the Centre of Head and Orthopaedics, Copenhagen University Rigshospitalet Glostrup, Denmark, was published online March 9 in Rheumatology (Oxford).

LIMITATIONS:

There might have been chances of misclassification of metastatic S aureus infections owing to the lack of specificity in diagnoses or procedure codes. This study relied on administrative data to record osteoarticular infections, which might have led investigators to underestimate the true cumulative incidence of osteoarticular infections. Also, some patients might have passed away before being diagnosed with osteoarticular infection owing to the high mortality.

DISCLOSURES:

This work was supported by grants from The Danish Rheumatism Association and Beckett Fonden. Some of the authors, including the lead author, declared receiving grants from various funding agencies and other sources, including pharmaceutical companies.

A version of this article appeared on Medscape.com.

TOPLINE:

After Staphylococcus aureus bacteremia, patients with rheumatoid arthritis (RA) face nearly double the risk for osteoarticular infections compared with those without RA, with similar mortality risks in both groups.

METHODOLOGY:

• The contraction of S aureus bacteremia is linked to poor clinical outcomes in patients with RA; however, no well-sized studies have evaluated the risk for osteoarticular infections and mortality outcomes in patients with RA following S aureus bacteremia.
• This Danish nationwide cohort study aimed to explore whether the cumulative incidence of osteoarticular infections and death would be higher in patients with RA than in those without RA after contracting S aureus bacteremia.
• The study cohort included 18,274 patients with a first episode of S aureus bacteremia between 2006 and 2018, of whom 367 had been diagnosed with RA before contracting S aureus bacteremia.
• The RA cohort had more women (62%) and a higher median age of participants (73 years) than the non-RA cohort (37% women; median age of participants, 70 years).

TAKEAWAY:

• The 90-day cumulative incidence of osteoarticular infections (septic arthritis, spondylitis, osteomyelitis, psoas muscle abscess, or prosthetic joint infection) was nearly double in patients with RA compared with in those without RA (23.1% vs 12.5%; hazard ratio [HR], 1.93; 95% CI, 1.54-2.41).
• In patients with RA, the risk for osteoarticular infections increased with tumor necrosis factor inhibitor use (HR, 2.27; 95% CI, 1.29-3.98) and orthopedic implants (HR, 1.75; 95% CI, 1.08-2.85).
• Moreover, 90-day all-cause mortality was comparable in the RA (35.4%) and non-RA cohorts (33.9%).

IN PRACTICE:

“Our findings stress the need for vigilance in patients with RA who present with S aureus bacteremia to ensure timely identification and treatment of osteoarticular infections, especially in current TNFi [tumor necrosis factor inhibitor] users and patients with orthopedic implants,” the authors wrote.

SOURCE:

This study, led by Sabine S. Dieperink, MD, of the Centre of Head and Orthopaedics, Copenhagen University Rigshospitalet Glostrup, Denmark, was published online March 9 in Rheumatology (Oxford).

LIMITATIONS:

There might have been chances of misclassification of metastatic S aureus infections owing to the lack of specificity in diagnoses or procedure codes. This study relied on administrative data to record osteoarticular infections, which might have led investigators to underestimate the true cumulative incidence of osteoarticular infections. Also, some patients might have passed away before being diagnosed with osteoarticular infection owing to the high mortality.

DISCLOSURES:

This work was supported by grants from The Danish Rheumatism Association and Beckett Fonden. Some of the authors, including the lead author, declared receiving grants from various funding agencies and other sources, including pharmaceutical companies.

A version of this article appeared on Medscape.com.

Paxlovid does not significantly alleviate symptoms of COVID-19 compared with placebo among nonhospitalized adults, a new study published April 3 in The New England Journal of Medicine found. 

The results suggest that the drug, a combination of nirmatrelvir and ritonavir, may not be particularly helpful for patients who are not at high risk for severe COVID-19. However, although the rate of hospitalization and death from any cause was low overall, the group that received Paxlovid had a reduced rate compared with people in the placebo group, according to the researchers. 

“Clearly, the benefit observed among unvaccinated high-risk persons does not extend to those at lower risk for severe COVID-19,” Rajesh T. Gandhi, MD, and Martin Hirsch, MD, of Massachusetts General Hospital in Boston, wrote in an editorial accompanying the journal article. “This result supports guidelines that recommend nirmatrelvir–ritonavir only for persons who are at high risk for disease progression.”

The time from onset to relief of COVID-19 symptoms — including cough, shortness of breath, body aches, and chills — did not differ significantly between the two study groups, the researchers reported. The median time to sustained alleviation of symptoms was 12 days for the Paxlovid group compared with 13 days in the placebo group (P = .60).

However, the phase 2/3 trial found a 57.6% relative reduction in the risk for hospitalizations or death among people who took Paxlovid and were vaccinated but were at high risk for poor outcomes, according to Jennifer Hammond, PhD, head of antiviral development for Pfizer, which makes the drug, and the corresponding author on the study.

Paxlovid has “an increasing body of evidence supporting the strong clinical value of the treatment in preventing hospitalization and death among eligible patients across age groups, vaccination status, and predominant variants,” Dr. Hammond said. 

She and her colleagues analyzed data from 1250 adults with symptomatic COVID-19. Participants were fully vaccinated and had a high risk for progression to severe disease or were never vaccinated or had not been in the previous year and had no risk factors for progression to severe disease.

More than half of participants were women, 78.5% were White and 41.4% identified as Hispanic or Latinx. Almost three quarters underwent randomization within 3 days of the start of symptoms, and a little over half had previously received a COVID-19 vaccination. Almost half had one risk factor for severe illness, the most common of these being hypertension (12.3%). 

In a subgroup analysis of high-risk participants, hospitalization or death occurred in 0.9% of patients in the Paxlovid group and 2.2% in the placebo group (95% CI, -3.3 to 0.7). 

The study’s limitations include that the statistical analysis of COVID-19–related hospitalizations or death from any cause was only descriptive, “because the results for the primary efficacy end point were not significant,” the authors wrote. 

Participants who were vaccinated and at high risk were also enrolled regardless of when they had last had a vaccine dose. Furthermore, Paxlovid has a telltale taste, which may have affected the blinding. Finally, the trial was started when the B.1.617.2 (Delta) variant was predominant.

Dr. Gandhi and Dr. Hirsch pointed out that only 5% of participants in the trial were older than 65 years and that other than risk factors such as obesity and smoking, just 2% of people had heart or lung disease. 

“As with many medical interventions, there is likely to be a gradient of benefit for nirmatrelvir–ritonavir, with the patients at highest risk for progression most likely to derive the greatest benefit,” Dr. Gandhi and Dr. Hirsch wrote in the editorial. “Thus, it appears reasonable to recommend nirmatrelvir–ritonavir primarily for the treatment of COVID-19 in older patients (particularly those ≥ 65 years of age), those who are immunocompromised, and those who have conditions that substantially increase the risk of severe COVID-19, regardless of previous vaccination or infection status.”

The study was supported by Pfizer. 

A version of this article appeared on Medscape.com .

Paxlovid does not significantly alleviate symptoms of COVID-19 compared with placebo among nonhospitalized adults, a new study published April 3 in The New England Journal of Medicine found. 

The results suggest that the drug, a combination of nirmatrelvir and ritonavir, may not be particularly helpful for patients who are not at high risk for severe COVID-19. However, although the rate of hospitalization and death from any cause was low overall, the group that received Paxlovid had a reduced rate compared with people in the placebo group, according to the researchers. 

“Clearly, the benefit observed among unvaccinated high-risk persons does not extend to those at lower risk for severe COVID-19,” Rajesh T. Gandhi, MD, and Martin Hirsch, MD, of Massachusetts General Hospital in Boston, wrote in an editorial accompanying the journal article. “This result supports guidelines that recommend nirmatrelvir–ritonavir only for persons who are at high risk for disease progression.”

The time from onset to relief of COVID-19 symptoms — including cough, shortness of breath, body aches, and chills — did not differ significantly between the two study groups, the researchers reported. The median time to sustained alleviation of symptoms was 12 days for the Paxlovid group compared with 13 days in the placebo group (P = .60).

However, the phase 2/3 trial found a 57.6% relative reduction in the risk for hospitalizations or death among people who took Paxlovid and were vaccinated but were at high risk for poor outcomes, according to Jennifer Hammond, PhD, head of antiviral development for Pfizer, which makes the drug, and the corresponding author on the study.

Paxlovid has “an increasing body of evidence supporting the strong clinical value of the treatment in preventing hospitalization and death among eligible patients across age groups, vaccination status, and predominant variants,” Dr. Hammond said. 

She and her colleagues analyzed data from 1250 adults with symptomatic COVID-19. Participants were fully vaccinated and had a high risk for progression to severe disease or were never vaccinated or had not been in the previous year and had no risk factors for progression to severe disease.

More than half of participants were women, 78.5% were White and 41.4% identified as Hispanic or Latinx. Almost three quarters underwent randomization within 3 days of the start of symptoms, and a little over half had previously received a COVID-19 vaccination. Almost half had one risk factor for severe illness, the most common of these being hypertension (12.3%). 

In a subgroup analysis of high-risk participants, hospitalization or death occurred in 0.9% of patients in the Paxlovid group and 2.2% in the placebo group (95% CI, -3.3 to 0.7). 

The study’s limitations include that the statistical analysis of COVID-19–related hospitalizations or death from any cause was only descriptive, “because the results for the primary efficacy end point were not significant,” the authors wrote. 

Participants who were vaccinated and at high risk were also enrolled regardless of when they had last had a vaccine dose. Furthermore, Paxlovid has a telltale taste, which may have affected the blinding. Finally, the trial was started when the B.1.617.2 (Delta) variant was predominant.

Dr. Gandhi and Dr. Hirsch pointed out that only 5% of participants in the trial were older than 65 years and that other than risk factors such as obesity and smoking, just 2% of people had heart or lung disease. 

“As with many medical interventions, there is likely to be a gradient of benefit for nirmatrelvir–ritonavir, with the patients at highest risk for progression most likely to derive the greatest benefit,” Dr. Gandhi and Dr. Hirsch wrote in the editorial. “Thus, it appears reasonable to recommend nirmatrelvir–ritonavir primarily for the treatment of COVID-19 in older patients (particularly those ≥ 65 years of age), those who are immunocompromised, and those who have conditions that substantially increase the risk of severe COVID-19, regardless of previous vaccination or infection status.”

The study was supported by Pfizer. 

A version of this article appeared on Medscape.com .

Paxlovid does not significantly alleviate symptoms of COVID-19 compared with placebo among nonhospitalized adults, a new study published April 3 in The New England Journal of Medicine found. 

The results suggest that the drug, a combination of nirmatrelvir and ritonavir, may not be particularly helpful for patients who are not at high risk for severe COVID-19. However, although the rate of hospitalization and death from any cause was low overall, the group that received Paxlovid had a reduced rate compared with people in the placebo group, according to the researchers. 

“Clearly, the benefit observed among unvaccinated high-risk persons does not extend to those at lower risk for severe COVID-19,” Rajesh T. Gandhi, MD, and Martin Hirsch, MD, of Massachusetts General Hospital in Boston, wrote in an editorial accompanying the journal article. “This result supports guidelines that recommend nirmatrelvir–ritonavir only for persons who are at high risk for disease progression.”

The time from onset to relief of COVID-19 symptoms — including cough, shortness of breath, body aches, and chills — did not differ significantly between the two study groups, the researchers reported. The median time to sustained alleviation of symptoms was 12 days for the Paxlovid group compared with 13 days in the placebo group (P = .60).

However, the phase 2/3 trial found a 57.6% relative reduction in the risk for hospitalizations or death among people who took Paxlovid and were vaccinated but were at high risk for poor outcomes, according to Jennifer Hammond, PhD, head of antiviral development for Pfizer, which makes the drug, and the corresponding author on the study.

Paxlovid has “an increasing body of evidence supporting the strong clinical value of the treatment in preventing hospitalization and death among eligible patients across age groups, vaccination status, and predominant variants,” Dr. Hammond said. 

She and her colleagues analyzed data from 1250 adults with symptomatic COVID-19. Participants were fully vaccinated and had a high risk for progression to severe disease or were never vaccinated or had not been in the previous year and had no risk factors for progression to severe disease.

More than half of participants were women, 78.5% were White and 41.4% identified as Hispanic or Latinx. Almost three quarters underwent randomization within 3 days of the start of symptoms, and a little over half had previously received a COVID-19 vaccination. Almost half had one risk factor for severe illness, the most common of these being hypertension (12.3%). 

In a subgroup analysis of high-risk participants, hospitalization or death occurred in 0.9% of patients in the Paxlovid group and 2.2% in the placebo group (95% CI, -3.3 to 0.7). 

The study’s limitations include that the statistical analysis of COVID-19–related hospitalizations or death from any cause was only descriptive, “because the results for the primary efficacy end point were not significant,” the authors wrote. 

Participants who were vaccinated and at high risk were also enrolled regardless of when they had last had a vaccine dose. Furthermore, Paxlovid has a telltale taste, which may have affected the blinding. Finally, the trial was started when the B.1.617.2 (Delta) variant was predominant.

Dr. Gandhi and Dr. Hirsch pointed out that only 5% of participants in the trial were older than 65 years and that other than risk factors such as obesity and smoking, just 2% of people had heart or lung disease. 

