Tara Haelle

A simple blood test that looks for a combination of specific RNA snippets may become a novel way to screen for early-onset colorectal cancer, suggests a new study published online in Gastroenterology.

Researchers identified four microRNAs that together comprise a signature biomarker that can be used to detect and diagnose the presence of colorectal cancer from a liquid biopsy in a younger population.

MicroRNAs, or miRNAs, are small RNA molecules that do not encode proteins but are used instead to regulate gene expression. The study authors developed and validated a panel that detects four miRNAs occurring at higher levels in plasma samples from patients with early-onset colorectal cancer, with high sensitivity and specificity.

“The point would be to use this test as a routine part of annual healthcare, or for people in high-risk families every 6 months,” study senior author Ajay Goel, PhD, MS, chair of the department of molecular diagnostics and experimental therapeutics at the City of Hope Comprehensive Cancer Center, Duarte, Calif., said in an interview.

“It’s affordable, it can be done easily from a small tube of blood, and as long as that test stays negative, you’re good,” Dr. Goel said, because even if patients miss a test, the next one, whether it’s 6 months or a year later, will catch any potential cancer.

“Colon cancer is not going to kill somebody overnight, so this should be used as a precursor to colonoscopy. As long as that test is negative, you can postpone a colonoscopy,” he said.

Andrew T. Chan, MD, MPH, a professor of medicine at Harvard Medical School and vice chair of gastroenterology at Massachusetts General Hospital, both in Boston, who was not involved in the research, said in an interview that the findings are exciting.

“It would be really value-added to have a blood-based screening test,” Dr. Chan said, adding that researchers have pursued multiple different avenues in pursuit of one. “It’s very nice to see that area progress and to actually have some evidence that microRNAs could be a potential biomarker for colorectal cancer.”
 

Screening now insufficient for early-onset disease

The U.S. Preventive Services Task Force recently lowered the recommended age to 45 years to begin screening for colorectal cancer. Part of the rationale for the change came from the rising rates of early-onset colorectal cancer, a distinct clinical and molecular entity that tends to have poorer survival than late-onset disease, the authors noted.

Early-onset disease, occurring primarily in people under 50 without a family or genetic history of colorectal cancer, now makes up about 10%-15% of all new cases and continues to rise, they write.

“Early-onset colorectal cancer patients are more likely to exhibit an advanced stage tumor at initial presentation, distal tumor localization, signet ring histology, and a disease presentation with concurrent metastasis,” the authors wrote. “This raises the logistical clinical concern that, since the tumors in early-onset colorectal cancer patients are often more aggressive than those with late-onset colorectal cancer, a delayed diagnosis could have a significant adverse impact and can lead to early death.”

Yet current screening strategies are insufficient for detecting enough early-onset cases, the authors assert.

Colonoscopies are invasive, carry a risk for complications, and are cost- and time-prohibitive for people at average risk. Meanwhile, existing fecal and blood tests “lack adequate diagnostic performance for the early detection of colorectal cancer, especially early-onset colorectal cancer, as these assays have yet to be explored or developed in this population,” they wrote.

The ideal “diagnostic modality should preferably be acceptable to healthy individuals, inexpensive, rapid, and preferably noninvasive,” they note.
 

Finding and validating miRNA

The researchers therefore turned to the concept of a liquid biopsy, focusing on identifying miRNAs associated with colorectal cancer, because their expression tends to be stable in tissues, blood, stool, and other body fluids.

They first analyzed an miRNA expression profiling dataset from 1,061 individuals to look for miRNAs whose expression was higher in colorectal cancer patients. The dataset included 42 patients with stage 1-2 early-onset colorectal cancer, 370 patients with stage 1-2 late-onset colorectal cancer, 62 patients younger than 50 years without cancer, and 587 patients aged 50 years or older without cancer.

The researchers found 28 miRNAs that were significantly unregulated in early-onset colorectal cancer tissue samples, compared with cancer-free samples and 11 miRNAs unregulated specifically in only the early-onset colorectal cancer samples. Four of these 11 miRNAs were adequately distinct from one another and were detectable in the plasma samples that the researchers would use to train and validate them as a combination biomarker.

The researchers used 117 plasma samples from Japan, including 72 from people with early-onset colorectal cancer and 45 from healthy donors, to develop and train an assay detecting the four miRNAs. They then validated the assay using 142 plasma samples from Spain, including 77 with early-onset colorectal cancer and 65 healthy donors.

In the Japan cohort, the four-miRNA assay had a sensitivity of 90% and a specificity of 80%, with a positive predictive value (PPV) of 88% and a negative predictive value (NPV) of 84%. In the Spain cohort used for validation, the assay performed with a sensitivity of 82%, a specificity of 86%, a PPV of 88%, and an NPV of 80%.

“Taken together, the genome-wide transcriptomic profiling approach was indeed robust, as it identified the biomarkers that were successfully trained and validated in plasma specimens from independent cohorts of patients with early-onset colorectal cancer, hence highlighting their translational potential in the clinic for the detection of this malignancy in early stages,” the authors wrote.

By disease stage, the four-miRNA panel identified both early-stage (stage 1-2; sensitivity, 92%; specificity, 80%) and late-stage (stage 3-4; sensitivity, 79%; specificity, 86%) early-onset colorectal cancer in the validation cohort.
 

Clinical benefit of blood test

The researchers also assessed the benefit-harm trade-off of this liquid biopsy assay compared with other screening modalities, taking into consideration the risk for false positives and false negatives.

A decision curve analysis “revealed that the miRNA panel achieved a higher net benefit regardless of threshold probability in comparison to intervention for all patients or none of the patients,” the researchers reported. “These findings suggest that this miRNA panel might offer more clinical benefit with regards to the avoidance of physical harm and misdiagnosis.”

They also found that expression levels of these four miRNAs significantly decreased after surgical removal of the colorectal cancer, strongly suggesting that the miRNAs do originate with the tumor.

“To have a relatively inexpensive and noninvasive means of screening a younger population is a very important unmet need,” said Dr. Chan.

It’s not feasible to recommend colonoscopies in people younger than 45 years because of resource constraints, he said, so “this is a wonderful new development to actually have the possibility of a blood-based screening test for younger individuals, especially given that rising incidence of young-onset colorectal cancer.”

Dr. Goel pointed out that only half of those recommended to get screened for colorectal cancer actually undergo screening, and a large reason for that is the desire to avoid colonoscopy, a concern echoed in the findings of a recent study by Christopher V. Almario, MD, MSHPM, and colleagues.

Dr. Goel expects that this strategy would increase compliance with screening because it’s less invasive and more affordable, particularly for younger patients. He estimates that a commercial assay using this panel, if approved by the Food and Drug Administration, should cost less than $100.

Dr. Almario, an assistant professor of medicine at the Cedars-Sinai Karsh Division of Gastroenterology and Hepatology in Los Angeles, agreed that an FDA-approved blood-based screening test would be a “game-changer,” as long as it’s accurate and effective.

Though Dr. Almario did not review the data in Goel’s study, he said in an interview that a blood test for colorectal cancer screening would be “the holy grail, so to speak, in terms of really moving the needle on screening uptake.”
 

Next steps

Dr. Chan noted that one caveat to consider with this study is that it was done in a relatively small population of individuals, even though the test was validated in a second set of plasma samples.

“Additional validation needs to be done in larger numbers of patients to really understand the performance characteristics because it is possible that some of these signatures may, when they’re using a broader group of individuals, not perform as well,” Dr. Chan said.

Dr. Goel said he is working with several companies right now to develop and further test a commercial product. He anticipates it may be shelf-ready in 2-5 years.

“The take-home message is that clinicians need to be more cognizant of the fact that incidence of this disease is rising, and we need to do something about it,” Dr. Goel said, particularly for those younger than 45 years who currently don’t have a screening option.

“Now we have at least a sliver of hope for those who might be suffering from this disease, for those for whom we have zero screening or diagnostic tests,” he said.

The research was funded by the National Cancer Institute and Fundación MAPFRE Guanarteme. Dr. Goel, Dr. Chan, and Dr. Almario reported no conflicts of interest.

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

A simple blood test that looks for a combination of specific RNA snippets may become a novel way to screen for early-onset colorectal cancer, suggests a new study published online in Gastroenterology.

Researchers identified four microRNAs that together comprise a signature biomarker that can be used to detect and diagnose the presence of colorectal cancer from a liquid biopsy in a younger population.

MicroRNAs, or miRNAs, are small RNA molecules that do not encode proteins but are used instead to regulate gene expression. The study authors developed and validated a panel that detects four miRNAs occurring at higher levels in plasma samples from patients with early-onset colorectal cancer, with high sensitivity and specificity.

“The point would be to use this test as a routine part of annual healthcare, or for people in high-risk families every 6 months,” study senior author Ajay Goel, PhD, MS, chair of the department of molecular diagnostics and experimental therapeutics at the City of Hope Comprehensive Cancer Center, Duarte, Calif., said in an interview.

“It’s affordable, it can be done easily from a small tube of blood, and as long as that test stays negative, you’re good,” Dr. Goel said, because even if patients miss a test, the next one, whether it’s 6 months or a year later, will catch any potential cancer.

“Colon cancer is not going to kill somebody overnight, so this should be used as a precursor to colonoscopy. As long as that test is negative, you can postpone a colonoscopy,” he said.

Andrew T. Chan, MD, MPH, a professor of medicine at Harvard Medical School and vice chair of gastroenterology at Massachusetts General Hospital, both in Boston, who was not involved in the research, said in an interview that the findings are exciting.

“It would be really value-added to have a blood-based screening test,” Dr. Chan said, adding that researchers have pursued multiple different avenues in pursuit of one. “It’s very nice to see that area progress and to actually have some evidence that microRNAs could be a potential biomarker for colorectal cancer.”
 

Screening now insufficient for early-onset disease

The U.S. Preventive Services Task Force recently lowered the recommended age to 45 years to begin screening for colorectal cancer. Part of the rationale for the change came from the rising rates of early-onset colorectal cancer, a distinct clinical and molecular entity that tends to have poorer survival than late-onset disease, the authors noted.

Early-onset disease, occurring primarily in people under 50 without a family or genetic history of colorectal cancer, now makes up about 10%-15% of all new cases and continues to rise, they write.

“Early-onset colorectal cancer patients are more likely to exhibit an advanced stage tumor at initial presentation, distal tumor localization, signet ring histology, and a disease presentation with concurrent metastasis,” the authors wrote. “This raises the logistical clinical concern that, since the tumors in early-onset colorectal cancer patients are often more aggressive than those with late-onset colorectal cancer, a delayed diagnosis could have a significant adverse impact and can lead to early death.”

Yet current screening strategies are insufficient for detecting enough early-onset cases, the authors assert.

Colonoscopies are invasive, carry a risk for complications, and are cost- and time-prohibitive for people at average risk. Meanwhile, existing fecal and blood tests “lack adequate diagnostic performance for the early detection of colorectal cancer, especially early-onset colorectal cancer, as these assays have yet to be explored or developed in this population,” they wrote.

The ideal “diagnostic modality should preferably be acceptable to healthy individuals, inexpensive, rapid, and preferably noninvasive,” they note.
 

Finding and validating miRNA

The researchers therefore turned to the concept of a liquid biopsy, focusing on identifying miRNAs associated with colorectal cancer, because their expression tends to be stable in tissues, blood, stool, and other body fluids.

They first analyzed an miRNA expression profiling dataset from 1,061 individuals to look for miRNAs whose expression was higher in colorectal cancer patients. The dataset included 42 patients with stage 1-2 early-onset colorectal cancer, 370 patients with stage 1-2 late-onset colorectal cancer, 62 patients younger than 50 years without cancer, and 587 patients aged 50 years or older without cancer.

The researchers found 28 miRNAs that were significantly unregulated in early-onset colorectal cancer tissue samples, compared with cancer-free samples and 11 miRNAs unregulated specifically in only the early-onset colorectal cancer samples. Four of these 11 miRNAs were adequately distinct from one another and were detectable in the plasma samples that the researchers would use to train and validate them as a combination biomarker.