“As with many medical interventions, there is likely to be a gradient of benefit for nirmatrelvir–ritonavir, with the patients at highest risk for progression most likely to derive the greatest benefit,” Dr. Gandhi and Dr. Hirsch wrote in the editorial. “Thus, it appears reasonable to recommend nirmatrelvir–ritonavir primarily for the treatment of COVID-19 in older patients (particularly those ≥ 65 years of age), those who are immunocompromised, and those who have conditions that substantially increase the risk of severe COVID-19, regardless of previous vaccination or infection status.”

The study was supported by Pfizer. 

A version of this article appeared on Medscape.com .

The second-floor operating rooms at Lehigh Valley Hospital in Allentown, Pennsylvania, are numbered sequentially — except when you get to what should be operation room (OR) 13. It’s OR M. The M doesn’t stand for Maternity or any other specialty. Rather in this high-tech, state-of-the art healthcare center, it’s there to ward off bad juju and evil spirits.

“Just as taller buildings usually don’t have a 13th floor or hotels don’t have a room 13, it revolves around the common superstition of the unlucky nature of number 13,” said a hospital spokesperson.

During the pandemic, the public was told repeatedly that modern medicine is science-based. But when I started talking to surgeons and other physicians for this article, I uncovered something decidedly unscientific.

In ORs and emergency rooms (ERs), small-town doctor’s offices, and mega hospitals, there’s a measure of dread before full moons and Friday the 13th, and no one dares utter the Q word (as in, “It sure is quiet today.”) That would risk bringing the wrath of the medical gods, and you’d earn the reputation of being a jinx or “black cloud.” Likewise, the songs “Stairway to Heaven” or “Another One Bites the Dust” will never be heard in any waiting room, elevator, or OR.

Indeed, when it comes to superstitions and rituals in medicine, it seems everyone has a story or a belief. …
 

A 2-Hour Ritual

Carmen Fong, MD, a colorectal surgeon in New York City, had a presurgical ritual that took her nearly 2 hours to complete. “I’d wake up at the same time every day, pack two hard-boiled eggs and a thermos of coffee in my small leather bag, walk to work via the same route, and swipe into the preop area while waving hi to the front desk,” she recounted. “I’d talk to the patient, sign the consent with the same ballpoint pen, go upstairs to my office, change into my scrubs [same cap and Danskos], then turn on my computer, and take a sip of coffee before heading back down to the OR. I’d always remove my badge and place it near the nurses’ workstation, then put on the patient’s SCDs [sequential compression devices] myself. I’d hold the oxygen mask while telling the patient, ‘See you later.’ Never ‘It will be okay’ or ‘Have a good sleep.’ Always ‘See you later.’ ”

Dr. Fong did this for 5 years prior to more than a thousand surgeries. She did it because it made her feel calm and in control, which translated to more successful operations. “It never failed me.”
 

Wonder Woman Clogs

Anureet Bajaj, MD, a plastic surgeon in Oklahoma City, wore Wonder Woman clogs in the OR for years because “they made me feel stronger, and my surgeries went better.” She’s also very specific about her OR playlist; “it must be ‘80s music.” And for a time, she wore a friendship bracelet that one of her employees made to commemorate getting through a particularly hard day. “If I forgot it, my heart sank, and my anxiety rose,” she said. “Wearing it gave me security and confidence that the day would go well.”

A Moment of Silence

Juliet Emamaullee, MD, PhD, is a liver and kidney transplant surgeon at Keck Hospital and Children’s Hospital Los Angeles. Because of the complexity of her operations, she must know every aspect of her patients’ medical history. This leads to a level of intimacy that most people never have with their doctors. “Transplant surgeons are playing god in many ways,” she said. “During procurement, after we prep and drape the donor and right before I make the incision, everyone in the OR has a moment of silence to acknowledge the donation. If the organ has been transported, then I’ll say a prayer to myself that I do good work with this generous gift of life.”

Magical Thinking

Before we go any further, I should clarify that there’s a difference between rituals and superstitions like the ones just shared and routines and practices such as handwashing or doublechecking that it’s the right hip and not the left. All pilots have a preflight checklist that’s necessary for safety, but some might also make the sign of the cross.

Lester Gottesman, MD, has been a surgeon at the Icahn School of Medicine at Mount Sinai Hospital in New York City for nearly 50 years. He believes rituals and superstitions are more prevalent in medicine than in any other profession, despite there being no definitive research confirming their effectiveness.

In fact, it’s the opposite.

One of the few studies to examine superstitions among physicians was published in the Annals of Surgery in 2021. Researchers analyzed the operational records of 27,914 consecutive patients who underwent general, visceral, or vascular surgery. They found no association of moon phases, zodiac signs, or Friday the 13th with poor outcomes. Having acute coronary syndrome on Friday the 13th also did not influence the 13-year mortality rate compared to other dates in the year. And although 70% of physicians believe that some colleagues are “black clouds,” an analysis of 96 physicians and 6149 admissions found no such pattern.

Granted, this is just one analysis, but the results aren’t surprising. No one really believes in this stuff. So, why does it persist?

Dr. Gottesman cited an episode from the popular medical TV show Grey’s Anatomy, in which chief surgeon Meredith Grey puts it this way: “Superstition lies in the space between what we can control and what we can’t. …We rely on superstitions because we are smart enough to know we don’t have all the answers and that life works in mysterious ways. Don’t diss the juju from wherever it comes.”

“Superstition and science both start at the same place — to explain an unexplainable event,” said Dr. Gottesman, who always checks his suture lines at the end of a surgery in the order in which he did them. “If science provides a coherent answer, so be it. If not, the human’s need for order will assign causality to otherwise inanimate objects, noncausal events, or divine influence.”

In other words, the more unknowns and trepidation, the greater the tendency toward what Dr. Gottesman called “magical thinking.” And when you consider healing’s long history, you realize that ritual and superstition defined medicine for centuries. Gottesman pointed out that it wasn’t until Hippocrates separated religion and superstition from disease around 430 BC that modern medicine was born. But because doctors still don’t know everything, an element of magic endures.

The question is, in this high-tech age, do these stubborn beliefs still have a place? Do they help or hinder doctors, and, most important, do they have any effect on patient outcomes?
 

Five Benefits

To reiterate, there are no studies showing that Wonder Woman clogs convey surgical superpowers or that eating two hard-boiled eggs boosts OR performance. But anecdotally, many doctors admit to experiencing noticeable perks from their quirks. Let’s start with the supposed benefits:

• Less stress: A quarter of US clinicians are considering switching careers, primarily due to burnout, according to a 2022 Bain survey. “The fact that [rituals and superstitions] are so prevalent in such a high-stress field can’t be coincidence,” said Dr. Fong. “Offloading some of the responsibility to whatever gods there may be is a way of taming our anxieties so we can function better.”
• Hyperfocus: Dr. Emamaullee played volleyball in high school and college. She suggested that her presurgical routine isn’t all that different from her warmup before a championship match. It’s habitual behavior that helps induce a state of heightened concentration, confidence, and immersion. Athletes call it being “in the zone” or in a “state of flow,” and Dr. Emamaullee said she experiences the same thing in the OR.
• More control: Remember those horrific images of patients with COVID-19 overwhelming ERs in Brooklyn and Queens during the pandemic? Dr. Fong was in the middle of that. “In crisis situations where there are more unknowns, rituals and superstitions become even more important,” she said. “I may not be able to control what’s happening, but I can control myself. Rituals help restore some normalcy and organization, and they give me a sense of calm.”
• Better performance: A series of general-population experiments published in the journal Psychological Science in 2010 concluded that “good-luck–related superstitions” boosted self-confidence in mastering upcoming tasks and improved motor dexterity, memory, and overall performance.
• Placebo effect: This phenomenon is well-established in medicine. Give someone a special pill or treatment, and a significant portion will claim benefit. “Placebo is magical thinking,” said Dr. Gottesman. “It has identifiable and quantifiable effects on human disease.” And perhaps on medical practitioners, too. If a doctor believes her friendship bracelet has special powers and helps her be a better physician, then it just might.

Four Drawbacks

• Compulsive behavior: When superstitious beliefs or repetitive behaviors begin causing personal distress, interfering with daily duties, or negatively affecting patient outcomes, then there’s a problem. There’s a story on Quora about a neurosurgeon who always ate two Hostess Ho Hos chocolate cakes before operations. When he forgot to do so one day, he supposedly left his patient on the table and ran off to eat them. Even if it’s urban legend, it’s a useful illustration of quirk disrupting work.
• Less flexibility: Every human body and every surgery is different. “When ritualistic behaviors or habits become so rigid that you lose the ability to adapt, then that becomes dangerous for the patient,” said Dr. Fong. “The art of medicine, not unlike jazz, often comes from the improvisation.”
• Self-fulfilling: Just as rituals and superstitions can empower and provide a sense of control, they can quickly turn on physicians who forget a part of their routine or leave their talisman on the bureau. Instead of confidence, they supply doubt. The karma becomes kryptonite.
• Avoiding responsibility: After years of friendship bracelets and Wonder Woman clogs, Dr. Bajaj is making a deliberate effort to excise magical thinking from her practice. “It can hold you back if you’re not careful,” she said. “If you start using it as a crutch when something goes wrong — like ‘Oh, I wasn’t wearing my clogs today and that’s why my flap failed’ — then you’re not doing your due diligence and figuring out what really happened.” Rather than placing the responsibility for her day going well on superstition, she’s trying to own it herself by living with more intent.

The Diagnosis

Most of the medical experts I spoke with didn’t think there was anything wrong with rituals or superstitions as long as they didn’t become compulsive or a convenient repository of blame.

“Rituals and superstitions are an acknowledgment that forces external to ourselves exist,” concluded Dr. Fong. “They’re like tiny offerings to whatever gods are out there to please be on our side. And we keep doing them because there’s a reward — better patient outcomes, which is all we want to achieve in the end. I say embrace them.”

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

The second-floor operating rooms at Lehigh Valley Hospital in Allentown, Pennsylvania, are numbered sequentially — except when you get to what should be operation room (OR) 13. It’s OR M. The M doesn’t stand for Maternity or any other specialty. Rather in this high-tech, state-of-the art healthcare center, it’s there to ward off bad juju and evil spirits.

“Just as taller buildings usually don’t have a 13th floor or hotels don’t have a room 13, it revolves around the common superstition of the unlucky nature of number 13,” said a hospital spokesperson.

During the pandemic, the public was told repeatedly that modern medicine is science-based. But when I started talking to surgeons and other physicians for this article, I uncovered something decidedly unscientific.

In ORs and emergency rooms (ERs), small-town doctor’s offices, and mega hospitals, there’s a measure of dread before full moons and Friday the 13th, and no one dares utter the Q word (as in, “It sure is quiet today.”) That would risk bringing the wrath of the medical gods, and you’d earn the reputation of being a jinx or “black cloud.” Likewise, the songs “Stairway to Heaven” or “Another One Bites the Dust” will never be heard in any waiting room, elevator, or OR.

Indeed, when it comes to superstitions and rituals in medicine, it seems everyone has a story or a belief. …
 

A 2-Hour Ritual

Carmen Fong, MD, a colorectal surgeon in New York City, had a presurgical ritual that took her nearly 2 hours to complete. “I’d wake up at the same time every day, pack two hard-boiled eggs and a thermos of coffee in my small leather bag, walk to work via the same route, and swipe into the preop area while waving hi to the front desk,” she recounted. “I’d talk to the patient, sign the consent with the same ballpoint pen, go upstairs to my office, change into my scrubs [same cap and Danskos], then turn on my computer, and take a sip of coffee before heading back down to the OR. I’d always remove my badge and place it near the nurses’ workstation, then put on the patient’s SCDs [sequential compression devices] myself. I’d hold the oxygen mask while telling the patient, ‘See you later.’ Never ‘It will be okay’ or ‘Have a good sleep.’ Always ‘See you later.’ ”

Dr. Fong did this for 5 years prior to more than a thousand surgeries. She did it because it made her feel calm and in control, which translated to more successful operations. “It never failed me.”
 

Wonder Woman Clogs

Anureet Bajaj, MD, a plastic surgeon in Oklahoma City, wore Wonder Woman clogs in the OR for years because “they made me feel stronger, and my surgeries went better.” She’s also very specific about her OR playlist; “it must be ‘80s music.” And for a time, she wore a friendship bracelet that one of her employees made to commemorate getting through a particularly hard day. “If I forgot it, my heart sank, and my anxiety rose,” she said. “Wearing it gave me security and confidence that the day would go well.”

A Moment of Silence

Juliet Emamaullee, MD, PhD, is a liver and kidney transplant surgeon at Keck Hospital and Children’s Hospital Los Angeles. Because of the complexity of her operations, she must know every aspect of her patients’ medical history. This leads to a level of intimacy that most people never have with their doctors. “Transplant surgeons are playing god in many ways,” she said. “During procurement, after we prep and drape the donor and right before I make the incision, everyone in the OR has a moment of silence to acknowledge the donation. If the organ has been transported, then I’ll say a prayer to myself that I do good work with this generous gift of life.”

Magical Thinking

Before we go any further, I should clarify that there’s a difference between rituals and superstitions like the ones just shared and routines and practices such as handwashing or doublechecking that it’s the right hip and not the left. All pilots have a preflight checklist that’s necessary for safety, but some might also make the sign of the cross.