The researchers used 117 plasma samples from Japan, including 72 from people with early-onset colorectal cancer and 45 from healthy donors, to develop and train an assay detecting the four miRNAs. They then validated the assay using 142 plasma samples from Spain, including 77 with early-onset colorectal cancer and 65 healthy donors.

In the Japan cohort, the four-miRNA assay had a sensitivity of 90% and a specificity of 80%, with a positive predictive value (PPV) of 88% and a negative predictive value (NPV) of 84%. In the Spain cohort used for validation, the assay performed with a sensitivity of 82%, a specificity of 86%, a PPV of 88%, and an NPV of 80%.

“Taken together, the genome-wide transcriptomic profiling approach was indeed robust, as it identified the biomarkers that were successfully trained and validated in plasma specimens from independent cohorts of patients with early-onset colorectal cancer, hence highlighting their translational potential in the clinic for the detection of this malignancy in early stages,” the authors wrote.

By disease stage, the four-miRNA panel identified both early-stage (stage 1-2; sensitivity, 92%; specificity, 80%) and late-stage (stage 3-4; sensitivity, 79%; specificity, 86%) early-onset colorectal cancer in the validation cohort.
 

Clinical benefit of blood test

The researchers also assessed the benefit-harm trade-off of this liquid biopsy assay compared with other screening modalities, taking into consideration the risk for false positives and false negatives.

A decision curve analysis “revealed that the miRNA panel achieved a higher net benefit regardless of threshold probability in comparison to intervention for all patients or none of the patients,” the researchers reported. “These findings suggest that this miRNA panel might offer more clinical benefit with regards to the avoidance of physical harm and misdiagnosis.”

They also found that expression levels of these four miRNAs significantly decreased after surgical removal of the colorectal cancer, strongly suggesting that the miRNAs do originate with the tumor.

“To have a relatively inexpensive and noninvasive means of screening a younger population is a very important unmet need,” said Dr. Chan.

It’s not feasible to recommend colonoscopies in people younger than 45 years because of resource constraints, he said, so “this is a wonderful new development to actually have the possibility of a blood-based screening test for younger individuals, especially given that rising incidence of young-onset colorectal cancer.”

Dr. Goel pointed out that only half of those recommended to get screened for colorectal cancer actually undergo screening, and a large reason for that is the desire to avoid colonoscopy, a concern echoed in the findings of a recent study by Christopher V. Almario, MD, MSHPM, and colleagues.

Dr. Goel expects that this strategy would increase compliance with screening because it’s less invasive and more affordable, particularly for younger patients. He estimates that a commercial assay using this panel, if approved by the Food and Drug Administration, should cost less than $100.

Dr. Almario, an assistant professor of medicine at the Cedars-Sinai Karsh Division of Gastroenterology and Hepatology in Los Angeles, agreed that an FDA-approved blood-based screening test would be a “game-changer,” as long as it’s accurate and effective.

Though Dr. Almario did not review the data in Goel’s study, he said in an interview that a blood test for colorectal cancer screening would be “the holy grail, so to speak, in terms of really moving the needle on screening uptake.”
 

Next steps

Dr. Chan noted that one caveat to consider with this study is that it was done in a relatively small population of individuals, even though the test was validated in a second set of plasma samples.

“Additional validation needs to be done in larger numbers of patients to really understand the performance characteristics because it is possible that some of these signatures may, when they’re using a broader group of individuals, not perform as well,” Dr. Chan said.

Dr. Goel said he is working with several companies right now to develop and further test a commercial product. He anticipates it may be shelf-ready in 2-5 years.

“The take-home message is that clinicians need to be more cognizant of the fact that incidence of this disease is rising, and we need to do something about it,” Dr. Goel said, particularly for those younger than 45 years who currently don’t have a screening option.

“Now we have at least a sliver of hope for those who might be suffering from this disease, for those for whom we have zero screening or diagnostic tests,” he said.

The research was funded by the National Cancer Institute and Fundación MAPFRE Guanarteme. Dr. Goel, Dr. Chan, and Dr. Almario reported no conflicts of interest.

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

A simple blood test that looks for a combination of specific RNA snippets may become a novel way to screen for early-onset colorectal cancer, suggests a new study published online in Gastroenterology.

Researchers identified four microRNAs that together comprise a signature biomarker that can be used to detect and diagnose the presence of colorectal cancer from a liquid biopsy in a younger population.

MicroRNAs, or miRNAs, are small RNA molecules that do not encode proteins but are used instead to regulate gene expression. The study authors developed and validated a panel that detects four miRNAs occurring at higher levels in plasma samples from patients with early-onset colorectal cancer, with high sensitivity and specificity.

“The point would be to use this test as a routine part of annual healthcare, or for people in high-risk families every 6 months,” study senior author Ajay Goel, PhD, MS, chair of the department of molecular diagnostics and experimental therapeutics at the City of Hope Comprehensive Cancer Center, Duarte, Calif., said in an interview.

“It’s affordable, it can be done easily from a small tube of blood, and as long as that test stays negative, you’re good,” Dr. Goel said, because even if patients miss a test, the next one, whether it’s 6 months or a year later, will catch any potential cancer.

“Colon cancer is not going to kill somebody overnight, so this should be used as a precursor to colonoscopy. As long as that test is negative, you can postpone a colonoscopy,” he said.

Andrew T. Chan, MD, MPH, a professor of medicine at Harvard Medical School and vice chair of gastroenterology at Massachusetts General Hospital, both in Boston, who was not involved in the research, said in an interview that the findings are exciting.

“It would be really value-added to have a blood-based screening test,” Dr. Chan said, adding that researchers have pursued multiple different avenues in pursuit of one. “It’s very nice to see that area progress and to actually have some evidence that microRNAs could be a potential biomarker for colorectal cancer.”
 

Screening now insufficient for early-onset disease

The U.S. Preventive Services Task Force recently lowered the recommended age to 45 years to begin screening for colorectal cancer. Part of the rationale for the change came from the rising rates of early-onset colorectal cancer, a distinct clinical and molecular entity that tends to have poorer survival than late-onset disease, the authors noted.

Early-onset disease, occurring primarily in people under 50 without a family or genetic history of colorectal cancer, now makes up about 10%-15% of all new cases and continues to rise, they write.

“Early-onset colorectal cancer patients are more likely to exhibit an advanced stage tumor at initial presentation, distal tumor localization, signet ring histology, and a disease presentation with concurrent metastasis,” the authors wrote. “This raises the logistical clinical concern that, since the tumors in early-onset colorectal cancer patients are often more aggressive than those with late-onset colorectal cancer, a delayed diagnosis could have a significant adverse impact and can lead to early death.”

Yet current screening strategies are insufficient for detecting enough early-onset cases, the authors assert.

Colonoscopies are invasive, carry a risk for complications, and are cost- and time-prohibitive for people at average risk. Meanwhile, existing fecal and blood tests “lack adequate diagnostic performance for the early detection of colorectal cancer, especially early-onset colorectal cancer, as these assays have yet to be explored or developed in this population,” they wrote.

The ideal “diagnostic modality should preferably be acceptable to healthy individuals, inexpensive, rapid, and preferably noninvasive,” they note.
 

Finding and validating miRNA

The researchers therefore turned to the concept of a liquid biopsy, focusing on identifying miRNAs associated with colorectal cancer, because their expression tends to be stable in tissues, blood, stool, and other body fluids.

They first analyzed an miRNA expression profiling dataset from 1,061 individuals to look for miRNAs whose expression was higher in colorectal cancer patients. The dataset included 42 patients with stage 1-2 early-onset colorectal cancer, 370 patients with stage 1-2 late-onset colorectal cancer, 62 patients younger than 50 years without cancer, and 587 patients aged 50 years or older without cancer.

The researchers found 28 miRNAs that were significantly unregulated in early-onset colorectal cancer tissue samples, compared with cancer-free samples and 11 miRNAs unregulated specifically in only the early-onset colorectal cancer samples. Four of these 11 miRNAs were adequately distinct from one another and were detectable in the plasma samples that the researchers would use to train and validate them as a combination biomarker.

The researchers used 117 plasma samples from Japan, including 72 from people with early-onset colorectal cancer and 45 from healthy donors, to develop and train an assay detecting the four miRNAs. They then validated the assay using 142 plasma samples from Spain, including 77 with early-onset colorectal cancer and 65 healthy donors.

In the Japan cohort, the four-miRNA assay had a sensitivity of 90% and a specificity of 80%, with a positive predictive value (PPV) of 88% and a negative predictive value (NPV) of 84%. In the Spain cohort used for validation, the assay performed with a sensitivity of 82%, a specificity of 86%, a PPV of 88%, and an NPV of 80%.

“Taken together, the genome-wide transcriptomic profiling approach was indeed robust, as it identified the biomarkers that were successfully trained and validated in plasma specimens from independent cohorts of patients with early-onset colorectal cancer, hence highlighting their translational potential in the clinic for the detection of this malignancy in early stages,” the authors wrote.

By disease stage, the four-miRNA panel identified both early-stage (stage 1-2; sensitivity, 92%; specificity, 80%) and late-stage (stage 3-4; sensitivity, 79%; specificity, 86%) early-onset colorectal cancer in the validation cohort.
 

Clinical benefit of blood test

The researchers also assessed the benefit-harm trade-off of this liquid biopsy assay compared with other screening modalities, taking into consideration the risk for false positives and false negatives.

A decision curve analysis “revealed that the miRNA panel achieved a higher net benefit regardless of threshold probability in comparison to intervention for all patients or none of the patients,” the researchers reported. “These findings suggest that this miRNA panel might offer more clinical benefit with regards to the avoidance of physical harm and misdiagnosis.”

They also found that expression levels of these four miRNAs significantly decreased after surgical removal of the colorectal cancer, strongly suggesting that the miRNAs do originate with the tumor.

“To have a relatively inexpensive and noninvasive means of screening a younger population is a very important unmet need,” said Dr. Chan.

It’s not feasible to recommend colonoscopies in people younger than 45 years because of resource constraints, he said, so “this is a wonderful new development to actually have the possibility of a blood-based screening test for younger individuals, especially given that rising incidence of young-onset colorectal cancer.”

Dr. Goel pointed out that only half of those recommended to get screened for colorectal cancer actually undergo screening, and a large reason for that is the desire to avoid colonoscopy, a concern echoed in the findings of a recent study by Christopher V. Almario, MD, MSHPM, and colleagues.

Dr. Goel expects that this strategy would increase compliance with screening because it’s less invasive and more affordable, particularly for younger patients. He estimates that a commercial assay using this panel, if approved by the Food and Drug Administration, should cost less than $100.

Dr. Almario, an assistant professor of medicine at the Cedars-Sinai Karsh Division of Gastroenterology and Hepatology in Los Angeles, agreed that an FDA-approved blood-based screening test would be a “game-changer,” as long as it’s accurate and effective.

Though Dr. Almario did not review the data in Goel’s study, he said in an interview that a blood test for colorectal cancer screening would be “the holy grail, so to speak, in terms of really moving the needle on screening uptake.”
 

Next steps

Dr. Chan noted that one caveat to consider with this study is that it was done in a relatively small population of individuals, even though the test was validated in a second set of plasma samples.

“Additional validation needs to be done in larger numbers of patients to really understand the performance characteristics because it is possible that some of these signatures may, when they’re using a broader group of individuals, not perform as well,” Dr. Chan said.

Dr. Goel said he is working with several companies right now to develop and further test a commercial product. He anticipates it may be shelf-ready in 2-5 years.

“The take-home message is that clinicians need to be more cognizant of the fact that incidence of this disease is rising, and we need to do something about it,” Dr. Goel said, particularly for those younger than 45 years who currently don’t have a screening option.

“Now we have at least a sliver of hope for those who might be suffering from this disease, for those for whom we have zero screening or diagnostic tests,” he said.

The research was funded by the National Cancer Institute and Fundación MAPFRE Guanarteme. Dr. Goel, Dr. Chan, and Dr. Almario reported no conflicts of interest.

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

Patients said they’d prefer fecal immunochemical test (FIT)–fecal DNA tests over any of the other colorectal cancer screening (CRC) modalities currently recommended by the U.S. Multi-Society Task Force, according to a study published in Clinical Gastroenterology and Hepatology.

Just over a third of American adults aged 40 and older who hadn’t yet been screened for CRC preferred the FIT–fecal DNA test every 3 years, whereas just one in seven respondents preferred a colonoscopy – considered the gold standard in colorectal cancer screening – every 10 years.

"When you talk to patients and to your friends and family members, people tend to think colonoscopy is synonymous with colon cancer screening, but we have lots of different tests,” senior author Christopher V. Almario, MD, MSHPM, of the department of medicine at the Karsh division of gastroenterology and hepatology, Cedars-Sinai Medical Center, Los Angeles, said in an interview.

“Most people in general tend to prefer noninvasive stool tests, and when we try to predict who would prefer what, we actually couldn’t, so this is a very personal decision,” Dr. Almario said. “It’s important for clinicians to offer multiple choices to their patients, not to mention just colonoscopy. We have data from observing clinician-patient interactions showing that, a lot of times, colonoscopy is the only test that’s offered, despite there being multiple options.”

At the very least, Dr. Almario said, providers should offer patients a colonoscopy along with a noninvasive test, particularly a stool test, and discuss the two options, getting the patient’s input in terms of what they prefer. “The best test is the test that actually gets done,” he said.
 

Offering patients options

Reid M. Ness, MD, MPH, an associate professor of medicine in the division of gastroenterology, hepatology and nutrition at Vanderbilt University Medical Center in Nashville, was not involved with the study but wasn’t surprised at the findings since “most people wisely prefer to avoid invasive procedures,” he said in an interview. He agreed that many patients aren’t necessarily informed of all their options for screening.

“Many people who are now being offered colonoscopy as their only screening option may prefer a noninvasive option, such as FIT or multitarget stool DNA testing,” Dr. Ness said. “Also, people now refusing colonoscopy for colorectal cancer screening may instead accept FIT or multitarget stool DNA testing. It is difficult to know how many people now refusing colorectal cancer screening may have accepted screening if it had been offered differently.”

That’s precisely what Dr. Almario and his colleagues wanted to find out. They surveyed 1,000 people aged 40 and older who were at average risk for colorectal cancer to find out their preferences for different screening modalities and what features of different screening types they most valued. The researchers asked about the following screening tests recommended by the U.S. Multi-Society Task Force:

• FIT every year.
• FIT–fecal DNA every 3 years.
• Colon video capsule every 5 years.
• CT colonography every 5 years.
• Colonoscopy every 10 years.

The respondents who completed the online survey were recruited from a sample of more than 20 million people across the United States who have agreed to receive survey invitations. Respondents were excluded if they had a first-degree relative with colorectal cancer, had already undergone colorectal cancer screening or had been diagnosed with colon polyps, Crohn’s disease, or ulcerative colitis.

The respondents were split into those aged 40-49 (61% of the sample) who had not yet discussed colorectal cancer screening with their providers and those aged 50 and older, who might have already discussed it and declined. Eighty percent of the respondents were White, 6% were Black, 6% were Hispanic, 4% were Asian, and 3% reported another race/ethnicity. Just over half (52%) had at least two comorbidities. A quarter (25%) reported one comorbidity, and 22% reported none.



In thinking about the decision to get screened, respondents ranked the test type as the most important consideration, followed by the reduction in their chance of developing colorectal cancer and then frequency of the test. Lower priority on the list of considerations were their chances of a complication, bowel prep before the test, and required diet changes before the test.

The test preferred by the highest proportion of respondents was the FIT–fecal DNA test every 3 years, preferred by 35% of respondents, followed by the colon capsule video test every 5 years (28%). About one in seven respondents (14%) preferred a colonoscopy every 10 years, followed by the annual FIT (12%) and CT colonography every 5 years (11%). When limited only to the two tier 1–option tests – the annual FIT or a colonoscopy every 10 years – a substantial majority of the younger (69%) and older (77%) groups preferred the annual FIT.

”This finding is discordant with current CRC screening utilization in the United States where colonoscopy is the most commonly performed test, and this may partially explain our suboptimal screening rates,” the authors wrote. “Our findings suggest that screening programs should strongly consider a sequential-based strategy where FIT is offered first, and if declined then colonoscopy.”
 

Underlying factors

Dr. Ness said that many primary care providers might prefer to offer colonoscopies instead of annual FIT tests because it’s easier to track a test given every 10 years instead of every year or every 3 years.

“Providers across most of the U.S. are incentivized to recommend colonoscopy as the primary screening modality because the burden of follow-up on them is less,” Dr. Ness said. “They are able to justify this choice given colonoscopy remains the most accurate screening modality.”

Dr. Ness pointed to the programmatic screening program at Kaiser Permanente of Northern California health care system as a model for a program that utilizes FIT tests more often.

“The only way to accomplish an efficient and equitable colorectal cancer screening program is within the context of a national health service or plan,” Dr. Ness added. “Otherwise, the uninsured and underinsured will remain excluded from the benefits of colorectal cancer screening.”

Preferences did not differ a great deal between the age groups, with 35% of the younger group and 37% of the older group both preferring the FIT–fecal DNA tests every 3 years. Slightly more people in the 50+ age group preferred an annual fit (19% vs. 12%) as opposed to the colon capsule video every 5 years (28% of younger group vs. 23%) or colon CT scan every 5 years (11% of younger group vs. 8%), but the differences were statistically significant (P = .019).

In fact, “sociodemographic, clinical characteristics, and colorectal cancer screening knowledge, attitudes, and beliefs were not predictive of selecting FIT or colonoscopy,” the authors found. ”This demonstrates the individualized nature of decision making on colorectal cancer screening tests. Moreover, as most individuals preferred FIT, it again emphasizes the importance of sequential or choice-based strategies for colorectal cancer screening.”

However, one of the study’s notable limitations was its high proportion of White patients relative to other racial/ethnic groups, so additional research may illuminate whether different sociodemographic groups do have slight preferences for one test over another, Dr. Almario said. The advantage to colonoscopies, he noted, is that they only occur every 10 years and if polyps are discovered, they can be taken care of right away.

”You don’t have to think about it for a decade, which is certainly a pro for the colonoscopy,” Dr. Almario said. “The FIT test is obviously less invasive, but you have to do it every year for it to be an effective screening test.” He noted that some data have shown a drop-off in compliance over multiple years. “We certainly need more systems in place to remind patients and providers to do it annually so that we can see the ultimate screening benefit from doing that test specifically.”

“The most important point from the clinical perspective is, when we’re talking to patients about colon cancer screening, make sure to give them a choice,” Dr. Almario said. “We just can’t look at someone’s chart, their clinical characteristics or demographics, and predict what tests they would prefer. We need to ask them. We need to present them with the options, go over the pros and cons of colonoscopy, the pros and cons of the stool test, and ask the patient what they would prefer to do.”

The research was funded by the National Cancer Institute and the National Institutes of Health. One author served on an advisory panel with Exact Sciences. The other authors and Dr. Ness had no disclosures.

Help your patients understand colorectal cancer prevention and screening options by sharing AGA’s patient education from the GI Patient Center: www.gastro.org/CRC.

This article was updated on Aug. 18, 2022.

Patients said they’d prefer fecal immunochemical test (FIT)–fecal DNA tests over any of the other colorectal cancer screening (CRC) modalities currently recommended by the U.S. Multi-Society Task Force, according to a study published in Clinical Gastroenterology and Hepatology.

Just over a third of American adults aged 40 and older who hadn’t yet been screened for CRC preferred the FIT–fecal DNA test every 3 years, whereas just one in seven respondents preferred a colonoscopy – considered the gold standard in colorectal cancer screening – every 10 years.

"When you talk to patients and to your friends and family members, people tend to think colonoscopy is synonymous with colon cancer screening, but we have lots of different tests,” senior author Christopher V. Almario, MD, MSHPM, of the department of medicine at the Karsh division of gastroenterology and hepatology, Cedars-Sinai Medical Center, Los Angeles, said in an interview.

“Most people in general tend to prefer noninvasive stool tests, and when we try to predict who would prefer what, we actually couldn’t, so this is a very personal decision,” Dr. Almario said. “It’s important for clinicians to offer multiple choices to their patients, not to mention just colonoscopy. We have data from observing clinician-patient interactions showing that, a lot of times, colonoscopy is the only test that’s offered, despite there being multiple options.”

At the very least, Dr. Almario said, providers should offer patients a colonoscopy along with a noninvasive test, particularly a stool test, and discuss the two options, getting the patient’s input in terms of what they prefer. “The best test is the test that actually gets done,” he said.
 

Offering patients options

Reid M. Ness, MD, MPH, an associate professor of medicine in the division of gastroenterology, hepatology and nutrition at Vanderbilt University Medical Center in Nashville, was not involved with the study but wasn’t surprised at the findings since “most people wisely prefer to avoid invasive procedures,” he said in an interview. He agreed that many patients aren’t necessarily informed of all their options for screening.

“Many people who are now being offered colonoscopy as their only screening option may prefer a noninvasive option, such as FIT or multitarget stool DNA testing,” Dr. Ness said. “Also, people now refusing colonoscopy for colorectal cancer screening may instead accept FIT or multitarget stool DNA testing. It is difficult to know how many people now refusing colorectal cancer screening may have accepted screening if it had been offered differently.”

That’s precisely what Dr. Almario and his colleagues wanted to find out. They surveyed 1,000 people aged 40 and older who were at average risk for colorectal cancer to find out their preferences for different screening modalities and what features of different screening types they most valued. The researchers asked about the following screening tests recommended by the U.S. Multi-Society Task Force:

• FIT every year.
• FIT–fecal DNA every 3 years.
• Colon video capsule every 5 years.
• CT colonography every 5 years.
• Colonoscopy every 10 years.

The respondents who completed the online survey were recruited from a sample of more than 20 million people across the United States who have agreed to receive survey invitations. Respondents were excluded if they had a first-degree relative with colorectal cancer, had already undergone colorectal cancer screening or had been diagnosed with colon polyps, Crohn’s disease, or ulcerative colitis.

The respondents were split into those aged 40-49 (61% of the sample) who had not yet discussed colorectal cancer screening with their providers and those aged 50 and older, who might have already discussed it and declined. Eighty percent of the respondents were White, 6% were Black, 6% were Hispanic, 4% were Asian, and 3% reported another race/ethnicity. Just over half (52%) had at least two comorbidities. A quarter (25%) reported one comorbidity, and 22% reported none.



In thinking about the decision to get screened, respondents ranked the test type as the most important consideration, followed by the reduction in their chance of developing colorectal cancer and then frequency of the test. Lower priority on the list of considerations were their chances of a complication, bowel prep before the test, and required diet changes before the test.

The test preferred by the highest proportion of respondents was the FIT–fecal DNA test every 3 years, preferred by 35% of respondents, followed by the colon capsule video test every 5 years (28%). About one in seven respondents (14%) preferred a colonoscopy every 10 years, followed by the annual FIT (12%) and CT colonography every 5 years (11%). When limited only to the two tier 1–option tests – the annual FIT or a colonoscopy every 10 years – a substantial majority of the younger (69%) and older (77%) groups preferred the annual FIT.

”This finding is discordant with current CRC screening utilization in the United States where colonoscopy is the most commonly performed test, and this may partially explain our suboptimal screening rates,” the authors wrote. “Our findings suggest that screening programs should strongly consider a sequential-based strategy where FIT is offered first, and if declined then colonoscopy.”
 

Underlying factors

Dr. Ness said that many primary care providers might prefer to offer colonoscopies instead of annual FIT tests because it’s easier to track a test given every 10 years instead of every year or every 3 years.

“Providers across most of the U.S. are incentivized to recommend colonoscopy as the primary screening modality because the burden of follow-up on them is less,” Dr. Ness said. “They are able to justify this choice given colonoscopy remains the most accurate screening modality.”

Dr. Ness pointed to the programmatic screening program at Kaiser Permanente of Northern California health care system as a model for a program that utilizes FIT tests more often.

“The only way to accomplish an efficient and equitable colorectal cancer screening program is within the context of a national health service or plan,” Dr. Ness added. “Otherwise, the uninsured and underinsured will remain excluded from the benefits of colorectal cancer screening.”