Lester Gottesman, MD, has been a surgeon at the Icahn School of Medicine at Mount Sinai Hospital in New York City for nearly 50 years. He believes rituals and superstitions are more prevalent in medicine than in any other profession, despite there being no definitive research confirming their effectiveness.

In fact, it’s the opposite.

One of the few studies to examine superstitions among physicians was published in the Annals of Surgery in 2021. Researchers analyzed the operational records of 27,914 consecutive patients who underwent general, visceral, or vascular surgery. They found no association of moon phases, zodiac signs, or Friday the 13th with poor outcomes. Having acute coronary syndrome on Friday the 13th also did not influence the 13-year mortality rate compared to other dates in the year. And although 70% of physicians believe that some colleagues are “black clouds,” an analysis of 96 physicians and 6149 admissions found no such pattern.

Granted, this is just one analysis, but the results aren’t surprising. No one really believes in this stuff. So, why does it persist?

Dr. Gottesman cited an episode from the popular medical TV show Grey’s Anatomy, in which chief surgeon Meredith Grey puts it this way: “Superstition lies in the space between what we can control and what we can’t. …We rely on superstitions because we are smart enough to know we don’t have all the answers and that life works in mysterious ways. Don’t diss the juju from wherever it comes.”

“Superstition and science both start at the same place — to explain an unexplainable event,” said Dr. Gottesman, who always checks his suture lines at the end of a surgery in the order in which he did them. “If science provides a coherent answer, so be it. If not, the human’s need for order will assign causality to otherwise inanimate objects, noncausal events, or divine influence.”

In other words, the more unknowns and trepidation, the greater the tendency toward what Dr. Gottesman called “magical thinking.” And when you consider healing’s long history, you realize that ritual and superstition defined medicine for centuries. Gottesman pointed out that it wasn’t until Hippocrates separated religion and superstition from disease around 430 BC that modern medicine was born. But because doctors still don’t know everything, an element of magic endures.

The question is, in this high-tech age, do these stubborn beliefs still have a place? Do they help or hinder doctors, and, most important, do they have any effect on patient outcomes?
 

Five Benefits

To reiterate, there are no studies showing that Wonder Woman clogs convey surgical superpowers or that eating two hard-boiled eggs boosts OR performance. But anecdotally, many doctors admit to experiencing noticeable perks from their quirks. Let’s start with the supposed benefits:

• Less stress: A quarter of US clinicians are considering switching careers, primarily due to burnout, according to a 2022 Bain survey. “The fact that [rituals and superstitions] are so prevalent in such a high-stress field can’t be coincidence,” said Dr. Fong. “Offloading some of the responsibility to whatever gods there may be is a way of taming our anxieties so we can function better.”
• Hyperfocus: Dr. Emamaullee played volleyball in high school and college. She suggested that her presurgical routine isn’t all that different from her warmup before a championship match. It’s habitual behavior that helps induce a state of heightened concentration, confidence, and immersion. Athletes call it being “in the zone” or in a “state of flow,” and Dr. Emamaullee said she experiences the same thing in the OR.
• More control: Remember those horrific images of patients with COVID-19 overwhelming ERs in Brooklyn and Queens during the pandemic? Dr. Fong was in the middle of that. “In crisis situations where there are more unknowns, rituals and superstitions become even more important,” she said. “I may not be able to control what’s happening, but I can control myself. Rituals help restore some normalcy and organization, and they give me a sense of calm.”
• Better performance: A series of general-population experiments published in the journal Psychological Science in 2010 concluded that “good-luck–related superstitions” boosted self-confidence in mastering upcoming tasks and improved motor dexterity, memory, and overall performance.
• Placebo effect: This phenomenon is well-established in medicine. Give someone a special pill or treatment, and a significant portion will claim benefit. “Placebo is magical thinking,” said Dr. Gottesman. “It has identifiable and quantifiable effects on human disease.” And perhaps on medical practitioners, too. If a doctor believes her friendship bracelet has special powers and helps her be a better physician, then it just might.

Four Drawbacks

• Compulsive behavior: When superstitious beliefs or repetitive behaviors begin causing personal distress, interfering with daily duties, or negatively affecting patient outcomes, then there’s a problem. There’s a story on Quora about a neurosurgeon who always ate two Hostess Ho Hos chocolate cakes before operations. When he forgot to do so one day, he supposedly left his patient on the table and ran off to eat them. Even if it’s urban legend, it’s a useful illustration of quirk disrupting work.
• Less flexibility: Every human body and every surgery is different. “When ritualistic behaviors or habits become so rigid that you lose the ability to adapt, then that becomes dangerous for the patient,” said Dr. Fong. “The art of medicine, not unlike jazz, often comes from the improvisation.”
• Self-fulfilling: Just as rituals and superstitions can empower and provide a sense of control, they can quickly turn on physicians who forget a part of their routine or leave their talisman on the bureau. Instead of confidence, they supply doubt. The karma becomes kryptonite.
• Avoiding responsibility: After years of friendship bracelets and Wonder Woman clogs, Dr. Bajaj is making a deliberate effort to excise magical thinking from her practice. “It can hold you back if you’re not careful,” she said. “If you start using it as a crutch when something goes wrong — like ‘Oh, I wasn’t wearing my clogs today and that’s why my flap failed’ — then you’re not doing your due diligence and figuring out what really happened.” Rather than placing the responsibility for her day going well on superstition, she’s trying to own it herself by living with more intent.

The Diagnosis

Most of the medical experts I spoke with didn’t think there was anything wrong with rituals or superstitions as long as they didn’t become compulsive or a convenient repository of blame.

“Rituals and superstitions are an acknowledgment that forces external to ourselves exist,” concluded Dr. Fong. “They’re like tiny offerings to whatever gods are out there to please be on our side. And we keep doing them because there’s a reward — better patient outcomes, which is all we want to achieve in the end. I say embrace them.”

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

The second-floor operating rooms at Lehigh Valley Hospital in Allentown, Pennsylvania, are numbered sequentially — except when you get to what should be operation room (OR) 13. It’s OR M. The M doesn’t stand for Maternity or any other specialty. Rather in this high-tech, state-of-the art healthcare center, it’s there to ward off bad juju and evil spirits.

“Just as taller buildings usually don’t have a 13th floor or hotels don’t have a room 13, it revolves around the common superstition of the unlucky nature of number 13,” said a hospital spokesperson.

During the pandemic, the public was told repeatedly that modern medicine is science-based. But when I started talking to surgeons and other physicians for this article, I uncovered something decidedly unscientific.

In ORs and emergency rooms (ERs), small-town doctor’s offices, and mega hospitals, there’s a measure of dread before full moons and Friday the 13th, and no one dares utter the Q word (as in, “It sure is quiet today.”) That would risk bringing the wrath of the medical gods, and you’d earn the reputation of being a jinx or “black cloud.” Likewise, the songs “Stairway to Heaven” or “Another One Bites the Dust” will never be heard in any waiting room, elevator, or OR.

Indeed, when it comes to superstitions and rituals in medicine, it seems everyone has a story or a belief. …
 

A 2-Hour Ritual

Carmen Fong, MD, a colorectal surgeon in New York City, had a presurgical ritual that took her nearly 2 hours to complete. “I’d wake up at the same time every day, pack two hard-boiled eggs and a thermos of coffee in my small leather bag, walk to work via the same route, and swipe into the preop area while waving hi to the front desk,” she recounted. “I’d talk to the patient, sign the consent with the same ballpoint pen, go upstairs to my office, change into my scrubs [same cap and Danskos], then turn on my computer, and take a sip of coffee before heading back down to the OR. I’d always remove my badge and place it near the nurses’ workstation, then put on the patient’s SCDs [sequential compression devices] myself. I’d hold the oxygen mask while telling the patient, ‘See you later.’ Never ‘It will be okay’ or ‘Have a good sleep.’ Always ‘See you later.’ ”

Dr. Fong did this for 5 years prior to more than a thousand surgeries. She did it because it made her feel calm and in control, which translated to more successful operations. “It never failed me.”
 

Wonder Woman Clogs

Anureet Bajaj, MD, a plastic surgeon in Oklahoma City, wore Wonder Woman clogs in the OR for years because “they made me feel stronger, and my surgeries went better.” She’s also very specific about her OR playlist; “it must be ‘80s music.” And for a time, she wore a friendship bracelet that one of her employees made to commemorate getting through a particularly hard day. “If I forgot it, my heart sank, and my anxiety rose,” she said. “Wearing it gave me security and confidence that the day would go well.”

A Moment of Silence

Juliet Emamaullee, MD, PhD, is a liver and kidney transplant surgeon at Keck Hospital and Children’s Hospital Los Angeles. Because of the complexity of her operations, she must know every aspect of her patients’ medical history. This leads to a level of intimacy that most people never have with their doctors. “Transplant surgeons are playing god in many ways,” she said. “During procurement, after we prep and drape the donor and right before I make the incision, everyone in the OR has a moment of silence to acknowledge the donation. If the organ has been transported, then I’ll say a prayer to myself that I do good work with this generous gift of life.”

Magical Thinking

Before we go any further, I should clarify that there’s a difference between rituals and superstitions like the ones just shared and routines and practices such as handwashing or doublechecking that it’s the right hip and not the left. All pilots have a preflight checklist that’s necessary for safety, but some might also make the sign of the cross.

Lester Gottesman, MD, has been a surgeon at the Icahn School of Medicine at Mount Sinai Hospital in New York City for nearly 50 years. He believes rituals and superstitions are more prevalent in medicine than in any other profession, despite there being no definitive research confirming their effectiveness.

In fact, it’s the opposite.

One of the few studies to examine superstitions among physicians was published in the Annals of Surgery in 2021. Researchers analyzed the operational records of 27,914 consecutive patients who underwent general, visceral, or vascular surgery. They found no association of moon phases, zodiac signs, or Friday the 13th with poor outcomes. Having acute coronary syndrome on Friday the 13th also did not influence the 13-year mortality rate compared to other dates in the year. And although 70% of physicians believe that some colleagues are “black clouds,” an analysis of 96 physicians and 6149 admissions found no such pattern.

Granted, this is just one analysis, but the results aren’t surprising. No one really believes in this stuff. So, why does it persist?

Dr. Gottesman cited an episode from the popular medical TV show Grey’s Anatomy, in which chief surgeon Meredith Grey puts it this way: “Superstition lies in the space between what we can control and what we can’t. …We rely on superstitions because we are smart enough to know we don’t have all the answers and that life works in mysterious ways. Don’t diss the juju from wherever it comes.”

“Superstition and science both start at the same place — to explain an unexplainable event,” said Dr. Gottesman, who always checks his suture lines at the end of a surgery in the order in which he did them. “If science provides a coherent answer, so be it. If not, the human’s need for order will assign causality to otherwise inanimate objects, noncausal events, or divine influence.”

In other words, the more unknowns and trepidation, the greater the tendency toward what Dr. Gottesman called “magical thinking.” And when you consider healing’s long history, you realize that ritual and superstition defined medicine for centuries. Gottesman pointed out that it wasn’t until Hippocrates separated religion and superstition from disease around 430 BC that modern medicine was born. But because doctors still don’t know everything, an element of magic endures.

The question is, in this high-tech age, do these stubborn beliefs still have a place? Do they help or hinder doctors, and, most important, do they have any effect on patient outcomes?
 

Five Benefits

To reiterate, there are no studies showing that Wonder Woman clogs convey surgical superpowers or that eating two hard-boiled eggs boosts OR performance. But anecdotally, many doctors admit to experiencing noticeable perks from their quirks. Let’s start with the supposed benefits:

• Less stress: A quarter of US clinicians are considering switching careers, primarily due to burnout, according to a 2022 Bain survey. “The fact that [rituals and superstitions] are so prevalent in such a high-stress field can’t be coincidence,” said Dr. Fong. “Offloading some of the responsibility to whatever gods there may be is a way of taming our anxieties so we can function better.”
• Hyperfocus: Dr. Emamaullee played volleyball in high school and college. She suggested that her presurgical routine isn’t all that different from her warmup before a championship match. It’s habitual behavior that helps induce a state of heightened concentration, confidence, and immersion. Athletes call it being “in the zone” or in a “state of flow,” and Dr. Emamaullee said she experiences the same thing in the OR.
• More control: Remember those horrific images of patients with COVID-19 overwhelming ERs in Brooklyn and Queens during the pandemic? Dr. Fong was in the middle of that. “In crisis situations where there are more unknowns, rituals and superstitions become even more important,” she said. “I may not be able to control what’s happening, but I can control myself. Rituals help restore some normalcy and organization, and they give me a sense of calm.”
• Better performance: A series of general-population experiments published in the journal Psychological Science in 2010 concluded that “good-luck–related superstitions” boosted self-confidence in mastering upcoming tasks and improved motor dexterity, memory, and overall performance.
• Placebo effect: This phenomenon is well-established in medicine. Give someone a special pill or treatment, and a significant portion will claim benefit. “Placebo is magical thinking,” said Dr. Gottesman. “It has identifiable and quantifiable effects on human disease.” And perhaps on medical practitioners, too. If a doctor believes her friendship bracelet has special powers and helps her be a better physician, then it just might.