Preferences did not differ a great deal between the age groups, with 35% of the younger group and 37% of the older group both preferring the FIT–fecal DNA tests every 3 years. Slightly more people in the 50+ age group preferred an annual fit (19% vs. 12%) as opposed to the colon capsule video every 5 years (28% of younger group vs. 23%) or colon CT scan every 5 years (11% of younger group vs. 8%), but the differences were statistically significant (P = .019).

In fact, “sociodemographic, clinical characteristics, and colorectal cancer screening knowledge, attitudes, and beliefs were not predictive of selecting FIT or colonoscopy,” the authors found. ”This demonstrates the individualized nature of decision making on colorectal cancer screening tests. Moreover, as most individuals preferred FIT, it again emphasizes the importance of sequential or choice-based strategies for colorectal cancer screening.”

However, one of the study’s notable limitations was its high proportion of White patients relative to other racial/ethnic groups, so additional research may illuminate whether different sociodemographic groups do have slight preferences for one test over another, Dr. Almario said. The advantage to colonoscopies, he noted, is that they only occur every 10 years and if polyps are discovered, they can be taken care of right away.

”You don’t have to think about it for a decade, which is certainly a pro for the colonoscopy,” Dr. Almario said. “The FIT test is obviously less invasive, but you have to do it every year for it to be an effective screening test.” He noted that some data have shown a drop-off in compliance over multiple years. “We certainly need more systems in place to remind patients and providers to do it annually so that we can see the ultimate screening benefit from doing that test specifically.”

“The most important point from the clinical perspective is, when we’re talking to patients about colon cancer screening, make sure to give them a choice,” Dr. Almario said. “We just can’t look at someone’s chart, their clinical characteristics or demographics, and predict what tests they would prefer. We need to ask them. We need to present them with the options, go over the pros and cons of colonoscopy, the pros and cons of the stool test, and ask the patient what they would prefer to do.”

The research was funded by the National Cancer Institute and the National Institutes of Health. One author served on an advisory panel with Exact Sciences. The other authors and Dr. Ness had no disclosures.

Help your patients understand colorectal cancer prevention and screening options by sharing AGA’s patient education from the GI Patient Center: www.gastro.org/CRC.

This article was updated on Aug. 18, 2022.

Patients said they’d prefer fecal immunochemical test (FIT)–fecal DNA tests over any of the other colorectal cancer screening (CRC) modalities currently recommended by the U.S. Multi-Society Task Force, according to a study published in Clinical Gastroenterology and Hepatology.

Just over a third of American adults aged 40 and older who hadn’t yet been screened for CRC preferred the FIT–fecal DNA test every 3 years, whereas just one in seven respondents preferred a colonoscopy – considered the gold standard in colorectal cancer screening – every 10 years.

"When you talk to patients and to your friends and family members, people tend to think colonoscopy is synonymous with colon cancer screening, but we have lots of different tests,” senior author Christopher V. Almario, MD, MSHPM, of the department of medicine at the Karsh division of gastroenterology and hepatology, Cedars-Sinai Medical Center, Los Angeles, said in an interview.

“Most people in general tend to prefer noninvasive stool tests, and when we try to predict who would prefer what, we actually couldn’t, so this is a very personal decision,” Dr. Almario said. “It’s important for clinicians to offer multiple choices to their patients, not to mention just colonoscopy. We have data from observing clinician-patient interactions showing that, a lot of times, colonoscopy is the only test that’s offered, despite there being multiple options.”

At the very least, Dr. Almario said, providers should offer patients a colonoscopy along with a noninvasive test, particularly a stool test, and discuss the two options, getting the patient’s input in terms of what they prefer. “The best test is the test that actually gets done,” he said.
 

Offering patients options

Reid M. Ness, MD, MPH, an associate professor of medicine in the division of gastroenterology, hepatology and nutrition at Vanderbilt University Medical Center in Nashville, was not involved with the study but wasn’t surprised at the findings since “most people wisely prefer to avoid invasive procedures,” he said in an interview. He agreed that many patients aren’t necessarily informed of all their options for screening.

“Many people who are now being offered colonoscopy as their only screening option may prefer a noninvasive option, such as FIT or multitarget stool DNA testing,” Dr. Ness said. “Also, people now refusing colonoscopy for colorectal cancer screening may instead accept FIT or multitarget stool DNA testing. It is difficult to know how many people now refusing colorectal cancer screening may have accepted screening if it had been offered differently.”

That’s precisely what Dr. Almario and his colleagues wanted to find out. They surveyed 1,000 people aged 40 and older who were at average risk for colorectal cancer to find out their preferences for different screening modalities and what features of different screening types they most valued. The researchers asked about the following screening tests recommended by the U.S. Multi-Society Task Force:

• FIT every year.
• FIT–fecal DNA every 3 years.
• Colon video capsule every 5 years.
• CT colonography every 5 years.
• Colonoscopy every 10 years.

The respondents who completed the online survey were recruited from a sample of more than 20 million people across the United States who have agreed to receive survey invitations. Respondents were excluded if they had a first-degree relative with colorectal cancer, had already undergone colorectal cancer screening or had been diagnosed with colon polyps, Crohn’s disease, or ulcerative colitis.

The respondents were split into those aged 40-49 (61% of the sample) who had not yet discussed colorectal cancer screening with their providers and those aged 50 and older, who might have already discussed it and declined. Eighty percent of the respondents were White, 6% were Black, 6% were Hispanic, 4% were Asian, and 3% reported another race/ethnicity. Just over half (52%) had at least two comorbidities. A quarter (25%) reported one comorbidity, and 22% reported none.



In thinking about the decision to get screened, respondents ranked the test type as the most important consideration, followed by the reduction in their chance of developing colorectal cancer and then frequency of the test. Lower priority on the list of considerations were their chances of a complication, bowel prep before the test, and required diet changes before the test.

The test preferred by the highest proportion of respondents was the FIT–fecal DNA test every 3 years, preferred by 35% of respondents, followed by the colon capsule video test every 5 years (28%). About one in seven respondents (14%) preferred a colonoscopy every 10 years, followed by the annual FIT (12%) and CT colonography every 5 years (11%). When limited only to the two tier 1–option tests – the annual FIT or a colonoscopy every 10 years – a substantial majority of the younger (69%) and older (77%) groups preferred the annual FIT.

”This finding is discordant with current CRC screening utilization in the United States where colonoscopy is the most commonly performed test, and this may partially explain our suboptimal screening rates,” the authors wrote. “Our findings suggest that screening programs should strongly consider a sequential-based strategy where FIT is offered first, and if declined then colonoscopy.”
 

Underlying factors

Dr. Ness said that many primary care providers might prefer to offer colonoscopies instead of annual FIT tests because it’s easier to track a test given every 10 years instead of every year or every 3 years.

“Providers across most of the U.S. are incentivized to recommend colonoscopy as the primary screening modality because the burden of follow-up on them is less,” Dr. Ness said. “They are able to justify this choice given colonoscopy remains the most accurate screening modality.”

Dr. Ness pointed to the programmatic screening program at Kaiser Permanente of Northern California health care system as a model for a program that utilizes FIT tests more often.

“The only way to accomplish an efficient and equitable colorectal cancer screening program is within the context of a national health service or plan,” Dr. Ness added. “Otherwise, the uninsured and underinsured will remain excluded from the benefits of colorectal cancer screening.”

Preferences did not differ a great deal between the age groups, with 35% of the younger group and 37% of the older group both preferring the FIT–fecal DNA tests every 3 years. Slightly more people in the 50+ age group preferred an annual fit (19% vs. 12%) as opposed to the colon capsule video every 5 years (28% of younger group vs. 23%) or colon CT scan every 5 years (11% of younger group vs. 8%), but the differences were statistically significant (P = .019).

In fact, “sociodemographic, clinical characteristics, and colorectal cancer screening knowledge, attitudes, and beliefs were not predictive of selecting FIT or colonoscopy,” the authors found. ”This demonstrates the individualized nature of decision making on colorectal cancer screening tests. Moreover, as most individuals preferred FIT, it again emphasizes the importance of sequential or choice-based strategies for colorectal cancer screening.”

However, one of the study’s notable limitations was its high proportion of White patients relative to other racial/ethnic groups, so additional research may illuminate whether different sociodemographic groups do have slight preferences for one test over another, Dr. Almario said. The advantage to colonoscopies, he noted, is that they only occur every 10 years and if polyps are discovered, they can be taken care of right away.

”You don’t have to think about it for a decade, which is certainly a pro for the colonoscopy,” Dr. Almario said. “The FIT test is obviously less invasive, but you have to do it every year for it to be an effective screening test.” He noted that some data have shown a drop-off in compliance over multiple years. “We certainly need more systems in place to remind patients and providers to do it annually so that we can see the ultimate screening benefit from doing that test specifically.”

“The most important point from the clinical perspective is, when we’re talking to patients about colon cancer screening, make sure to give them a choice,” Dr. Almario said. “We just can’t look at someone’s chart, their clinical characteristics or demographics, and predict what tests they would prefer. We need to ask them. We need to present them with the options, go over the pros and cons of colonoscopy, the pros and cons of the stool test, and ask the patient what they would prefer to do.”

The research was funded by the National Cancer Institute and the National Institutes of Health. One author served on an advisory panel with Exact Sciences. The other authors and Dr. Ness had no disclosures.

Help your patients understand colorectal cancer prevention and screening options by sharing AGA’s patient education from the GI Patient Center: www.gastro.org/CRC.

This article was updated on Aug. 18, 2022.

Patients said they’d prefer fecal immunochemical test (FIT)–fecal DNA tests over any of the other colorectal cancer screening (CRC) modalities currently recommended by the U.S. Multi-Society Task Force, according to a study published in Clinical Gastroenterology and Hepatology.

Just over a third of American adults aged 40 and older who hadn’t yet been screened for CRC preferred the FIT–fecal DNA test every 3 years, whereas just one in seven respondents preferred a colonoscopy – considered the gold standard in colorectal cancer screening – every 10 years.

”When you talk to patients and to your friends and family members, people tend to think colonoscopy is synonymous with colon cancer screening, but we have lots of different tests,” senior author Christopher V. Almario, MD, MSHPM, of the department of medicine at the Karsh division of gastroenterology and hepatology, Cedars-Sinai Medical Center, Los Angeles, said in an interview.

“Most people in general tend to prefer noninvasive stool tests, and when we try to predict who would prefer what, we actually couldn’t, so this is a very personal decision,” Dr. Almario said. “It’s important for clinicians to offer multiple choices to their patients, not to mention just colonoscopy. We have data from observing clinician-patient interactions showing that, a lot of times, colonoscopy is the only test that’s offered, despite there being multiple options.”

At the very least, Dr. Almario said, providers should offer patients a colonoscopy along with a noninvasive test, particularly a stool test, and discuss the two options, getting the patient’s input in terms of what they prefer. “The best test is the test that actually gets done,” he said.
 

Offering patients options

Reid M. Ness, MD, MPH, an associate professor of medicine in the division of gastroenterology, hepatology and nutrition at Vanderbilt University Medical Center in Nashville, was not involved with the study but wasn’t surprised at the findings since “most people wisely prefer to avoid invasive procedures,” he said in an interview. He agreed that many patients aren’t necessarily informed of all their options for screening.

“Many people who are now being offered colonoscopy as their only screening option may prefer a noninvasive option, such as FIT or multitarget stool DNA testing,” Dr. Ness said. “Also, people now refusing colonoscopy for colorectal cancer screening may instead accept FIT or multitarget stool DNA testing. It is difficult to know how many people now refusing colorectal cancer screening may have accepted screening if it had been offered differently.”

That’s precisely what Dr. Almario and his colleagues wanted to find out. They surveyed 1,000 people aged 40 and older who were at average risk for colorectal cancer to find out their preferences for different screening modalities and what features of different screening types they most valued. The researchers asked about the following screening tests recommended by the U.S. Multi-Society Task Force:

• FIT every year.
• FIT–fecal DNA every 3 years.
• Colon video capsule every 5 years.
• CT colonography every 5 years.
• Colonoscopy every 10 years.

The respondents who completed the online survey were recruited from a sample of more than 20 million people across the United States who have agreed to receive survey invitations. Respondents were excluded if they had a first-degree relative with colorectal cancer, had already undergone colorectal cancer screening or had been diagnosed with colon polyps, Crohn’s disease, or ulcerative colitis.

The respondents were split into those aged 40-49 (61% of the sample) who had not yet discussed colorectal cancer screening with their providers and those aged 50 and older, who might have already discussed it and declined. Eighty percent of the respondents were White, 6% were Black, 6% were Hispanic, 4% were Asian, and 3% reported another race/ethnicity. Just over half (52%) had at least two comorbidities. A quarter (25%) reported one comorbidity, and 22% reported none.



In thinking about the decision to get screened, respondents ranked the test type as the most important consideration, followed by the reduction in their chance of developing colorectal cancer and then frequency of the test. Lower priority on the list of considerations were their chances of a complication, bowel prep before the test, and required diet changes before the test.

The test preferred by the highest proportion of respondents was the FIT–fecal DNA test every 3 years, preferred by 35% of respondents, followed by the colon capsule video test every 5 years (28%). About one in seven respondents (14%) preferred a colonoscopy every 10 years, followed by the annual FIT (12%) and CT colonography every 5 years (11%). When limited only to the two tier 1–option tests – the annual FIT or a colonoscopy every 10 years – a substantial majority of the younger (69%) and older (77%) groups preferred the annual FIT.

”This finding is discordant with current CRC screening utilization in the United States where colonoscopy is the most commonly performed test, and this may partially explain our suboptimal screening rates,” the authors wrote. “Our findings suggest that screening programs should strongly consider a sequential-based strategy where FIT is offered first, and if declined then colonoscopy.”
 

Underlying factors

Dr. Ness said that many primary care providers might prefer to offer colonoscopies instead of annual FIT tests because it’s easier to track a test given every 10 years instead of every year or every 3 years.

“Providers across most of the U.S. are incentivized to recommend colonoscopy as the primary screening modality because the burden of follow-up on them is less,” Dr. Ness said. “They are able to justify this choice given colonoscopy remains the most accurate screening modality.”

Dr. Ness pointed to the programmatic screening program at Kaiser Permanente of Northern California health care system as a model for a program that utilizes FIT tests more often.

“The only way to accomplish an efficient and equitable colorectal cancer screening program is within the context of a national health service or plan,” Dr. Ness added. “Otherwise, the uninsured and underinsured will remain excluded from the benefits of colorectal cancer screening.”

Preferences did not differ a great deal between the age groups, with 35% of the younger group and 37% of the older group both preferring the FIT–fecal DNA tests every 3 years. Slightly more people in the 50+ age group preferred an annual fit (19% vs. 12%) as opposed to the colon capsule video every 5 years (28% of younger group vs. 23%) or colon CT scan every 5 years (11% of younger group vs. 8%), but the differences were statistically significant (P = .019).

In fact, “sociodemographic, clinical characteristics, and colorectal cancer screening knowledge, attitudes, and beliefs were not predictive of selecting FIT or colonoscopy,” the authors found. ”This demonstrates the individualized nature of decision making on colorectal cancer screening tests. Moreover, as most individuals preferred FIT, it again emphasizes the importance of sequential or choice-based strategies for colorectal cancer screening.”

However, one of the study’s notable limitations was its high proportion of White patients relative to other racial/ethnic groups, so additional research may illuminate whether different sociodemographic groups do have slight preferences for one test over another, Dr. Almario said. The advantage to colonoscopies, he noted, is that they only occur every 10 years and if polyps are discovered, they can be taken care of right away.

”You don’t have to think about it for a decade, which is certainly a pro for the colonoscopy,” Dr. Almario said. “The FIT test is obviously less invasive, but you have to do it every year for it to be an effective screening test.” He noted that some data have shown a drop-off in compliance over multiple years. “We certainly need more systems in place to remind patients and providers to do it annually so that we can see the ultimate screening benefit from doing that test specifically.”

“The most important point from the clinical perspective is, when we’re talking to patients about colon cancer screening, make sure to give them a choice,” Dr. Almario said. “We just can’t look at someone’s chart, their clinical characteristics or demographics, and predict what tests they would prefer. We need to ask them. We need to present them with the options, go over the pros and cons of colonoscopy, the pros and cons of the stool test, and ask the patient what they would prefer to do.”

The research was funded by the National Cancer Institute and the National Institutes of Health. One author served on an advisory board with Exact Sciences. The other authors and Dr. Ness had no disclosures.

Patients said they’d prefer fecal immunochemical test (FIT)–fecal DNA tests over any of the other colorectal cancer screening (CRC) modalities currently recommended by the U.S. Multi-Society Task Force, according to a study published in Clinical Gastroenterology and Hepatology.

Just over a third of American adults aged 40 and older who hadn’t yet been screened for CRC preferred the FIT–fecal DNA test every 3 years, whereas just one in seven respondents preferred a colonoscopy – considered the gold standard in colorectal cancer screening – every 10 years.

”When you talk to patients and to your friends and family members, people tend to think colonoscopy is synonymous with colon cancer screening, but we have lots of different tests,” senior author Christopher V. Almario, MD, MSHPM, of the department of medicine at the Karsh division of gastroenterology and hepatology, Cedars-Sinai Medical Center, Los Angeles, said in an interview.

“Most people in general tend to prefer noninvasive stool tests, and when we try to predict who would prefer what, we actually couldn’t, so this is a very personal decision,” Dr. Almario said. “It’s important for clinicians to offer multiple choices to their patients, not to mention just colonoscopy. We have data from observing clinician-patient interactions showing that, a lot of times, colonoscopy is the only test that’s offered, despite there being multiple options.”

At the very least, Dr. Almario said, providers should offer patients a colonoscopy along with a noninvasive test, particularly a stool test, and discuss the two options, getting the patient’s input in terms of what they prefer. “The best test is the test that actually gets done,” he said.
 

Offering patients options

Reid M. Ness, MD, MPH, an associate professor of medicine in the division of gastroenterology, hepatology and nutrition at Vanderbilt University Medical Center in Nashville, was not involved with the study but wasn’t surprised at the findings since “most people wisely prefer to avoid invasive procedures,” he said in an interview. He agreed that many patients aren’t necessarily informed of all their options for screening.

“Many people who are now being offered colonoscopy as their only screening option may prefer a noninvasive option, such as FIT or multitarget stool DNA testing,” Dr. Ness said. “Also, people now refusing colonoscopy for colorectal cancer screening may instead accept FIT or multitarget stool DNA testing. It is difficult to know how many people now refusing colorectal cancer screening may have accepted screening if it had been offered differently.”

That’s precisely what Dr. Almario and his colleagues wanted to find out. They surveyed 1,000 people aged 40 and older who were at average risk for colorectal cancer to find out their preferences for different screening modalities and what features of different screening types they most valued. The researchers asked about the following screening tests recommended by the U.S. Multi-Society Task Force:

• FIT every year.
• FIT–fecal DNA every 3 years.
• Colon video capsule every 5 years.
• CT colonography every 5 years.
• Colonoscopy every 10 years.

The respondents who completed the online survey were recruited from a sample of more than 20 million people across the United States who have agreed to receive survey invitations. Respondents were excluded if they had a first-degree relative with colorectal cancer, had already undergone colorectal cancer screening or had been diagnosed with colon polyps, Crohn’s disease, or ulcerative colitis.

The respondents were split into those aged 40-49 (61% of the sample) who had not yet discussed colorectal cancer screening with their providers and those aged 50 and older, who might have already discussed it and declined. Eighty percent of the respondents were White, 6% were Black, 6% were Hispanic, 4% were Asian, and 3% reported another race/ethnicity. Just over half (52%) had at least two comorbidities. A quarter (25%) reported one comorbidity, and 22% reported none.



In thinking about the decision to get screened, respondents ranked the test type as the most important consideration, followed by the reduction in their chance of developing colorectal cancer and then frequency of the test. Lower priority on the list of considerations were their chances of a complication, bowel prep before the test, and required diet changes before the test.

The test preferred by the highest proportion of respondents was the FIT–fecal DNA test every 3 years, preferred by 35% of respondents, followed by the colon capsule video test every 5 years (28%). About one in seven respondents (14%) preferred a colonoscopy every 10 years, followed by the annual FIT (12%) and CT colonography every 5 years (11%). When limited only to the two tier 1–option tests – the annual FIT or a colonoscopy every 10 years – a substantial majority of the younger (69%) and older (77%) groups preferred the annual FIT.

”This finding is discordant with current CRC screening utilization in the United States where colonoscopy is the most commonly performed test, and this may partially explain our suboptimal screening rates,” the authors wrote. “Our findings suggest that screening programs should strongly consider a sequential-based strategy where FIT is offered first, and if declined then colonoscopy.”
 

Underlying factors

Dr. Ness said that many primary care providers might prefer to offer colonoscopies instead of annual FIT tests because it’s easier to track a test given every 10 years instead of every year or every 3 years.

“Providers across most of the U.S. are incentivized to recommend colonoscopy as the primary screening modality because the burden of follow-up on them is less,” Dr. Ness said. “They are able to justify this choice given colonoscopy remains the most accurate screening modality.”

Dr. Ness pointed to the programmatic screening program at Kaiser Permanente of Northern California health care system as a model for a program that utilizes FIT tests more often.

“The only way to accomplish an efficient and equitable colorectal cancer screening program is within the context of a national health service or plan,” Dr. Ness added. “Otherwise, the uninsured and underinsured will remain excluded from the benefits of colorectal cancer screening.”

Preferences did not differ a great deal between the age groups, with 35% of the younger group and 37% of the older group both preferring the FIT–fecal DNA tests every 3 years. Slightly more people in the 50+ age group preferred an annual fit (19% vs. 12%) as opposed to the colon capsule video every 5 years (28% of younger group vs. 23%) or colon CT scan every 5 years (11% of younger group vs. 8%), but the differences were statistically significant (P = .019).

In fact, “sociodemographic, clinical characteristics, and colorectal cancer screening knowledge, attitudes, and beliefs were not predictive of selecting FIT or colonoscopy,” the authors found. ”This demonstrates the individualized nature of decision making on colorectal cancer screening tests. Moreover, as most individuals preferred FIT, it again emphasizes the importance of sequential or choice-based strategies for colorectal cancer screening.”

However, one of the study’s notable limitations was its high proportion of White patients relative to other racial/ethnic groups, so additional research may illuminate whether different sociodemographic groups do have slight preferences for one test over another, Dr. Almario said. The advantage to colonoscopies, he noted, is that they only occur every 10 years and if polyps are discovered, they can be taken care of right away.

”You don’t have to think about it for a decade, which is certainly a pro for the colonoscopy,” Dr. Almario said. “The FIT test is obviously less invasive, but you have to do it every year for it to be an effective screening test.” He noted that some data have shown a drop-off in compliance over multiple years. “We certainly need more systems in place to remind patients and providers to do it annually so that we can see the ultimate screening benefit from doing that test specifically.”

“The most important point from the clinical perspective is, when we’re talking to patients about colon cancer screening, make sure to give them a choice,” Dr. Almario said. “We just can’t look at someone’s chart, their clinical characteristics or demographics, and predict what tests they would prefer. We need to ask them. We need to present them with the options, go over the pros and cons of colonoscopy, the pros and cons of the stool test, and ask the patient what they would prefer to do.”

The research was funded by the National Cancer Institute and the National Institutes of Health. One author served on an advisory board with Exact Sciences. The other authors and Dr. Ness had no disclosures.

Patients said they’d prefer fecal immunochemical test (FIT)–fecal DNA tests over any of the other colorectal cancer screening (CRC) modalities currently recommended by the U.S. Multi-Society Task Force, according to a study published in Clinical Gastroenterology and Hepatology.

Just over a third of American adults aged 40 and older who hadn’t yet been screened for CRC preferred the FIT–fecal DNA test every 3 years, whereas just one in seven respondents preferred a colonoscopy – considered the gold standard in colorectal cancer screening – every 10 years.

”When you talk to patients and to your friends and family members, people tend to think colonoscopy is synonymous with colon cancer screening, but we have lots of different tests,” senior author Christopher V. Almario, MD, MSHPM, of the department of medicine at the Karsh division of gastroenterology and hepatology, Cedars-Sinai Medical Center, Los Angeles, said in an interview.