Four Drawbacks

• Compulsive behavior: When superstitious beliefs or repetitive behaviors begin causing personal distress, interfering with daily duties, or negatively affecting patient outcomes, then there’s a problem. There’s a story on Quora about a neurosurgeon who always ate two Hostess Ho Hos chocolate cakes before operations. When he forgot to do so one day, he supposedly left his patient on the table and ran off to eat them. Even if it’s urban legend, it’s a useful illustration of quirk disrupting work.
• Less flexibility: Every human body and every surgery is different. “When ritualistic behaviors or habits become so rigid that you lose the ability to adapt, then that becomes dangerous for the patient,” said Dr. Fong. “The art of medicine, not unlike jazz, often comes from the improvisation.”
• Self-fulfilling: Just as rituals and superstitions can empower and provide a sense of control, they can quickly turn on physicians who forget a part of their routine or leave their talisman on the bureau. Instead of confidence, they supply doubt. The karma becomes kryptonite.
• Avoiding responsibility: After years of friendship bracelets and Wonder Woman clogs, Dr. Bajaj is making a deliberate effort to excise magical thinking from her practice. “It can hold you back if you’re not careful,” she said. “If you start using it as a crutch when something goes wrong — like ‘Oh, I wasn’t wearing my clogs today and that’s why my flap failed’ — then you’re not doing your due diligence and figuring out what really happened.” Rather than placing the responsibility for her day going well on superstition, she’s trying to own it herself by living with more intent.

The Diagnosis

Most of the medical experts I spoke with didn’t think there was anything wrong with rituals or superstitions as long as they didn’t become compulsive or a convenient repository of blame.

“Rituals and superstitions are an acknowledgment that forces external to ourselves exist,” concluded Dr. Fong. “They’re like tiny offerings to whatever gods are out there to please be on our side. And we keep doing them because there’s a reward — better patient outcomes, which is all we want to achieve in the end. I say embrace them.”

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

Nonprofit hospitals created largely to serve the poor are adding concierge physician practices, charging patients annual membership fees of $2,000 or more for easier access to their doctors.

It’s a trend that began decades ago with physician practices. Thousands of doctors have shifted to the concierge model, in which they can increase their income while decreasing their patient load.

Northwestern Medicine in Chicago, Penn Medicine in Philadelphia, University Hospitals in the Cleveland area, and Baptist Health in Miami are among the large hospital systems offering concierge physician services. The fees, which can exceed $4,000 a year, are in addition to copayments, deductibles, and other charges not paid by patients’ insurance plans.

Critics of concierge medicine say the practice exacerbates primary care shortages, ensuring access only for the affluent, while driving up health care costs. But for tax-exempt hospitals, the financial benefits can be twofold. Concierge fees provide new revenue directly and serve as a tool to help recruit and retain physicians. Those doctors then provide lucrative referrals of their well-heeled patients to the hospitals that employ them.

“Hospitals are attracted to physicians that offer concierge services because their patients do not come with bad debts or a need for charity care, and most of them have private insurance which pays the hospital very well,” said Gerard Anderson, a hospital finance expert at Johns Hopkins University.

“They are the ideal patient, from the hospitals’ perspective.”

Concierge physicians typically limit their practices to a few hundred patients, compared with a couple of thousand for a traditional primary care doctor, so they can promise immediate access and longer visits.

“Every time we see these models expand, we are contracting the availability of primary care doctors for the general population,” said Jewel Mullen, associate dean for health equity at the University of Texas-Austin’s Dell Medical School. The former Connecticut health commissioner said concierge doctors join large hospital systems because of the institutions’ reputations, while hospitals sign up concierge physicians to ensure referrals to specialists and inpatient care. “It helps hospitals secure a bigger piece of their market,” she said.

Concierge physicians typically promise same-day or next-day appointments. Many provide patients their mobile phone number.

Aaron Klein, who oversees the concierge physician practices at Baptist Health, said the program was initially intended to serve donors.

“High-end donors wanted to make sure they have doctors to care for them,” he said.

Baptist opened its concierge program in 2019 and now has three practices across South Florida, where patients pay $2,500 a year.

“My philosophy is: It’s better to give world-class care to a few hundred patients rather than provide inadequate care to a few thousand patients,” Klein said.

Concierge physician practices started more than 20 years ago, mainly in upscale areas such as Boca Raton, Florida, and La Jolla, California. They catered mostly to wealthy retirees willing to pay extra for better physician access. Some of the first physician practices to enter the business were backed by private equity firms.

One of the largest, Boca Raton-based MDVIP, has more than 1,100 physicians and more than 390,000 patients. It was started in 2000, and since 2014 private equity firms have owned a majority stake in the company.

Some concierge physicians say their more attentive care means healthier patients. A study published last year by researchers at the University of California-Berkeley and University of Pennsylvania found no impact on mortality rates. What the study did find: higher costs.

Using Medicare claims data, the researchers found that concierge medicine enrollment corresponded with a 30%-50% increase in total health care spending by patients.

For hospitals, “this is an extension of them consolidating the market,” said Adam Leive, a study co-author and an assistant professor of public policy at UC Berkeley. Inova Health Care Services in Fairfax, Virginia, one of the state’s largest tax-exempt hospital chains, employs 18 concierge doctors, who each handle no more than 400 patients. Those patients pay $2,200 a year for the privilege.

George Salem, 70, of McLean, Virginia, has been a patient in Inova’s concierge practice for several years along with his wife. Earlier this year he slammed his finger in a hotel door, he said. As soon as he got home, he called his physician, who saw him immediately and stitched up the wound. He said he sees his doctor about 10 to 12 times a year.

“I loved my internist before, but it was impossible to get to see him,” Salem said. Immediate access to his doctor “very much gives me peace of mind,” he said.

Craig Cheifetz, a vice president at Inova who oversees the concierge program, said the hospital system took interest in the model after MDVIP began moving aggressively into the Washington, D.C., suburbs about a decade ago. Today, Inova’s program has 6,000 patients.

Cheifetz disputes the charge that concierge physician programs exacerbate primary care shortages. The model keeps doctors who were considering retiring early in the business with a lighter caseload, he said. And the fees amount to no more than a few dollars a day — about what some people spend on coffee, he said.

“Inova has an incredible primary care network for those who can’t afford the concierge care,” he said. “We are still providing all that is necessary in primary care for those who need it.”

Some hospitals are starting concierge physician practices far from their home locations. For example, Tampa General Hospital in Florida last year opened a concierge practice in upper-middle-class Palm Beach Gardens, a roughly three-hour drive from Tampa. Mount Sinai Health System in New York runs a concierge physician practice in West Palm Beach.

NCH Healthcare System in Naples, Florida, employs 12 concierge physicians who treat about 3,000 patients total. “We found a need in this community for those who wanted a more personalized health care experience,” said James Brinkert, regional administrator for the system. Members pay an annual fee of at least $3,500.

NCH patients whose doctors convert to concierge and who don’t want to pay the membership fee are referred to other primary care practices or to urgent care, Brinkert said.

KFF Health News  is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about  KFF .

Nonprofit hospitals created largely to serve the poor are adding concierge physician practices, charging patients annual membership fees of $2,000 or more for easier access to their doctors.

It’s a trend that began decades ago with physician practices. Thousands of doctors have shifted to the concierge model, in which they can increase their income while decreasing their patient load.

Northwestern Medicine in Chicago, Penn Medicine in Philadelphia, University Hospitals in the Cleveland area, and Baptist Health in Miami are among the large hospital systems offering concierge physician services. The fees, which can exceed $4,000 a year, are in addition to copayments, deductibles, and other charges not paid by patients’ insurance plans.

Critics of concierge medicine say the practice exacerbates primary care shortages, ensuring access only for the affluent, while driving up health care costs. But for tax-exempt hospitals, the financial benefits can be twofold. Concierge fees provide new revenue directly and serve as a tool to help recruit and retain physicians. Those doctors then provide lucrative referrals of their well-heeled patients to the hospitals that employ them.

“Hospitals are attracted to physicians that offer concierge services because their patients do not come with bad debts or a need for charity care, and most of them have private insurance which pays the hospital very well,” said Gerard Anderson, a hospital finance expert at Johns Hopkins University.

“They are the ideal patient, from the hospitals’ perspective.”

Concierge physicians typically limit their practices to a few hundred patients, compared with a couple of thousand for a traditional primary care doctor, so they can promise immediate access and longer visits.

“Every time we see these models expand, we are contracting the availability of primary care doctors for the general population,” said Jewel Mullen, associate dean for health equity at the University of Texas-Austin’s Dell Medical School. The former Connecticut health commissioner said concierge doctors join large hospital systems because of the institutions’ reputations, while hospitals sign up concierge physicians to ensure referrals to specialists and inpatient care. “It helps hospitals secure a bigger piece of their market,” she said.

Concierge physicians typically promise same-day or next-day appointments. Many provide patients their mobile phone number.

Aaron Klein, who oversees the concierge physician practices at Baptist Health, said the program was initially intended to serve donors.

“High-end donors wanted to make sure they have doctors to care for them,” he said.

Baptist opened its concierge program in 2019 and now has three practices across South Florida, where patients pay $2,500 a year.

“My philosophy is: It’s better to give world-class care to a few hundred patients rather than provide inadequate care to a few thousand patients,” Klein said.

Concierge physician practices started more than 20 years ago, mainly in upscale areas such as Boca Raton, Florida, and La Jolla, California. They catered mostly to wealthy retirees willing to pay extra for better physician access. Some of the first physician practices to enter the business were backed by private equity firms.

One of the largest, Boca Raton-based MDVIP, has more than 1,100 physicians and more than 390,000 patients. It was started in 2000, and since 2014 private equity firms have owned a majority stake in the company.

Some concierge physicians say their more attentive care means healthier patients. A study published last year by researchers at the University of California-Berkeley and University of Pennsylvania found no impact on mortality rates. What the study did find: higher costs.

Using Medicare claims data, the researchers found that concierge medicine enrollment corresponded with a 30%-50% increase in total health care spending by patients.

For hospitals, “this is an extension of them consolidating the market,” said Adam Leive, a study co-author and an assistant professor of public policy at UC Berkeley. Inova Health Care Services in Fairfax, Virginia, one of the state’s largest tax-exempt hospital chains, employs 18 concierge doctors, who each handle no more than 400 patients. Those patients pay $2,200 a year for the privilege.

George Salem, 70, of McLean, Virginia, has been a patient in Inova’s concierge practice for several years along with his wife. Earlier this year he slammed his finger in a hotel door, he said. As soon as he got home, he called his physician, who saw him immediately and stitched up the wound. He said he sees his doctor about 10 to 12 times a year.

“I loved my internist before, but it was impossible to get to see him,” Salem said. Immediate access to his doctor “very much gives me peace of mind,” he said.

Craig Cheifetz, a vice president at Inova who oversees the concierge program, said the hospital system took interest in the model after MDVIP began moving aggressively into the Washington, D.C., suburbs about a decade ago. Today, Inova’s program has 6,000 patients.

Cheifetz disputes the charge that concierge physician programs exacerbate primary care shortages. The model keeps doctors who were considering retiring early in the business with a lighter caseload, he said. And the fees amount to no more than a few dollars a day — about what some people spend on coffee, he said.

“Inova has an incredible primary care network for those who can’t afford the concierge care,” he said. “We are still providing all that is necessary in primary care for those who need it.”

Some hospitals are starting concierge physician practices far from their home locations. For example, Tampa General Hospital in Florida last year opened a concierge practice in upper-middle-class Palm Beach Gardens, a roughly three-hour drive from Tampa. Mount Sinai Health System in New York runs a concierge physician practice in West Palm Beach.

NCH Healthcare System in Naples, Florida, employs 12 concierge physicians who treat about 3,000 patients total. “We found a need in this community for those who wanted a more personalized health care experience,” said James Brinkert, regional administrator for the system. Members pay an annual fee of at least $3,500.

NCH patients whose doctors convert to concierge and who don’t want to pay the membership fee are referred to other primary care practices or to urgent care, Brinkert said.

KFF Health News  is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about  KFF .

Nonprofit hospitals created largely to serve the poor are adding concierge physician practices, charging patients annual membership fees of $2,000 or more for easier access to their doctors.

It’s a trend that began decades ago with physician practices. Thousands of doctors have shifted to the concierge model, in which they can increase their income while decreasing their patient load.

Northwestern Medicine in Chicago, Penn Medicine in Philadelphia, University Hospitals in the Cleveland area, and Baptist Health in Miami are among the large hospital systems offering concierge physician services. The fees, which can exceed $4,000 a year, are in addition to copayments, deductibles, and other charges not paid by patients’ insurance plans.

Critics of concierge medicine say the practice exacerbates primary care shortages, ensuring access only for the affluent, while driving up health care costs. But for tax-exempt hospitals, the financial benefits can be twofold. Concierge fees provide new revenue directly and serve as a tool to help recruit and retain physicians. Those doctors then provide lucrative referrals of their well-heeled patients to the hospitals that employ them.

“Hospitals are attracted to physicians that offer concierge services because their patients do not come with bad debts or a need for charity care, and most of them have private insurance which pays the hospital very well,” said Gerard Anderson, a hospital finance expert at Johns Hopkins University.

“They are the ideal patient, from the hospitals’ perspective.”

Concierge physicians typically limit their practices to a few hundred patients, compared with a couple of thousand for a traditional primary care doctor, so they can promise immediate access and longer visits.