“Most people in general tend to prefer noninvasive stool tests, and when we try to predict who would prefer what, we actually couldn’t, so this is a very personal decision,” Dr. Almario said. “It’s important for clinicians to offer multiple choices to their patients, not to mention just colonoscopy. We have data from observing clinician-patient interactions showing that, a lot of times, colonoscopy is the only test that’s offered, despite there being multiple options.”

At the very least, Dr. Almario said, providers should offer patients a colonoscopy along with a noninvasive test, particularly a stool test, and discuss the two options, getting the patient’s input in terms of what they prefer. “The best test is the test that actually gets done,” he said.
 

Offering patients options

Reid M. Ness, MD, MPH, an associate professor of medicine in the division of gastroenterology, hepatology and nutrition at Vanderbilt University Medical Center in Nashville, was not involved with the study but wasn’t surprised at the findings since “most people wisely prefer to avoid invasive procedures,” he said in an interview. He agreed that many patients aren’t necessarily informed of all their options for screening.

“Many people who are now being offered colonoscopy as their only screening option may prefer a noninvasive option, such as FIT or multitarget stool DNA testing,” Dr. Ness said. “Also, people now refusing colonoscopy for colorectal cancer screening may instead accept FIT or multitarget stool DNA testing. It is difficult to know how many people now refusing colorectal cancer screening may have accepted screening if it had been offered differently.”

That’s precisely what Dr. Almario and his colleagues wanted to find out. They surveyed 1,000 people aged 40 and older who were at average risk for colorectal cancer to find out their preferences for different screening modalities and what features of different screening types they most valued. The researchers asked about the following screening tests recommended by the U.S. Multi-Society Task Force:

• FIT every year.
• FIT–fecal DNA every 3 years.
• Colon video capsule every 5 years.
• CT colonography every 5 years.
• Colonoscopy every 10 years.

The respondents who completed the online survey were recruited from a sample of more than 20 million people across the United States who have agreed to receive survey invitations. Respondents were excluded if they had a first-degree relative with colorectal cancer, had already undergone colorectal cancer screening or had been diagnosed with colon polyps, Crohn’s disease, or ulcerative colitis.

The respondents were split into those aged 40-49 (61% of the sample) who had not yet discussed colorectal cancer screening with their providers and those aged 50 and older, who might have already discussed it and declined. Eighty percent of the respondents were White, 6% were Black, 6% were Hispanic, 4% were Asian, and 3% reported another race/ethnicity. Just over half (52%) had at least two comorbidities. A quarter (25%) reported one comorbidity, and 22% reported none.



In thinking about the decision to get screened, respondents ranked the test type as the most important consideration, followed by the reduction in their chance of developing colorectal cancer and then frequency of the test. Lower priority on the list of considerations were their chances of a complication, bowel prep before the test, and required diet changes before the test.

The test preferred by the highest proportion of respondents was the FIT–fecal DNA test every 3 years, preferred by 35% of respondents, followed by the colon capsule video test every 5 years (28%). About one in seven respondents (14%) preferred a colonoscopy every 10 years, followed by the annual FIT (12%) and CT colonography every 5 years (11%). When limited only to the two tier 1–option tests – the annual FIT or a colonoscopy every 10 years – a substantial majority of the younger (69%) and older (77%) groups preferred the annual FIT.

”This finding is discordant with current CRC screening utilization in the United States where colonoscopy is the most commonly performed test, and this may partially explain our suboptimal screening rates,” the authors wrote. “Our findings suggest that screening programs should strongly consider a sequential-based strategy where FIT is offered first, and if declined then colonoscopy.”
 

Underlying factors

Dr. Ness said that many primary care providers might prefer to offer colonoscopies instead of annual FIT tests because it’s easier to track a test given every 10 years instead of every year or every 3 years.

“Providers across most of the U.S. are incentivized to recommend colonoscopy as the primary screening modality because the burden of follow-up on them is less,” Dr. Ness said. “They are able to justify this choice given colonoscopy remains the most accurate screening modality.”

Dr. Ness pointed to the programmatic screening program at Kaiser Permanente of Northern California health care system as a model for a program that utilizes FIT tests more often.

“The only way to accomplish an efficient and equitable colorectal cancer screening program is within the context of a national health service or plan,” Dr. Ness added. “Otherwise, the uninsured and underinsured will remain excluded from the benefits of colorectal cancer screening.”

Preferences did not differ a great deal between the age groups, with 35% of the younger group and 37% of the older group both preferring the FIT–fecal DNA tests every 3 years. Slightly more people in the 50+ age group preferred an annual fit (19% vs. 12%) as opposed to the colon capsule video every 5 years (28% of younger group vs. 23%) or colon CT scan every 5 years (11% of younger group vs. 8%), but the differences were statistically significant (P = .019).

In fact, “sociodemographic, clinical characteristics, and colorectal cancer screening knowledge, attitudes, and beliefs were not predictive of selecting FIT or colonoscopy,” the authors found. ”This demonstrates the individualized nature of decision making on colorectal cancer screening tests. Moreover, as most individuals preferred FIT, it again emphasizes the importance of sequential or choice-based strategies for colorectal cancer screening.”

However, one of the study’s notable limitations was its high proportion of White patients relative to other racial/ethnic groups, so additional research may illuminate whether different sociodemographic groups do have slight preferences for one test over another, Dr. Almario said. The advantage to colonoscopies, he noted, is that they only occur every 10 years and if polyps are discovered, they can be taken care of right away.

”You don’t have to think about it for a decade, which is certainly a pro for the colonoscopy,” Dr. Almario said. “The FIT test is obviously less invasive, but you have to do it every year for it to be an effective screening test.” He noted that some data have shown a drop-off in compliance over multiple years. “We certainly need more systems in place to remind patients and providers to do it annually so that we can see the ultimate screening benefit from doing that test specifically.”

“The most important point from the clinical perspective is, when we’re talking to patients about colon cancer screening, make sure to give them a choice,” Dr. Almario said. “We just can’t look at someone’s chart, their clinical characteristics or demographics, and predict what tests they would prefer. We need to ask them. We need to present them with the options, go over the pros and cons of colonoscopy, the pros and cons of the stool test, and ask the patient what they would prefer to do.”

The research was funded by the National Cancer Institute and the National Institutes of Health. One author served on an advisory board with Exact Sciences. The other authors and Dr. Ness had no disclosures.

Marital status is a relevant risk factor in considering the prognosis of patients with gastric cancer, according to research published in the Journal of Investigative Medicine.

Tumor size remained the largest contributor to overall survival, but marital status was among several other significant factors, such as age, race, gender, treatment style, and pathologic stage, that can provide insight into a patient’s likelihood of overall survival, as it does with several other cancers.

“Married patients had the best prognosis, followed by single patients, and the prognosis of separated patients was the worst,” write Lixiang Zhang and colleagues at the First Affiliated Hospital of Anhui Medical University, Hefei, China. “We speculate that this might be due to the fact that married patients had better financial conditions and emotional encouragement, while separated patients might be more likely to experience financial difficulties [and] emotional loss.”

The results were not necessarily surprising to Richard M. Peek, Jr., MD, director of the division of gastroenterology and a professor of medicine at Vanderbilt University Medical Center, who was not involved in the research.

“Marital status is a reflection of support systems, and a strong support system is a prognosticator for increased compliance with medical appointments and medical therapies,” Dr. Peek told this news organization. “It is something to consider when somebody is being treated for gastric cancer, because if they don’t have a strong support system – and marital status can be a proxy for that – then they may need more intensive follow-up and surveillance, for example, than somebody who does not have that support system.”
 

Exploring the marital status–cancer survival connection

Gastric cancer is the third leading cause of cancer deaths across the world, causing 780,000 deaths in 2018, the authors note. Yet it’s difficult to accurately predict the prognosis in patients who undergo treatment for early stage gastric cancer. Previous research has found marital status to be associated with survival in prostate, cervical, and rectal cancers.

Mark A. Lewis, MD, director of gastrointestinal oncology at Intermountain Healthcare Cancer Center, Utah, told this news organization that the connection between marital status and cancer outcomes has been described previously, including in an even larger analysis using the U.S. Surveillance, Epidemiology, and End Results (SEER) database from 2013. That study found that “unmarried patients are at significantly higher risk of presentation with metastatic cancer, undertreatment, and death resulting from their cancer.”

In this study, the researchers compared marital status and survival rates among 3,647 patients with early-stage gastric cancer, using data from the SEER database. The study only included patients with tumors in the lamina propria, mucosa, and submucosa and excluded those with distant metastasis or distant lymph node metastases, a second cancer, no data on chemotherapy received, or unknown survival time.

Because they were using a nomogram and building a new predictive nomogram that would include marital status, the researchers divided the patient population into a training set of 2,719 patients and a testing set of 928 patients. Using overall survival as the primary endpoint, the analysis included the variables of “age at diagnosis, race, gender, tumor location, histology, grade, stage_T and stage_N, surgery in the primary site, lymph node dissection, chemotherapy, radiation, tumor size, insurance, and marital status,” the authors report.

Among the study population, 53.7% were married, 17.3% were widowed, 14% were single and never married, 7.5% were divorced, 1.1% were separated, and the status of 6.4% was unknown. Age at diagnosis, race, gender, histology, tumor grade, stage T, stage N, surgery type, tumor size, and insurance status were all significantly different between the marital status subgroups.

Married patients had the best prognosis, with an average overall survival of 72 months, compared with an average 60 months in widowed persons, the group with the poorest overall survival. Overall survival was higher in married women (76 months) than in married men (69 months). The same pattern held for women (62 months) and men (52 months) who had been widowed.

“It is worthy to note that survival was significantly better in divorced female patients than in divorced male patients,” the authors report. “Survival was better in female patients than in male patients” across all marital groups.
 

What long-term relationships reveal

These findings do not mean that simply getting married changes one’s likelihood of survival, however. Rather, a long-term relationship is revealing about other aspects in a person’s life.

“I think it represents more stability in the supportive relationship that you need to really deal with a serious disease like cancer,” Dr. Peek said.

If a patient does not have a long-term partner, their care team can ask other questions to get a sense of what their support network is like, Dr. Peek added. “We want to know, does anybody else live in the house with them? Do they have adequate transportation? Can they make medical appointments? Do they have somebody who can help with the medical issues that are going to come up? Do they have family in the area?”

Cancer treatment requires a multidisciplinary approach, and having someone other than just the patient around to help bring together the different aspects of care from different care teams can make a difference in how the patient fares, Dr. Peek explained. Patients without a strong support system may need closer follow-up and other accommodations, he said.

Providers “may schedule their clinical appointments closer together if they don’t have a support system, or they may be able to reach out and offer transportation assistance and those kinds of things that somebody living alone may need,” Dr. Peek said. Outside resources may be a higher priority for those who lack a support system at home, he added.

Dr. Peek also noted other factors that may play a role in a patient’s survival that these researchers did not have the data to address, such as socioeconomic status, employment, alcohol use, smoking, and infection with Helicobacter pylori, the strongest known risk factor for gastric cancer.

A potentially relevant limitation of the study is that it probably has some selection bias, because the patients who were included probably had the means to have received an earlier diagnosis, said Dr. Lewis, who was not involved in the research.

“Furthermore, just in terms of the group sizes, the baseline characteristics section makes it clear that the preponderance of patients were married, lending that group more statistical weight,” Dr. Lewis said.

“Of the seven attributes in the nomogram, the impact of the marital status seems comparatively meager relative to conventional clinicopathology risk factors like T stage,” he added.

“All in all, I think this study reinforces our awareness that socioeconomic status and social determinants of health play a huge role in cancer outcomes, but it’s not entirely clear that’s modifiable just by getting married,” Dr. Lewis said. “There is a saying in oncology that ‘expensive liquor causes less cancer than cheap liquor,’ which is not negating the carcinogenicity of alcohol but rather identifying different outcomes by socioeconomic status.”