“Every time we see these models expand, we are contracting the availability of primary care doctors for the general population,” said Jewel Mullen, associate dean for health equity at the University of Texas-Austin’s Dell Medical School. The former Connecticut health commissioner said concierge doctors join large hospital systems because of the institutions’ reputations, while hospitals sign up concierge physicians to ensure referrals to specialists and inpatient care. “It helps hospitals secure a bigger piece of their market,” she said.

Concierge physicians typically promise same-day or next-day appointments. Many provide patients their mobile phone number.

Aaron Klein, who oversees the concierge physician practices at Baptist Health, said the program was initially intended to serve donors.

“High-end donors wanted to make sure they have doctors to care for them,” he said.

Baptist opened its concierge program in 2019 and now has three practices across South Florida, where patients pay $2,500 a year.

“My philosophy is: It’s better to give world-class care to a few hundred patients rather than provide inadequate care to a few thousand patients,” Klein said.

Concierge physician practices started more than 20 years ago, mainly in upscale areas such as Boca Raton, Florida, and La Jolla, California. They catered mostly to wealthy retirees willing to pay extra for better physician access. Some of the first physician practices to enter the business were backed by private equity firms.

One of the largest, Boca Raton-based MDVIP, has more than 1,100 physicians and more than 390,000 patients. It was started in 2000, and since 2014 private equity firms have owned a majority stake in the company.

Some concierge physicians say their more attentive care means healthier patients. A study published last year by researchers at the University of California-Berkeley and University of Pennsylvania found no impact on mortality rates. What the study did find: higher costs.

Using Medicare claims data, the researchers found that concierge medicine enrollment corresponded with a 30%-50% increase in total health care spending by patients.

For hospitals, “this is an extension of them consolidating the market,” said Adam Leive, a study co-author and an assistant professor of public policy at UC Berkeley. Inova Health Care Services in Fairfax, Virginia, one of the state’s largest tax-exempt hospital chains, employs 18 concierge doctors, who each handle no more than 400 patients. Those patients pay $2,200 a year for the privilege.

George Salem, 70, of McLean, Virginia, has been a patient in Inova’s concierge practice for several years along with his wife. Earlier this year he slammed his finger in a hotel door, he said. As soon as he got home, he called his physician, who saw him immediately and stitched up the wound. He said he sees his doctor about 10 to 12 times a year.

“I loved my internist before, but it was impossible to get to see him,” Salem said. Immediate access to his doctor “very much gives me peace of mind,” he said.

Craig Cheifetz, a vice president at Inova who oversees the concierge program, said the hospital system took interest in the model after MDVIP began moving aggressively into the Washington, D.C., suburbs about a decade ago. Today, Inova’s program has 6,000 patients.

Cheifetz disputes the charge that concierge physician programs exacerbate primary care shortages. The model keeps doctors who were considering retiring early in the business with a lighter caseload, he said. And the fees amount to no more than a few dollars a day — about what some people spend on coffee, he said.

“Inova has an incredible primary care network for those who can’t afford the concierge care,” he said. “We are still providing all that is necessary in primary care for those who need it.”

Some hospitals are starting concierge physician practices far from their home locations. For example, Tampa General Hospital in Florida last year opened a concierge practice in upper-middle-class Palm Beach Gardens, a roughly three-hour drive from Tampa. Mount Sinai Health System in New York runs a concierge physician practice in West Palm Beach.

NCH Healthcare System in Naples, Florida, employs 12 concierge physicians who treat about 3,000 patients total. “We found a need in this community for those who wanted a more personalized health care experience,” said James Brinkert, regional administrator for the system. Members pay an annual fee of at least $3,500.

NCH patients whose doctors convert to concierge and who don’t want to pay the membership fee are referred to other primary care practices or to urgent care, Brinkert said.

KFF Health News  is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about  KFF .

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.

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.

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.

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 .

TOPLINE:

The rates of screening for latent tuberculosis remain suboptimal among new users of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), with notable variations by medication type and demographic characteristics. 

METHODOLOGY:

• Professional society guidelines recommend screening for tuberculosis before starting treatment with most b/tsDMARDs.
• In an attempt to estimate the extent of latent tuberculosis screening, researchers combined claims and electronic health record datasets to evaluate 2853 new b/tsDMARD users (mean age, 73 years; 72% women; and 73% non-Hispanic White).
• The primary analysis focused on assessing the proportion of patients screened for latent tuberculosis in the year before starting a new b/tsDMARD.
• A sensitivity analysis evaluated the extent of screening within the 3 years preceding the initiation of a new b/tsDMARD.
• A total of 65.6% of patients received screening for latent tuberculosis in the year before initiating a new b/tsDMARD.
• Screening rates improved only slightly on expanding the window to 3 years, with 72.9% of patients receiving any tuberculosis screening.
• When stratified by drug type, over half of new users of Janus kinase inhibitors and nearly 90% of new users of interleukin-17 inhibitors had not received screening.
• Hispanic patients had lower odds of tuberculosis screening within 1 year than White patients (odds ratio [OR], 0.64; 95% CI, 0.46-0.90), as did those in the highest socioeconomic quartile, compared with the lowest (OR, 0.61; 95% CI, 0.40-0.94).

IN PRACTICE:

“Educational initiatives, team-based care delivery, task shifting, and technological interventions to address observed gaps in patient safety procedures are needed,” the authors wrote.

SOURCE:

The study was led by Eric T. Roberts, PhD, University of California, San Francisco, and published online in Arthritis Care & Research

LIMITATIONS:

The study lacked access to scanned documents or clinical notes, which may have resulted in the omission of a small number of tests that had no Medicare billing. Moreover, the study was restricted to a 3-year lookback period, potentially missing some remote screenings. The findings may have limited generalizability to younger patients or those not dually eligible for Medicare and Medicaid.

DISCLOSURES:

This study was funded by grants from the Agency for Healthcare Research and Quality and the National Institute for Arthritis and Musculoskeletal and Skin Diseases. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

The rates of screening for latent tuberculosis remain suboptimal among new users of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), with notable variations by medication type and demographic characteristics. 

METHODOLOGY:

• Professional society guidelines recommend screening for tuberculosis before starting treatment with most b/tsDMARDs.
• In an attempt to estimate the extent of latent tuberculosis screening, researchers combined claims and electronic health record datasets to evaluate 2853 new b/tsDMARD users (mean age, 73 years; 72% women; and 73% non-Hispanic White).
• The primary analysis focused on assessing the proportion of patients screened for latent tuberculosis in the year before starting a new b/tsDMARD.
• A sensitivity analysis evaluated the extent of screening within the 3 years preceding the initiation of a new b/tsDMARD.
• A total of 65.6% of patients received screening for latent tuberculosis in the year before initiating a new b/tsDMARD.
• Screening rates improved only slightly on expanding the window to 3 years, with 72.9% of patients receiving any tuberculosis screening.
• When stratified by drug type, over half of new users of Janus kinase inhibitors and nearly 90% of new users of interleukin-17 inhibitors had not received screening.
• Hispanic patients had lower odds of tuberculosis screening within 1 year than White patients (odds ratio [OR], 0.64; 95% CI, 0.46-0.90), as did those in the highest socioeconomic quartile, compared with the lowest (OR, 0.61; 95% CI, 0.40-0.94).

IN PRACTICE:

“Educational initiatives, team-based care delivery, task shifting, and technological interventions to address observed gaps in patient safety procedures are needed,” the authors wrote.

SOURCE:

The study was led by Eric T. Roberts, PhD, University of California, San Francisco, and published online in Arthritis Care & Research

LIMITATIONS:

The study lacked access to scanned documents or clinical notes, which may have resulted in the omission of a small number of tests that had no Medicare billing. Moreover, the study was restricted to a 3-year lookback period, potentially missing some remote screenings. The findings may have limited generalizability to younger patients or those not dually eligible for Medicare and Medicaid.

DISCLOSURES:

This study was funded by grants from the Agency for Healthcare Research and Quality and the National Institute for Arthritis and Musculoskeletal and Skin Diseases. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

The rates of screening for latent tuberculosis remain suboptimal among new users of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), with notable variations by medication type and demographic characteristics. 

METHODOLOGY:

• Professional society guidelines recommend screening for tuberculosis before starting treatment with most b/tsDMARDs.
• In an attempt to estimate the extent of latent tuberculosis screening, researchers combined claims and electronic health record datasets to evaluate 2853 new b/tsDMARD users (mean age, 73 years; 72% women; and 73% non-Hispanic White).
• The primary analysis focused on assessing the proportion of patients screened for latent tuberculosis in the year before starting a new b/tsDMARD.
• A sensitivity analysis evaluated the extent of screening within the 3 years preceding the initiation of a new b/tsDMARD.
• A total of 65.6% of patients received screening for latent tuberculosis in the year before initiating a new b/tsDMARD.
• Screening rates improved only slightly on expanding the window to 3 years, with 72.9% of patients receiving any tuberculosis screening.
• When stratified by drug type, over half of new users of Janus kinase inhibitors and nearly 90% of new users of interleukin-17 inhibitors had not received screening.
• Hispanic patients had lower odds of tuberculosis screening within 1 year than White patients (odds ratio [OR], 0.64; 95% CI, 0.46-0.90), as did those in the highest socioeconomic quartile, compared with the lowest (OR, 0.61; 95% CI, 0.40-0.94).

IN PRACTICE:

“Educational initiatives, team-based care delivery, task shifting, and technological interventions to address observed gaps in patient safety procedures are needed,” the authors wrote.

SOURCE:

The study was led by Eric T. Roberts, PhD, University of California, San Francisco, and published online in Arthritis Care & Research

LIMITATIONS:

The study lacked access to scanned documents or clinical notes, which may have resulted in the omission of a small number of tests that had no Medicare billing. Moreover, the study was restricted to a 3-year lookback period, potentially missing some remote screenings. The findings may have limited generalizability to younger patients or those not dually eligible for Medicare and Medicaid.

DISCLOSURES:

This study was funded by grants from the Agency for Healthcare Research and Quality and the National Institute for Arthritis and Musculoskeletal and Skin Diseases. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

A review of the federal Open Payments database found that the pharmaceutical and medical device industry paid physicians $12.1 billion over nearly a decade.

Almost two thirds of eligible physicians — 826,313 doctors — received a payment from a drug or device maker from 2013 to 2022, according to a study published online in JAMA on March 28. Overall, the median payment was $48 per physician.

Orthopedists received the largest amount of payments in aggregate, $1.3 billion, followed by neurologists and psychiatrists at $1.2 billion and cardiologists at $1.29 billion.

Geriatric and nuclear medicine specialists and trauma and pediatric surgeons received the least amount of money in aggregate, and the mean amount paid to a pediatric surgeon in the top 0.1% was just $338,183 over the 9-year study period.

Excluding 2013 (the database was established in August that year), the total value of payments was highest in 2019 at $1.6 billion, up from $1.34 billion in 2014. It was lowest in 2020, the peak year of the COVID-19 pandemic, but dipped to $864 billion that year and rebounded to $1.28 billion in 2022, wrote the authors.

The Open Payments database, administered by the Centers for Medicare & Medicaid Services, requires drug and device makers and group purchasing organizations to report payments made to physicians, including for consulting services, speaking fees, food and beverages, travel and lodging, education, gifts, grants, and honoraria.

The database was created to shed light on these payments, which have been linked in multiple studies to more prescribing of a particular drug or more use of a particular device.

The JAMA review appeared to show that with the exception of the pandemic year, the relationships have more or less stayed the same since Open Payments began.

“There’s been no sea change, no massive shift in how these interactions are happening,” said Deborah C. Marshall, MD, assistant professor in the Department of Radiation Oncology at the Icahn School of Medicine at Mount Sinai in New York City, who has studied industry payments.

“There’s no suggestion that anything is really changing other than that’s there is transparency,” said Robert Steinbrook, MD, director of the Health Research Group at Public Citizen.

Still, Dr. Steinbrook told this news organization, “it’s better to know this than to not know this.”

The unchanging nature of industry-physician relationships “suggests that to reduce the volume and magnitude of payments, more would need to be done,” he said.

“Really, this should be banned. Doctors should not be allowed to get gifts from pharmaceutical companies,” said Adriane Fugh-Berman, MD, professor of pharmacology and physiology at Georgetown University, and director of PharmedOut, a Georgetown-based project that advances evidence-based prescribing and educates healthcare professionals about pharmaceutical marketing practices.

“The interactions wouldn’t be happening unless there was a purpose for them,” said Dr. Marshall. The relationships are “built with intention,” Dr. Marshall told this news organization.
 

Top Earners Range From $195,000 to $4.8 Million

Payments to the median physician over the study period ranged from $0 to $2339, but the mean payment to top earners — those in the top 0.1% — ranged from $194,933 for hospitalists to $4.8 million for orthopedic specialists.

Overall, the median payment was $48 per physician.

But small dollar amounts should not be discounted — even if it’s just a $25-catered lunch — said Aaron Mitchell, MD, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center in New York City who has studied industry-physician relationships. “The influence is not just in the dollar value,” Dr. Mitchell told this news organization. “It’s about the time listening to and the time in personal contact with industry representatives that these dollars are a marker for,” he said.