The research was funded by the Natural Science Foundation of Anhui Province. The authors report no relevant financial relationships. Dr. Peek reports no relevant financial relationships. Dr. Lewis reports receiving speaking fees for AstraZeneca/Daiichi Sankyo and having done educational videos for Astellas.

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

Marital status is a relevant risk factor in considering the prognosis of patients with gastric cancer, according to research published in the Journal of Investigative Medicine.

Tumor size remained the largest contributor to overall survival, but marital status was among several other significant factors, such as age, race, gender, treatment style, and pathologic stage, that can provide insight into a patient’s likelihood of overall survival, as it does with several other cancers.

“Married patients had the best prognosis, followed by single patients, and the prognosis of separated patients was the worst,” write Lixiang Zhang and colleagues at the First Affiliated Hospital of Anhui Medical University, Hefei, China. “We speculate that this might be due to the fact that married patients had better financial conditions and emotional encouragement, while separated patients might be more likely to experience financial difficulties [and] emotional loss.”

The results were not necessarily surprising to Richard M. Peek, Jr., MD, director of the division of gastroenterology and a professor of medicine at Vanderbilt University Medical Center, who was not involved in the research.

“Marital status is a reflection of support systems, and a strong support system is a prognosticator for increased compliance with medical appointments and medical therapies,” Dr. Peek told this news organization. “It is something to consider when somebody is being treated for gastric cancer, because if they don’t have a strong support system – and marital status can be a proxy for that – then they may need more intensive follow-up and surveillance, for example, than somebody who does not have that support system.”
 

Exploring the marital status–cancer survival connection

Gastric cancer is the third leading cause of cancer deaths across the world, causing 780,000 deaths in 2018, the authors note. Yet it’s difficult to accurately predict the prognosis in patients who undergo treatment for early stage gastric cancer. Previous research has found marital status to be associated with survival in prostate, cervical, and rectal cancers.

Mark A. Lewis, MD, director of gastrointestinal oncology at Intermountain Healthcare Cancer Center, Utah, told this news organization that the connection between marital status and cancer outcomes has been described previously, including in an even larger analysis using the U.S. Surveillance, Epidemiology, and End Results (SEER) database from 2013. That study found that “unmarried patients are at significantly higher risk of presentation with metastatic cancer, undertreatment, and death resulting from their cancer.”

In this study, the researchers compared marital status and survival rates among 3,647 patients with early-stage gastric cancer, using data from the SEER database. The study only included patients with tumors in the lamina propria, mucosa, and submucosa and excluded those with distant metastasis or distant lymph node metastases, a second cancer, no data on chemotherapy received, or unknown survival time.

Because they were using a nomogram and building a new predictive nomogram that would include marital status, the researchers divided the patient population into a training set of 2,719 patients and a testing set of 928 patients. Using overall survival as the primary endpoint, the analysis included the variables of “age at diagnosis, race, gender, tumor location, histology, grade, stage_T and stage_N, surgery in the primary site, lymph node dissection, chemotherapy, radiation, tumor size, insurance, and marital status,” the authors report.

Among the study population, 53.7% were married, 17.3% were widowed, 14% were single and never married, 7.5% were divorced, 1.1% were separated, and the status of 6.4% was unknown. Age at diagnosis, race, gender, histology, tumor grade, stage T, stage N, surgery type, tumor size, and insurance status were all significantly different between the marital status subgroups.

Married patients had the best prognosis, with an average overall survival of 72 months, compared with an average 60 months in widowed persons, the group with the poorest overall survival. Overall survival was higher in married women (76 months) than in married men (69 months). The same pattern held for women (62 months) and men (52 months) who had been widowed.

“It is worthy to note that survival was significantly better in divorced female patients than in divorced male patients,” the authors report. “Survival was better in female patients than in male patients” across all marital groups.
 

What long-term relationships reveal

These findings do not mean that simply getting married changes one’s likelihood of survival, however. Rather, a long-term relationship is revealing about other aspects in a person’s life.

“I think it represents more stability in the supportive relationship that you need to really deal with a serious disease like cancer,” Dr. Peek said.

If a patient does not have a long-term partner, their care team can ask other questions to get a sense of what their support network is like, Dr. Peek added. “We want to know, does anybody else live in the house with them? Do they have adequate transportation? Can they make medical appointments? Do they have somebody who can help with the medical issues that are going to come up? Do they have family in the area?”

Cancer treatment requires a multidisciplinary approach, and having someone other than just the patient around to help bring together the different aspects of care from different care teams can make a difference in how the patient fares, Dr. Peek explained. Patients without a strong support system may need closer follow-up and other accommodations, he said.

Providers “may schedule their clinical appointments closer together if they don’t have a support system, or they may be able to reach out and offer transportation assistance and those kinds of things that somebody living alone may need,” Dr. Peek said. Outside resources may be a higher priority for those who lack a support system at home, he added.

Dr. Peek also noted other factors that may play a role in a patient’s survival that these researchers did not have the data to address, such as socioeconomic status, employment, alcohol use, smoking, and infection with Helicobacter pylori, the strongest known risk factor for gastric cancer.

A potentially relevant limitation of the study is that it probably has some selection bias, because the patients who were included probably had the means to have received an earlier diagnosis, said Dr. Lewis, who was not involved in the research.

“Furthermore, just in terms of the group sizes, the baseline characteristics section makes it clear that the preponderance of patients were married, lending that group more statistical weight,” Dr. Lewis said.

“Of the seven attributes in the nomogram, the impact of the marital status seems comparatively meager relative to conventional clinicopathology risk factors like T stage,” he added.

“All in all, I think this study reinforces our awareness that socioeconomic status and social determinants of health play a huge role in cancer outcomes, but it’s not entirely clear that’s modifiable just by getting married,” Dr. Lewis said. “There is a saying in oncology that ‘expensive liquor causes less cancer than cheap liquor,’ which is not negating the carcinogenicity of alcohol but rather identifying different outcomes by socioeconomic status.”

The research was funded by the Natural Science Foundation of Anhui Province. The authors report no relevant financial relationships. Dr. Peek reports no relevant financial relationships. Dr. Lewis reports receiving speaking fees for AstraZeneca/Daiichi Sankyo and having done educational videos for Astellas.

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

Marital status is a relevant risk factor in considering the prognosis of patients with gastric cancer, according to research published in the Journal of Investigative Medicine.

Tumor size remained the largest contributor to overall survival, but marital status was among several other significant factors, such as age, race, gender, treatment style, and pathologic stage, that can provide insight into a patient’s likelihood of overall survival, as it does with several other cancers.

“Married patients had the best prognosis, followed by single patients, and the prognosis of separated patients was the worst,” write Lixiang Zhang and colleagues at the First Affiliated Hospital of Anhui Medical University, Hefei, China. “We speculate that this might be due to the fact that married patients had better financial conditions and emotional encouragement, while separated patients might be more likely to experience financial difficulties [and] emotional loss.”

The results were not necessarily surprising to Richard M. Peek, Jr., MD, director of the division of gastroenterology and a professor of medicine at Vanderbilt University Medical Center, who was not involved in the research.

“Marital status is a reflection of support systems, and a strong support system is a prognosticator for increased compliance with medical appointments and medical therapies,” Dr. Peek told this news organization. “It is something to consider when somebody is being treated for gastric cancer, because if they don’t have a strong support system – and marital status can be a proxy for that – then they may need more intensive follow-up and surveillance, for example, than somebody who does not have that support system.”
 

Exploring the marital status–cancer survival connection

Gastric cancer is the third leading cause of cancer deaths across the world, causing 780,000 deaths in 2018, the authors note. Yet it’s difficult to accurately predict the prognosis in patients who undergo treatment for early stage gastric cancer. Previous research has found marital status to be associated with survival in prostate, cervical, and rectal cancers.

Mark A. Lewis, MD, director of gastrointestinal oncology at Intermountain Healthcare Cancer Center, Utah, told this news organization that the connection between marital status and cancer outcomes has been described previously, including in an even larger analysis using the U.S. Surveillance, Epidemiology, and End Results (SEER) database from 2013. That study found that “unmarried patients are at significantly higher risk of presentation with metastatic cancer, undertreatment, and death resulting from their cancer.”

In this study, the researchers compared marital status and survival rates among 3,647 patients with early-stage gastric cancer, using data from the SEER database. The study only included patients with tumors in the lamina propria, mucosa, and submucosa and excluded those with distant metastasis or distant lymph node metastases, a second cancer, no data on chemotherapy received, or unknown survival time.

Because they were using a nomogram and building a new predictive nomogram that would include marital status, the researchers divided the patient population into a training set of 2,719 patients and a testing set of 928 patients. Using overall survival as the primary endpoint, the analysis included the variables of “age at diagnosis, race, gender, tumor location, histology, grade, stage_T and stage_N, surgery in the primary site, lymph node dissection, chemotherapy, radiation, tumor size, insurance, and marital status,” the authors report.

Among the study population, 53.7% were married, 17.3% were widowed, 14% were single and never married, 7.5% were divorced, 1.1% were separated, and the status of 6.4% was unknown. Age at diagnosis, race, gender, histology, tumor grade, stage T, stage N, surgery type, tumor size, and insurance status were all significantly different between the marital status subgroups.

Married patients had the best prognosis, with an average overall survival of 72 months, compared with an average 60 months in widowed persons, the group with the poorest overall survival. Overall survival was higher in married women (76 months) than in married men (69 months). The same pattern held for women (62 months) and men (52 months) who had been widowed.

“It is worthy to note that survival was significantly better in divorced female patients than in divorced male patients,” the authors report. “Survival was better in female patients than in male patients” across all marital groups.
 

What long-term relationships reveal

These findings do not mean that simply getting married changes one’s likelihood of survival, however. Rather, a long-term relationship is revealing about other aspects in a person’s life.

“I think it represents more stability in the supportive relationship that you need to really deal with a serious disease like cancer,” Dr. Peek said.

If a patient does not have a long-term partner, their care team can ask other questions to get a sense of what their support network is like, Dr. Peek added. “We want to know, does anybody else live in the house with them? Do they have adequate transportation? Can they make medical appointments? Do they have somebody who can help with the medical issues that are going to come up? Do they have family in the area?”

Cancer treatment requires a multidisciplinary approach, and having someone other than just the patient around to help bring together the different aspects of care from different care teams can make a difference in how the patient fares, Dr. Peek explained. Patients without a strong support system may need closer follow-up and other accommodations, he said.

Providers “may schedule their clinical appointments closer together if they don’t have a support system, or they may be able to reach out and offer transportation assistance and those kinds of things that somebody living alone may need,” Dr. Peek said. Outside resources may be a higher priority for those who lack a support system at home, he added.

Dr. Peek also noted other factors that may play a role in a patient’s survival that these researchers did not have the data to address, such as socioeconomic status, employment, alcohol use, smoking, and infection with Helicobacter pylori, the strongest known risk factor for gastric cancer.

A potentially relevant limitation of the study is that it probably has some selection bias, because the patients who were included probably had the means to have received an earlier diagnosis, said Dr. Lewis, who was not involved in the research.

“Furthermore, just in terms of the group sizes, the baseline characteristics section makes it clear that the preponderance of patients were married, lending that group more statistical weight,” Dr. Lewis said.

“Of the seven attributes in the nomogram, the impact of the marital status seems comparatively meager relative to conventional clinicopathology risk factors like T stage,” he added.

“All in all, I think this study reinforces our awareness that socioeconomic status and social determinants of health play a huge role in cancer outcomes, but it’s not entirely clear that’s modifiable just by getting married,” Dr. Lewis said. “There is a saying in oncology that ‘expensive liquor causes less cancer than cheap liquor,’ which is not negating the carcinogenicity of alcohol but rather identifying different outcomes by socioeconomic status.”

The research was funded by the Natural Science Foundation of Anhui Province. The authors report no relevant financial relationships. Dr. Peek reports no relevant financial relationships. Dr. Lewis reports receiving speaking fees for AstraZeneca/Daiichi Sankyo and having done educational videos for Astellas.

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

Adults younger than 55 years were least likely to get screened for colorectal cancer over the past 2 decades, particularly if they were Hispanic or Asian or had a low income, lower education level, or no health insurance, according to a new study published online in Cancer Epidemiology, Biomarkers & Prevention.