“There’s no such thing as a free lunch,” agreed Dr. Marshall. It’s “pretty well established” that lower-value payments do have influence, which is why academic institutions have established policies that limit gifts and meals and other payments from industry, she said.

Dr. Fugh-Berman said, “the size of the gift doesn’t really matter,” adding that research she conducted had shown that “accepting a meal increased not only the expense of the prescriptions that Medicare physicians wrote but also the number of prescriptions.”
 

Payments Mostly for High-Dollar Products

The top 25 drugs and devices that were related to industry payments tended to be high-cost brand-name products.

The top drug was Janssen’s Xarelto, an anticoagulant first approved in 2011 that costs about $600 a month, according to GoodRx. The drug has had annual sales of $4-$6 billion.

Xarelto was followed by Eliquis, another anticoagulant; Humira, used for a variety of autoimmune conditions including plaque psoriasis, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis; Invokana, Jardiance, and Farxiga, all for type 2 diabetes.

The top medical devices included the da Vinci Surgical System, Mako SmartRobotics, CoreValve Evolut, Natrelle Implants, and Impella, a heart pump that received a US Food and Drug Administration (FDA) warning that it was associated with a heightened risk for death.
 

Industry Influence May Lead to Higher Cost, Poor Quality Care

Multiple studies have shown that payments to physicians tend to lead to increased prescribing and, often, higher costs for Medicare, a health system, or patients.

“I’m sure there are still a lot of physicians out there who think they’re getting away with something, that they can take meals, or they can take consulting fees and not be influenced, but there’s overwhelming data showing that it always influences you,” said Dr. Fugh-Berman.

One study in 2020 that used the Open Payments database found that physicians increase prescribing of the drugs for which they receive payment in the months just after the payment. The authors also showed that physicians who are paid prescribe lower-quality drugs following the payment, “although the magnitude is small and unlikely to be clinically significant.”

Dr. Marshall said that more studies are needed to determine whether quality of care is being affected when a physician prescribes a drug after an industry payment.

For now, there seems to be little appetite among physicians to give up the payments, said Dr. Marshall and others.

Physicians in some specialties see the payments as “an implicit statement about their value,” said Dr. Marshall.

In oncology, having received a lot of payments “gets worn more as a badge of honor,” said Dr. Mitchell.

The clinicians believe that “by collaborating with industry we are providing scientific expertise to help develop the next generation of technology and cures,” Dr. Mitchell said, adding that they see the payments “as a mark of their impact.”

Among the JAMA study authors, Joseph S. Ross, MD, reported that he is a deputy editor of JAMA but was not involved in decisions regarding acceptance of the manuscript or its review. Dr. Ross also reported receiving grants from the FDA, Johnson and Johnson, the Medical Devices Innovation Consortium, the Agency for Healthcare Research and Quality, and the National Heart, Lung, and Blood Institute. He was an expert witness in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled in 2022. Dr. Steinbrook, Dr. Marshall, and Dr. Mitchell reported no relevant financial relationships. Dr. Fugh-Berman reported being an expert witness for plaintiffs in complaints about drug and device marketing practices.

A version of this article appeared on Medscape.com.

A review of the federal Open Payments database found that the pharmaceutical and medical device industry paid physicians $12.1 billion over nearly a decade.

Almost two thirds of eligible physicians — 826,313 doctors — received a payment from a drug or device maker from 2013 to 2022, according to a study published online in JAMA on March 28. Overall, the median payment was $48 per physician.

Orthopedists received the largest amount of payments in aggregate, $1.3 billion, followed by neurologists and psychiatrists at $1.2 billion and cardiologists at $1.29 billion.

Geriatric and nuclear medicine specialists and trauma and pediatric surgeons received the least amount of money in aggregate, and the mean amount paid to a pediatric surgeon in the top 0.1% was just $338,183 over the 9-year study period.

Excluding 2013 (the database was established in August that year), the total value of payments was highest in 2019 at $1.6 billion, up from $1.34 billion in 2014. It was lowest in 2020, the peak year of the COVID-19 pandemic, but dipped to $864 billion that year and rebounded to $1.28 billion in 2022, wrote the authors.

The Open Payments database, administered by the Centers for Medicare & Medicaid Services, requires drug and device makers and group purchasing organizations to report payments made to physicians, including for consulting services, speaking fees, food and beverages, travel and lodging, education, gifts, grants, and honoraria.

The database was created to shed light on these payments, which have been linked in multiple studies to more prescribing of a particular drug or more use of a particular device.

The JAMA review appeared to show that with the exception of the pandemic year, the relationships have more or less stayed the same since Open Payments began.

“There’s been no sea change, no massive shift in how these interactions are happening,” said Deborah C. Marshall, MD, assistant professor in the Department of Radiation Oncology at the Icahn School of Medicine at Mount Sinai in New York City, who has studied industry payments.

“There’s no suggestion that anything is really changing other than that’s there is transparency,” said Robert Steinbrook, MD, director of the Health Research Group at Public Citizen.

Still, Dr. Steinbrook told this news organization, “it’s better to know this than to not know this.”

The unchanging nature of industry-physician relationships “suggests that to reduce the volume and magnitude of payments, more would need to be done,” he said.

“Really, this should be banned. Doctors should not be allowed to get gifts from pharmaceutical companies,” said Adriane Fugh-Berman, MD, professor of pharmacology and physiology at Georgetown University, and director of PharmedOut, a Georgetown-based project that advances evidence-based prescribing and educates healthcare professionals about pharmaceutical marketing practices.

“The interactions wouldn’t be happening unless there was a purpose for them,” said Dr. Marshall. The relationships are “built with intention,” Dr. Marshall told this news organization.
 

Top Earners Range From $195,000 to $4.8 Million

Payments to the median physician over the study period ranged from $0 to $2339, but the mean payment to top earners — those in the top 0.1% — ranged from $194,933 for hospitalists to $4.8 million for orthopedic specialists.

Overall, the median payment was $48 per physician.

But small dollar amounts should not be discounted — even if it’s just a $25-catered lunch — said Aaron Mitchell, MD, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center in New York City who has studied industry-physician relationships. “The influence is not just in the dollar value,” Dr. Mitchell told this news organization. “It’s about the time listening to and the time in personal contact with industry representatives that these dollars are a marker for,” he said.

“There’s no such thing as a free lunch,” agreed Dr. Marshall. It’s “pretty well established” that lower-value payments do have influence, which is why academic institutions have established policies that limit gifts and meals and other payments from industry, she said.

Dr. Fugh-Berman said, “the size of the gift doesn’t really matter,” adding that research she conducted had shown that “accepting a meal increased not only the expense of the prescriptions that Medicare physicians wrote but also the number of prescriptions.”
 

Payments Mostly for High-Dollar Products

The top 25 drugs and devices that were related to industry payments tended to be high-cost brand-name products.

The top drug was Janssen’s Xarelto, an anticoagulant first approved in 2011 that costs about $600 a month, according to GoodRx. The drug has had annual sales of $4-$6 billion.

Xarelto was followed by Eliquis, another anticoagulant; Humira, used for a variety of autoimmune conditions including plaque psoriasis, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis; Invokana, Jardiance, and Farxiga, all for type 2 diabetes.

The top medical devices included the da Vinci Surgical System, Mako SmartRobotics, CoreValve Evolut, Natrelle Implants, and Impella, a heart pump that received a US Food and Drug Administration (FDA) warning that it was associated with a heightened risk for death.
 

Industry Influence May Lead to Higher Cost, Poor Quality Care

Multiple studies have shown that payments to physicians tend to lead to increased prescribing and, often, higher costs for Medicare, a health system, or patients.

“I’m sure there are still a lot of physicians out there who think they’re getting away with something, that they can take meals, or they can take consulting fees and not be influenced, but there’s overwhelming data showing that it always influences you,” said Dr. Fugh-Berman.

One study in 2020 that used the Open Payments database found that physicians increase prescribing of the drugs for which they receive payment in the months just after the payment. The authors also showed that physicians who are paid prescribe lower-quality drugs following the payment, “although the magnitude is small and unlikely to be clinically significant.”

Dr. Marshall said that more studies are needed to determine whether quality of care is being affected when a physician prescribes a drug after an industry payment.

For now, there seems to be little appetite among physicians to give up the payments, said Dr. Marshall and others.

Physicians in some specialties see the payments as “an implicit statement about their value,” said Dr. Marshall.

In oncology, having received a lot of payments “gets worn more as a badge of honor,” said Dr. Mitchell.

The clinicians believe that “by collaborating with industry we are providing scientific expertise to help develop the next generation of technology and cures,” Dr. Mitchell said, adding that they see the payments “as a mark of their impact.”

Among the JAMA study authors, Joseph S. Ross, MD, reported that he is a deputy editor of JAMA but was not involved in decisions regarding acceptance of the manuscript or its review. Dr. Ross also reported receiving grants from the FDA, Johnson and Johnson, the Medical Devices Innovation Consortium, the Agency for Healthcare Research and Quality, and the National Heart, Lung, and Blood Institute. He was an expert witness in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled in 2022. Dr. Steinbrook, Dr. Marshall, and Dr. Mitchell reported no relevant financial relationships. Dr. Fugh-Berman reported being an expert witness for plaintiffs in complaints about drug and device marketing practices.

A version of this article appeared on Medscape.com.

A review of the federal Open Payments database found that the pharmaceutical and medical device industry paid physicians $12.1 billion over nearly a decade.

Almost two thirds of eligible physicians — 826,313 doctors — received a payment from a drug or device maker from 2013 to 2022, according to a study published online in JAMA on March 28. Overall, the median payment was $48 per physician.

Orthopedists received the largest amount of payments in aggregate, $1.3 billion, followed by neurologists and psychiatrists at $1.2 billion and cardiologists at $1.29 billion.

Geriatric and nuclear medicine specialists and trauma and pediatric surgeons received the least amount of money in aggregate, and the mean amount paid to a pediatric surgeon in the top 0.1% was just $338,183 over the 9-year study period.

Excluding 2013 (the database was established in August that year), the total value of payments was highest in 2019 at $1.6 billion, up from $1.34 billion in 2014. It was lowest in 2020, the peak year of the COVID-19 pandemic, but dipped to $864 billion that year and rebounded to $1.28 billion in 2022, wrote the authors.

The Open Payments database, administered by the Centers for Medicare & Medicaid Services, requires drug and device makers and group purchasing organizations to report payments made to physicians, including for consulting services, speaking fees, food and beverages, travel and lodging, education, gifts, grants, and honoraria.

The database was created to shed light on these payments, which have been linked in multiple studies to more prescribing of a particular drug or more use of a particular device.

The JAMA review appeared to show that with the exception of the pandemic year, the relationships have more or less stayed the same since Open Payments began.

“There’s been no sea change, no massive shift in how these interactions are happening,” said Deborah C. Marshall, MD, assistant professor in the Department of Radiation Oncology at the Icahn School of Medicine at Mount Sinai in New York City, who has studied industry payments.

“There’s no suggestion that anything is really changing other than that’s there is transparency,” said Robert Steinbrook, MD, director of the Health Research Group at Public Citizen.

Still, Dr. Steinbrook told this news organization, “it’s better to know this than to not know this.”

The unchanging nature of industry-physician relationships “suggests that to reduce the volume and magnitude of payments, more would need to be done,” he said.

“Really, this should be banned. Doctors should not be allowed to get gifts from pharmaceutical companies,” said Adriane Fugh-Berman, MD, professor of pharmacology and physiology at Georgetown University, and director of PharmedOut, a Georgetown-based project that advances evidence-based prescribing and educates healthcare professionals about pharmaceutical marketing practices.

“The interactions wouldn’t be happening unless there was a purpose for them,” said Dr. Marshall. The relationships are “built with intention,” Dr. Marshall told this news organization.
 

Top Earners Range From $195,000 to $4.8 Million

Payments to the median physician over the study period ranged from $0 to $2339, but the mean payment to top earners — those in the top 0.1% — ranged from $194,933 for hospitalists to $4.8 million for orthopedic specialists.

Overall, the median payment was $48 per physician.

But small dollar amounts should not be discounted — even if it’s just a $25-catered lunch — said Aaron Mitchell, MD, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center in New York City who has studied industry-physician relationships. “The influence is not just in the dollar value,” Dr. Mitchell told this news organization. “It’s about the time listening to and the time in personal contact with industry representatives that these dollars are a marker for,” he said.

“There’s no such thing as a free lunch,” agreed Dr. Marshall. It’s “pretty well established” that lower-value payments do have influence, which is why academic institutions have established policies that limit gifts and meals and other payments from industry, she said.

Dr. Fugh-Berman said, “the size of the gift doesn’t really matter,” adding that research she conducted had shown that “accepting a meal increased not only the expense of the prescriptions that Medicare physicians wrote but also the number of prescriptions.”
 

Payments Mostly for High-Dollar Products

The top 25 drugs and devices that were related to industry payments tended to be high-cost brand-name products.

The top drug was Janssen’s Xarelto, an anticoagulant first approved in 2011 that costs about $600 a month, according to GoodRx. The drug has had annual sales of $4-$6 billion.

Xarelto was followed by Eliquis, another anticoagulant; Humira, used for a variety of autoimmune conditions including plaque psoriasis, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis; Invokana, Jardiance, and Farxiga, all for type 2 diabetes.

The top medical devices included the da Vinci Surgical System, Mako SmartRobotics, CoreValve Evolut, Natrelle Implants, and Impella, a heart pump that received a US Food and Drug Administration (FDA) warning that it was associated with a heightened risk for death.
 

Industry Influence May Lead to Higher Cost, Poor Quality Care

Multiple studies have shown that payments to physicians tend to lead to increased prescribing and, often, higher costs for Medicare, a health system, or patients.

“I’m sure there are still a lot of physicians out there who think they’re getting away with something, that they can take meals, or they can take consulting fees and not be influenced, but there’s overwhelming data showing that it always influences you,” said Dr. Fugh-Berman.

One study in 2020 that used the Open Payments database found that physicians increase prescribing of the drugs for which they receive payment in the months just after the payment. The authors also showed that physicians who are paid prescribe lower-quality drugs following the payment, “although the magnitude is small and unlikely to be clinically significant.”

Dr. Marshall said that more studies are needed to determine whether quality of care is being affected when a physician prescribes a drug after an industry payment.

For now, there seems to be little appetite among physicians to give up the payments, said Dr. Marshall and others.

Physicians in some specialties see the payments as “an implicit statement about their value,” said Dr. Marshall.

In oncology, having received a lot of payments “gets worn more as a badge of honor,” said Dr. Mitchell.

The clinicians believe that “by collaborating with industry we are providing scientific expertise to help develop the next generation of technology and cures,” Dr. Mitchell said, adding that they see the payments “as a mark of their impact.”

Among the JAMA study authors, Joseph S. Ross, MD, reported that he is a deputy editor of JAMA but was not involved in decisions regarding acceptance of the manuscript or its review. Dr. Ross also reported receiving grants from the FDA, Johnson and Johnson, the Medical Devices Innovation Consortium, the Agency for Healthcare Research and Quality, and the National Heart, Lung, and Blood Institute. He was an expert witness in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled in 2022. Dr. Steinbrook, Dr. Marshall, and Dr. Mitchell reported no relevant financial relationships. Dr. Fugh-Berman reported being an expert witness for plaintiffs in complaints about drug and device marketing practices.

A version of this article appeared on Medscape.com.

Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.

For years, researchers have worked to determine the reasons for sex-linked differences in immune response and autoimmunity, with environmental factors, sex hormones, and X-chromosome inactivation — the process by which a second X chromosome is silenced — all seen as having roles.

More recently, different groups of researchers have homed in on a long noncoding RNA fragment called X-inactive specific transcript, or Xist, as a potential driver of sex bias in autoimmune disease. Xist, which occurs in female mammals, has been known since the 1990s as the master regulator of X-chromosome inactivation, the process by which the second X chromosome is silenced, averting a fatal double dose of X-linked genes.

The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female’s life, allowing X inactivation to be maintained.

But is it possible that Xist, and the many dozens of proteins it recruits to keep that extra X chromosome silent, can also provoke autoimmunity? This is the question that several teams of researchers have been grappling with, resulting in provocative findings and opening exciting new avenues of discovery.
 

Xist Protein Complexes Make Male Mice Vulnerable to Lupus

In February, researchers Howard Chang, MD, PhD, and Diana Dou, PhD, of Stanford University in Stanford, California, made worldwide news when they published results from an experiment using male mice genetically engineered to carry a non-silencing form of Xist on one of their chromosomes.

Xist acts like a scaffold, recruiting multiple protein complexes to help it do its job. Dr. Dou explained in an interview that her team has been eyeing suspiciously for years the dozens of proteins Xist recruits in the process of X-chromosome inactivation, many of which are known autoantigens.

When the mice were injected with pristane, a chemical that induces lupus-like autoimmunity in mice, the Xist-producing males developed symptoms at a rate similar to that of females, while wild-type male mice did not.

By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. “Everything else about the animal is male,” Dr. Dou commented. “You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles. Is just having the particles present in these animals sufficient to increase their autoimmunity? This is what our paper showed: That just having expression of Xist, the presence of these Xist [ribonucleoproteins], is enough in permissive genetic backgrounds to invoke higher incidence and severity of autoimmune disease development in our pristane-induced lupus model.”

The Stanford group sees the Xist protein complex, which they have studied extensively, as a key to understanding how Xist might provoke autoimmunity. Nonetheless, Dr. Dou said, “It’s important to note that there are other contributing factors, which is why not all females develop autoimmunity, and we had very different results in our autoimmune-resistant mouse strain compared to the more autoimmune-prone strain. Xist is a factor, but many factors are required to subvert the checkpoints in immune balance and allow the progression to full-blown autoimmunity.”
 

Faulty X Inactivation and Gene Escape

The understanding that Xist might be implicated in autoimmune disease — and explain some of its female bias — is not new.

About a decade ago, Montserrat Anguera, PhD, a biologist at the University of Pennsylvania, Philadelphia, began looking at the relationship of X-chromosome inactivation, which by definition involves Xist, and lupus.

University of Pennsylvania

Dr. Anguera hypothesized that imperfect X inactivation allowed for greater escape of genes associated with immunity and autoimmunity. Studying patients with lupus, Dr. Anguera found that the silencing process was abnormal, allowing more of these genes to escape the silenced X — including toll-like receptor 7 (TLR-7) and other genes implicated in the pathogenesis of lupus.

“If you get increased expression of certain genes from the [silenced] X, like TLR-7, it can result in autoimmune disease,” Dr. Anguera said. “So what we think is that in the lupus patients, because the silencing is impacted, you’re going to have more expression happening from the inactive X. And then in conjunction with the active X, that’s going to throw off the dosage [of autoimmunity-linked genes]. You’re changing the dosage of genes, and that’s what’s critical.”

Even among patients with lupus whose symptoms are well controlled with medication, “if you look at their T cells and B cells, they still have messed up X inactivation,” Dr. Anguera said. “The Xist RNA that’s supposed to be tethered to the inactive X in a fluffy cloud is not localized, and instead is dispersed all over the nucleus.”

Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. “You also have a host of hormonal and environmental contributors, such as previous viral infections,” she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.

Dr. Anguera said that, while the findings by the Stanford scientists do not explain the full pathogenesis of lupus and related diseases, they still support a strong role for Xist in sex-biased autoimmune diseases. “It’s sort of another take on it,” she said.
 

Is It the Proteins, the RNA, or Both?

The Stanford team points to the proteins recruited by Xist in the process of X-chromosome inactivation as the likely trigger of autoimmunity. However, a group of researchers at Johns Hopkins University in Baltimore, Maryland, made the case in a 2022 paper that Xist RNA itself was dangerous. They found that numerous short RNA sequences within the Xist molecule serve as ligands for TLR-7. And TLR-7 ligation causes plasmacytoid dendritic cells to overproduce type 1 interferon, a classic hallmark of lupus.

Alexander Girgis

“Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon,” explained Brendan Antiochos, MD. “Lupus is an example of that. Sjögren’s syndrome is another. So there’s always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity. And are there specific pathways which could contribute? One of the key pathways that’s been shown in humans and in mice to be important in lupus is toll-like receptor signaling.” Most convincingly, one recent study showed that people who have a gain-of-function mutation in their TLR-7 gene get a spontaneous form of lupus.

Wes Linda

These findings led Erika Darrah, PhD, and her colleague Dr. Antiochos to begin looking more deeply into which RNAs could be triggering this signaling pathway. “We started to think: Well, there is this sex bias. Could it be that women have unique RNAs that could potentially act as triggers for TLR-7 signaling?” Dr. Darrah said.

Dr. Darrah and Dr. Antiochos looked at publicly available genetic data to identify sex-biased sources of self-RNA containing TLR-7 ligands. Xist, they found, was chock full of them. “Every time we analyzed that data, no matter what filter we applied, Xist kept popping out over and over again as the most highly female skewed RNA, the RNA most likely to contain these TLR-7 binding motifs,” Dr. Darrah said. “We started to formulate the hypothesis that Xist was actually promoting responses that were dangerous and pathogenic in lupus.”

That finding led the team to conduct in-vitro experiments that showed different fragments of Xist can activate TLR-7, resulting in higher interferon production. Finally, they looked at blood and kidney cells from women with lupus and found that higher Xist expression correlated with more interferon production, and higher disease activity. “The more Xist, the sicker people were,” Dr. Darrah said.
 

Xist’s Other Functions

Xist was first studied in the 1990s, and most research has centered on its primary role in X-chromosome inactivation. A research group led by Kathrin Plath, PhD, at the University of California, Los Angeles, has been occupied for years with untangling exactly how Xist does what it does. “It’s a very clever RNA, right? It can silence the whole chromosome,” Dr. Plath said in an interview.

In 2021, Dr. Plath and her colleagues established in detail how Xist executes silencing, setting down pairs of molecules in specific spots along the chromosome and building huge protein clouds around them. “We worked on learning where Xist binds and what proteins it binds, drilling down to understand how these proteins and the RNA are coming together.”

Dr. Plath has long suspected that Xist has other functions besides X inactivation, and she and her colleagues are starting to identify them. Early this year they published the surprising finding that Xist can regulate gene expression in autosomes, or non–sex-linked chromosomes, “which it might well also do in cancer cells and lymphocytes,” Dr. Plath said. “And now there is this new evidence of an autoimmune function,” she said. “It’s a super exciting time.”

The different hypotheses surrounding Xist’s role in sex-biased autoimmunity aren’t mutually exclusive, Dr. Plath said. “There’s a tremendous enrichment of proteins occurring” during X inactivation, she said, supporting the Stanford team’s hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers’ understanding that Xist RNA itself is the trigger, “I’m totally open to that,” she said. “Why can’t it be an autoantigen?”

The other model in the field, Dr. Plath noted, is the one proposed by Dr. Anguera — “that there’s [gene] escape from X-inactivation — that females have more escape expression, and that Xist is more dispersed in the lymphocytes [of patients with lupus]. In fact, Xist becoming a little dispersed might make it a better antigen. So I do think everything is possible.”

The plethora of new findings related to autoimmunity has caused Dr. Plath to consider redirecting her lab’s focus toward more translational work, “because we are obviously good at studying Xist.” Among the mysteries Dr. Plath would like to solve is how some genes manage to escape the Xist cloud.

What is needed, she said, is collaboration. “Everyone will come up with different ideas. So I think it’s good to have more people look at things together. Then the field will achieve a breakthrough treatment.”

Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.

For years, researchers have worked to determine the reasons for sex-linked differences in immune response and autoimmunity, with environmental factors, sex hormones, and X-chromosome inactivation — the process by which a second X chromosome is silenced — all seen as having roles.

More recently, different groups of researchers have homed in on a long noncoding RNA fragment called X-inactive specific transcript, or Xist, as a potential driver of sex bias in autoimmune disease. Xist, which occurs in female mammals, has been known since the 1990s as the master regulator of X-chromosome inactivation, the process by which the second X chromosome is silenced, averting a fatal double dose of X-linked genes.

The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female’s life, allowing X inactivation to be maintained.

But is it possible that Xist, and the many dozens of proteins it recruits to keep that extra X chromosome silent, can also provoke autoimmunity? This is the question that several teams of researchers have been grappling with, resulting in provocative findings and opening exciting new avenues of discovery.
 

Xist Protein Complexes Make Male Mice Vulnerable to Lupus

In February, researchers Howard Chang, MD, PhD, and Diana Dou, PhD, of Stanford University in Stanford, California, made worldwide news when they published results from an experiment using male mice genetically engineered to carry a non-silencing form of Xist on one of their chromosomes.

Xist acts like a scaffold, recruiting multiple protein complexes to help it do its job. Dr. Dou explained in an interview that her team has been eyeing suspiciously for years the dozens of proteins Xist recruits in the process of X-chromosome inactivation, many of which are known autoantigens.

When the mice were injected with pristane, a chemical that induces lupus-like autoimmunity in mice, the Xist-producing males developed symptoms at a rate similar to that of females, while wild-type male mice did not.

By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. “Everything else about the animal is male,” Dr. Dou commented. “You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles. Is just having the particles present in these animals sufficient to increase their autoimmunity? This is what our paper showed: That just having expression of Xist, the presence of these Xist [ribonucleoproteins], is enough in permissive genetic backgrounds to invoke higher incidence and severity of autoimmune disease development in our pristane-induced lupus model.”

The Stanford group sees the Xist protein complex, which they have studied extensively, as a key to understanding how Xist might provoke autoimmunity. Nonetheless, Dr. Dou said, “It’s important to note that there are other contributing factors, which is why not all females develop autoimmunity, and we had very different results in our autoimmune-resistant mouse strain compared to the more autoimmune-prone strain. Xist is a factor, but many factors are required to subvert the checkpoints in immune balance and allow the progression to full-blown autoimmunity.”
 

Faulty X Inactivation and Gene Escape

The understanding that Xist might be implicated in autoimmune disease — and explain some of its female bias — is not new.

About a decade ago, Montserrat Anguera, PhD, a biologist at the University of Pennsylvania, Philadelphia, began looking at the relationship of X-chromosome inactivation, which by definition involves Xist, and lupus.

University of Pennsylvania

Dr. Anguera hypothesized that imperfect X inactivation allowed for greater escape of genes associated with immunity and autoimmunity. Studying patients with lupus, Dr. Anguera found that the silencing process was abnormal, allowing more of these genes to escape the silenced X — including toll-like receptor 7 (TLR-7) and other genes implicated in the pathogenesis of lupus.

“If you get increased expression of certain genes from the [silenced] X, like TLR-7, it can result in autoimmune disease,” Dr. Anguera said. “So what we think is that in the lupus patients, because the silencing is impacted, you’re going to have more expression happening from the inactive X. And then in conjunction with the active X, that’s going to throw off the dosage [of autoimmunity-linked genes]. You’re changing the dosage of genes, and that’s what’s critical.”

Even among patients with lupus whose symptoms are well controlled with medication, “if you look at their T cells and B cells, they still have messed up X inactivation,” Dr. Anguera said. “The Xist RNA that’s supposed to be tethered to the inactive X in a fluffy cloud is not localized, and instead is dispersed all over the nucleus.”

Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. “You also have a host of hormonal and environmental contributors, such as previous viral infections,” she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.

Dr. Anguera said that, while the findings by the Stanford scientists do not explain the full pathogenesis of lupus and related diseases, they still support a strong role for Xist in sex-biased autoimmune diseases. “It’s sort of another take on it,” she said.
 

Is It the Proteins, the RNA, or Both?

The Stanford team points to the proteins recruited by Xist in the process of X-chromosome inactivation as the likely trigger of autoimmunity. However, a group of researchers at Johns Hopkins University in Baltimore, Maryland, made the case in a 2022 paper that Xist RNA itself was dangerous. They found that numerous short RNA sequences within the Xist molecule serve as ligands for TLR-7. And TLR-7 ligation causes plasmacytoid dendritic cells to overproduce type 1 interferon, a classic hallmark of lupus.

Alexander Girgis

“Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon,” explained Brendan Antiochos, MD. “Lupus is an example of that. Sjögren’s syndrome is another. So there’s always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity. And are there specific pathways which could contribute? One of the key pathways that’s been shown in humans and in mice to be important in lupus is toll-like receptor signaling.” Most convincingly, one recent study showed that people who have a gain-of-function mutation in their TLR-7 gene get a spontaneous form of lupus.

Wes Linda

These findings led Erika Darrah, PhD, and her colleague Dr. Antiochos to begin looking more deeply into which RNAs could be triggering this signaling pathway. “We started to think: Well, there is this sex bias. Could it be that women have unique RNAs that could potentially act as triggers for TLR-7 signaling?” Dr. Darrah said.

Dr. Darrah and Dr. Antiochos looked at publicly available genetic data to identify sex-biased sources of self-RNA containing TLR-7 ligands. Xist, they found, was chock full of them. “Every time we analyzed that data, no matter what filter we applied, Xist kept popping out over and over again as the most highly female skewed RNA, the RNA most likely to contain these TLR-7 binding motifs,” Dr. Darrah said. “We started to formulate the hypothesis that Xist was actually promoting responses that were dangerous and pathogenic in lupus.”

That finding led the team to conduct in-vitro experiments that showed different fragments of Xist can activate TLR-7, resulting in higher interferon production. Finally, they looked at blood and kidney cells from women with lupus and found that higher Xist expression correlated with more interferon production, and higher disease activity. “The more Xist, the sicker people were,” Dr. Darrah said.
 

Xist’s Other Functions

Xist was first studied in the 1990s, and most research has centered on its primary role in X-chromosome inactivation. A research group led by Kathrin Plath, PhD, at the University of California, Los Angeles, has been occupied for years with untangling exactly how Xist does what it does. “It’s a very clever RNA, right? It can silence the whole chromosome,” Dr. Plath said in an interview.

In 2021, Dr. Plath and her colleagues established in detail how Xist executes silencing, setting down pairs of molecules in specific spots along the chromosome and building huge protein clouds around them. “We worked on learning where Xist binds and what proteins it binds, drilling down to understand how these proteins and the RNA are coming together.”

Dr. Plath has long suspected that Xist has other functions besides X inactivation, and she and her colleagues are starting to identify them. Early this year they published the surprising finding that Xist can regulate gene expression in autosomes, or non–sex-linked chromosomes, “which it might well also do in cancer cells and lymphocytes,” Dr. Plath said. “And now there is this new evidence of an autoimmune function,” she said. “It’s a super exciting time.”

The different hypotheses surrounding Xist’s role in sex-biased autoimmunity aren’t mutually exclusive, Dr. Plath said. “There’s a tremendous enrichment of proteins occurring” during X inactivation, she said, supporting the Stanford team’s hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers’ understanding that Xist RNA itself is the trigger, “I’m totally open to that,” she said. “Why can’t it be an autoantigen?”

The other model in the field, Dr. Plath noted, is the one proposed by Dr. Anguera — “that there’s [gene] escape from X-inactivation — that females have more escape expression, and that Xist is more dispersed in the lymphocytes [of patients with lupus]. In fact, Xist becoming a little dispersed might make it a better antigen. So I do think everything is possible.”

The plethora of new findings related to autoimmunity has caused Dr. Plath to consider redirecting her lab’s focus toward more translational work, “because we are obviously good at studying Xist.” Among the mysteries Dr. Plath would like to solve is how some genes manage to escape the Xist cloud.

What is needed, she said, is collaboration. “Everyone will come up with different ideas. So I think it’s good to have more people look at things together. Then the field will achieve a breakthrough treatment.”

Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.

For years, researchers have worked to determine the reasons for sex-linked differences in immune response and autoimmunity, with environmental factors, sex hormones, and X-chromosome inactivation — the process by which a second X chromosome is silenced — all seen as having roles.

More recently, different groups of researchers have homed in on a long noncoding RNA fragment called X-inactive specific transcript, or Xist, as a potential driver of sex bias in autoimmune disease. Xist, which occurs in female mammals, has been known since the 1990s as the master regulator of X-chromosome inactivation, the process by which the second X chromosome is silenced, averting a fatal double dose of X-linked genes.

The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female’s life, allowing X inactivation to be maintained.

But is it possible that Xist, and the many dozens of proteins it recruits to keep that extra X chromosome silent, can also provoke autoimmunity? This is the question that several teams of researchers have been grappling with, resulting in provocative findings and opening exciting new avenues of discovery.
 

Xist Protein Complexes Make Male Mice Vulnerable to Lupus

In February, researchers Howard Chang, MD, PhD, and Diana Dou, PhD, of Stanford University in Stanford, California, made worldwide news when they published results from an experiment using male mice genetically engineered to carry a non-silencing form of Xist on one of their chromosomes.

Xist acts like a scaffold, recruiting multiple protein complexes to help it do its job. Dr. Dou explained in an interview that her team has been eyeing suspiciously for years the dozens of proteins Xist recruits in the process of X-chromosome inactivation, many of which are known autoantigens.

When the mice were injected with pristane, a chemical that induces lupus-like autoimmunity in mice, the Xist-producing males developed symptoms at a rate similar to that of females, while wild-type male mice did not.

By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. “Everything else about the animal is male,” Dr. Dou commented. “You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles. Is just having the particles present in these animals sufficient to increase their autoimmunity? This is what our paper showed: That just having expression of Xist, the presence of these Xist [ribonucleoproteins], is enough in permissive genetic backgrounds to invoke higher incidence and severity of autoimmune disease development in our pristane-induced lupus model.”

The Stanford group sees the Xist protein complex, which they have studied extensively, as a key to understanding how Xist might provoke autoimmunity. Nonetheless, Dr. Dou said, “It’s important to note that there are other contributing factors, which is why not all females develop autoimmunity, and we had very different results in our autoimmune-resistant mouse strain compared to the more autoimmune-prone strain. Xist is a factor, but many factors are required to subvert the checkpoints in immune balance and allow the progression to full-blown autoimmunity.”
 

Faulty X Inactivation and Gene Escape

The understanding that Xist might be implicated in autoimmune disease — and explain some of its female bias — is not new.

About a decade ago, Montserrat Anguera, PhD, a biologist at the University of Pennsylvania, Philadelphia, began looking at the relationship of X-chromosome inactivation, which by definition involves Xist, and lupus.

University of Pennsylvania

Dr. Anguera hypothesized that imperfect X inactivation allowed for greater escape of genes associated with immunity and autoimmunity. Studying patients with lupus, Dr. Anguera found that the silencing process was abnormal, allowing more of these genes to escape the silenced X — including toll-like receptor 7 (TLR-7) and other genes implicated in the pathogenesis of lupus.

“If you get increased expression of certain genes from the [silenced] X, like TLR-7, it can result in autoimmune disease,” Dr. Anguera said. “So what we think is that in the lupus patients, because the silencing is impacted, you’re going to have more expression happening from the inactive X. And then in conjunction with the active X, that’s going to throw off the dosage [of autoimmunity-linked genes]. You’re changing the dosage of genes, and that’s what’s critical.”

Even among patients with lupus whose symptoms are well controlled with medication, “if you look at their T cells and B cells, they still have messed up X inactivation,” Dr. Anguera said. “The Xist RNA that’s supposed to be tethered to the inactive X in a fluffy cloud is not localized, and instead is dispersed all over the nucleus.”

Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. “You also have a host of hormonal and environmental contributors, such as previous viral infections,” she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.

Dr. Anguera said that, while the findings by the Stanford scientists do not explain the full pathogenesis of lupus and related diseases, they still support a strong role for Xist in sex-biased autoimmune diseases. “It’s sort of another take on it,” she said.
 

Is It the Proteins, the RNA, or Both?

The Stanford team points to the proteins recruited by Xist in the process of X-chromosome inactivation as the likely trigger of autoimmunity. However, a group of researchers at Johns Hopkins University in Baltimore, Maryland, made the case in a 2022 paper that Xist RNA itself was dangerous. They found that numerous short RNA sequences within the Xist molecule serve as ligands for TLR-7. And TLR-7 ligation causes plasmacytoid dendritic cells to overproduce type 1 interferon, a classic hallmark of lupus.

Alexander Girgis

“Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon,” explained Brendan Antiochos, MD. “Lupus is an example of that. Sjögren’s syndrome is another. So there’s always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity. And are there specific pathways which could contribute? One of the key pathways that’s been shown in humans and in mice to be important in lupus is toll-like receptor signaling.” Most convincingly, one recent study showed that people who have a gain-of-function mutation in their TLR-7 gene get a spontaneous form of lupus.

Wes Linda

These findings led Erika Darrah, PhD, and her colleague Dr. Antiochos to begin looking more deeply into which RNAs could be triggering this signaling pathway. “We started to think: Well, there is this sex bias. Could it be that women have unique RNAs that could potentially act as triggers for TLR-7 signaling?” Dr. Darrah said.

Dr. Darrah and Dr. Antiochos looked at publicly available genetic data to identify sex-biased sources of self-RNA containing TLR-7 ligands. Xist, they found, was chock full of them. “Every time we analyzed that data, no matter what filter we applied, Xist kept popping out over and over again as the most highly female skewed RNA, the RNA most likely to contain these TLR-7 binding motifs,” Dr. Darrah said. “We started to formulate the hypothesis that Xist was actually promoting responses that were dangerous and pathogenic in lupus.”

That finding led the team to conduct in-vitro experiments that showed different fragments of Xist can activate TLR-7, resulting in higher interferon production. Finally, they looked at blood and kidney cells from women with lupus and found that higher Xist expression correlated with more interferon production, and higher disease activity. “The more Xist, the sicker people were,” Dr. Darrah said.
 

Xist’s Other Functions

Xist was first studied in the 1990s, and most research has centered on its primary role in X-chromosome inactivation. A research group led by Kathrin Plath, PhD, at the University of California, Los Angeles, has been occupied for years with untangling exactly how Xist does what it does. “It’s a very clever RNA, right? It can silence the whole chromosome,” Dr. Plath said in an interview.

In 2021, Dr. Plath and her colleagues established in detail how Xist executes silencing, setting down pairs of molecules in specific spots along the chromosome and building huge protein clouds around them. “We worked on learning where Xist binds and what proteins it binds, drilling down to understand how these proteins and the RNA are coming together.”

Dr. Plath has long suspected that Xist has other functions besides X inactivation, and she and her colleagues are starting to identify them. Early this year they published the surprising finding that Xist can regulate gene expression in autosomes, or non–sex-linked chromosomes, “which it might well also do in cancer cells and lymphocytes,” Dr. Plath said. “And now there is this new evidence of an autoimmune function,” she said. “It’s a super exciting time.”

The different hypotheses surrounding Xist’s role in sex-biased autoimmunity aren’t mutually exclusive, Dr. Plath said. “There’s a tremendous enrichment of proteins occurring” during X inactivation, she said, supporting the Stanford team’s hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers’ understanding that Xist RNA itself is the trigger, “I’m totally open to that,” she said. “Why can’t it be an autoantigen?”

The other model in the field, Dr. Plath noted, is the one proposed by Dr. Anguera — “that there’s [gene] escape from X-inactivation — that females have more escape expression, and that Xist is more dispersed in the lymphocytes [of patients with lupus]. In fact, Xist becoming a little dispersed might make it a better antigen. So I do think everything is possible.”

The plethora of new findings related to autoimmunity has caused Dr. Plath to consider redirecting her lab’s focus toward more translational work, “because we are obviously good at studying Xist.” Among the mysteries Dr. Plath would like to solve is how some genes manage to escape the Xist cloud.

What is needed, she said, is collaboration. “Everyone will come up with different ideas. So I think it’s good to have more people look at things together. Then the field will achieve a breakthrough treatment.”