The findings have raised concerns that disparities in screening rates will be even greater in adults aged 45-49 years, prompting the need for increased awareness and outreach to ensure that underserved groups have access to screenings.

“Differences in prevalence of screening by race and ethnicity, educational attainment, household income, and health insurance were most pronounced for those ages 50-54 years, whereas older adults experienced larger increases in prevalence across these groups,” wrote Po-Hong Liu, MD, MPH, a clinical investigator at Harvard University, Boston, and his colleagues. “The persistent and worsening disparities we observed in adults 50-54 years may extend to those ages 45-49 as they become eligible for screening.”

The U.S. Preventive Services Task Force shifted their recommendation for colorectal cancer screening in May 2021 to 5 years earlier, advising people to start screenings at 45 instead of 50, which aligns with the recommendations the American Cancer Society made 3 years earlier.

Both organizations made the change because of increasing rates of colorectal cancer in adults under age 50 and research indicating that beginning screenings at age 45 results in fewer cases, fewer deaths, and more life years gained.

“Across all age groups, colorectal cancer screening participation remains below national goals, and the benefits of screening are not equally realized across populations,” senior author Caitlin Murphy, PhD, MPH, associate professor, UTHealth School of Public Health, Houston, said in a prepared statement. “Extra care must be taken to ensure that expanding screening to younger ages does not negatively impact efforts to eliminate disparities in colorectal screening and outcomes nor jeopardize efforts to increase screening initiation among older adults who remain unscreened.”
 

Data analyzed from 8 years over 2 decades

The researchers analyzed data from the CDC’s cross-sectional National Health Interview Survey during 8 years over the past 2 decades: 2000, 2003, 2005, 2008, 2010, 2013, 2015, and 2018.

The number of participants each year ranged from a low of 21,781 in 2008 to a high of 34,557 in 2013. After excluding participants with a history of colorectal cancer or missing information on screenings, the total population sample included 80,220 participants 50-75 years old.

The researchers considered a person as having been screened if they received at least one recommended screening test within the year covered by the survey, regardless of why they underwent the test.

Recommended tests included sigmoidoscopy, colonoscopy, and stool-based tests for all survey years. In addition, the surveys for 2010, 2015, and 2018 included CT colonography, and the 2018 survey included FIT-DNA.
 

Screening across population groups

Colorectal cancer screening rates have doubled in the past 2 decades, from 36.7% in 2000 to 66.1% in 2018.

Rates are considerably lower, however, for several key groups, including the youngest group. Less than half (47.6%) of those aged 50-54 years received screenings in 2018, though this was still a nearly 20-point improvement over the 28.2% in this age group who were screened in 2000.

Separate from age, several other groups continue to have low screening rates in general, including Hispanics (56.5%, up from 25.9% in 2000), Asians (57.1%, up from 22.6% in 2000), those who have not received a high school degree (53.6%, up from 26.8% in 2000), and those from low income families (56.6%, up from 30.2% in 2000).

The group with the greatest need for more outreach and screenings are people without insurance, only 39.7% of whom were screened in 2018, a modest increase from 30.2% in 2000.

The biggest increase in screenings over time occurred in those aged 70-75 years, from 46.4% in 2000 to 78% in 2018 overall.

Racial/ethnic, economic, education, and insurance-based disparities were particularly evident the younger people were, including in terms of progress made over time.

For example, screenings of non-Hispanic White people aged 50-54 years improved 21 points (30.3% to 51%) between 2000 and 2018, compared with 19 points in Hispanics (16.7% to 35.5%) and 15 points in Asians (17.3% to 32.3%). Fortunately, Black Americans made even greater strides than White Americans with a 27-point increase during that time (23.4% to 50%). 

Similarly, income correlated with expansion in screening rates for 50- to 54-year-olds: Those earning at least 400% over the federal poverty line improved 20 points (from 33.5% to 53.8%), compared with a 16-point improvement in those earning less than 200% above the poverty line (from 19.3% to 35%).

Those with private insurance likewise improved 21 points (from 30.7% to 51.7%), while those in this age group without insurance declined, with just 21.2% getting screened in 2018, compared with 28.2% in 2000. Those on public insurance saw a 15-point improvement, from 27.8% in 2000 to 43.1% in 2018.

“The individual and societal burden of colorectal cancer is especially great among younger adults,” the authors wrote.

The reasons for the much lower prevalence of screening in those under 55, the authors suggested, is likely due to less concern about colorectal cancer, less access to medical care (including being underinsured or uninsured), and the barriers created by competing priorities, such as work schedules, family responsibilities, and caregiving. The latter may be particularly true in underserved populations, the authors noted.

“Screening programs must consider the barriers unique to younger adults, ensuring the benefits of screening are equally realized by all population groups,” the authors concluded.

The research was funded by the National Institutes of Health and the Cancer Prevention and Research Institute of Texas. One author reported grants from Epigenomics and Freenome and personal fees from Guardant Health. Another author reported personal fees from Freenome, and a third author reported personal fees from Exact Sciences. No other authors had industry disclosures.

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

Adults younger than 55 years were least likely to get screened for colorectal cancer over the past 2 decades, particularly if they were Hispanic or Asian or had a low income, lower education level, or no health insurance, according to a new study published online in Cancer Epidemiology, Biomarkers & Prevention.

The findings have raised concerns that disparities in screening rates will be even greater in adults aged 45-49 years, prompting the need for increased awareness and outreach to ensure that underserved groups have access to screenings.

“Differences in prevalence of screening by race and ethnicity, educational attainment, household income, and health insurance were most pronounced for those ages 50-54 years, whereas older adults experienced larger increases in prevalence across these groups,” wrote Po-Hong Liu, MD, MPH, a clinical investigator at Harvard University, Boston, and his colleagues. “The persistent and worsening disparities we observed in adults 50-54 years may extend to those ages 45-49 as they become eligible for screening.”

The U.S. Preventive Services Task Force shifted their recommendation for colorectal cancer screening in May 2021 to 5 years earlier, advising people to start screenings at 45 instead of 50, which aligns with the recommendations the American Cancer Society made 3 years earlier.

Both organizations made the change because of increasing rates of colorectal cancer in adults under age 50 and research indicating that beginning screenings at age 45 results in fewer cases, fewer deaths, and more life years gained.

“Across all age groups, colorectal cancer screening participation remains below national goals, and the benefits of screening are not equally realized across populations,” senior author Caitlin Murphy, PhD, MPH, associate professor, UTHealth School of Public Health, Houston, said in a prepared statement. “Extra care must be taken to ensure that expanding screening to younger ages does not negatively impact efforts to eliminate disparities in colorectal screening and outcomes nor jeopardize efforts to increase screening initiation among older adults who remain unscreened.”
 

Data analyzed from 8 years over 2 decades

The researchers analyzed data from the CDC’s cross-sectional National Health Interview Survey during 8 years over the past 2 decades: 2000, 2003, 2005, 2008, 2010, 2013, 2015, and 2018.

The number of participants each year ranged from a low of 21,781 in 2008 to a high of 34,557 in 2013. After excluding participants with a history of colorectal cancer or missing information on screenings, the total population sample included 80,220 participants 50-75 years old.

The researchers considered a person as having been screened if they received at least one recommended screening test within the year covered by the survey, regardless of why they underwent the test.

Recommended tests included sigmoidoscopy, colonoscopy, and stool-based tests for all survey years. In addition, the surveys for 2010, 2015, and 2018 included CT colonography, and the 2018 survey included FIT-DNA.
 

Screening across population groups

Colorectal cancer screening rates have doubled in the past 2 decades, from 36.7% in 2000 to 66.1% in 2018.

Rates are considerably lower, however, for several key groups, including the youngest group. Less than half (47.6%) of those aged 50-54 years received screenings in 2018, though this was still a nearly 20-point improvement over the 28.2% in this age group who were screened in 2000.

Separate from age, several other groups continue to have low screening rates in general, including Hispanics (56.5%, up from 25.9% in 2000), Asians (57.1%, up from 22.6% in 2000), those who have not received a high school degree (53.6%, up from 26.8% in 2000), and those from low income families (56.6%, up from 30.2% in 2000).

The group with the greatest need for more outreach and screenings are people without insurance, only 39.7% of whom were screened in 2018, a modest increase from 30.2% in 2000.

The biggest increase in screenings over time occurred in those aged 70-75 years, from 46.4% in 2000 to 78% in 2018 overall.

Racial/ethnic, economic, education, and insurance-based disparities were particularly evident the younger people were, including in terms of progress made over time.

For example, screenings of non-Hispanic White people aged 50-54 years improved 21 points (30.3% to 51%) between 2000 and 2018, compared with 19 points in Hispanics (16.7% to 35.5%) and 15 points in Asians (17.3% to 32.3%). Fortunately, Black Americans made even greater strides than White Americans with a 27-point increase during that time (23.4% to 50%). 

Similarly, income correlated with expansion in screening rates for 50- to 54-year-olds: Those earning at least 400% over the federal poverty line improved 20 points (from 33.5% to 53.8%), compared with a 16-point improvement in those earning less than 200% above the poverty line (from 19.3% to 35%).

Those with private insurance likewise improved 21 points (from 30.7% to 51.7%), while those in this age group without insurance declined, with just 21.2% getting screened in 2018, compared with 28.2% in 2000. Those on public insurance saw a 15-point improvement, from 27.8% in 2000 to 43.1% in 2018.

“The individual and societal burden of colorectal cancer is especially great among younger adults,” the authors wrote.

The reasons for the much lower prevalence of screening in those under 55, the authors suggested, is likely due to less concern about colorectal cancer, less access to medical care (including being underinsured or uninsured), and the barriers created by competing priorities, such as work schedules, family responsibilities, and caregiving. The latter may be particularly true in underserved populations, the authors noted.

“Screening programs must consider the barriers unique to younger adults, ensuring the benefits of screening are equally realized by all population groups,” the authors concluded.

The research was funded by the National Institutes of Health and the Cancer Prevention and Research Institute of Texas. One author reported grants from Epigenomics and Freenome and personal fees from Guardant Health. Another author reported personal fees from Freenome, and a third author reported personal fees from Exact Sciences. No other authors had industry disclosures.

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

Adults younger than 55 years were least likely to get screened for colorectal cancer over the past 2 decades, particularly if they were Hispanic or Asian or had a low income, lower education level, or no health insurance, according to a new study published online in Cancer Epidemiology, Biomarkers & Prevention.

The findings have raised concerns that disparities in screening rates will be even greater in adults aged 45-49 years, prompting the need for increased awareness and outreach to ensure that underserved groups have access to screenings.

“Differences in prevalence of screening by race and ethnicity, educational attainment, household income, and health insurance were most pronounced for those ages 50-54 years, whereas older adults experienced larger increases in prevalence across these groups,” wrote Po-Hong Liu, MD, MPH, a clinical investigator at Harvard University, Boston, and his colleagues. “The persistent and worsening disparities we observed in adults 50-54 years may extend to those ages 45-49 as they become eligible for screening.”

The U.S. Preventive Services Task Force shifted their recommendation for colorectal cancer screening in May 2021 to 5 years earlier, advising people to start screenings at 45 instead of 50, which aligns with the recommendations the American Cancer Society made 3 years earlier.

Both organizations made the change because of increasing rates of colorectal cancer in adults under age 50 and research indicating that beginning screenings at age 45 results in fewer cases, fewer deaths, and more life years gained.

“Across all age groups, colorectal cancer screening participation remains below national goals, and the benefits of screening are not equally realized across populations,” senior author Caitlin Murphy, PhD, MPH, associate professor, UTHealth School of Public Health, Houston, said in a prepared statement. “Extra care must be taken to ensure that expanding screening to younger ages does not negatively impact efforts to eliminate disparities in colorectal screening and outcomes nor jeopardize efforts to increase screening initiation among older adults who remain unscreened.”
 

Data analyzed from 8 years over 2 decades

The researchers analyzed data from the CDC’s cross-sectional National Health Interview Survey during 8 years over the past 2 decades: 2000, 2003, 2005, 2008, 2010, 2013, 2015, and 2018.

The number of participants each year ranged from a low of 21,781 in 2008 to a high of 34,557 in 2013. After excluding participants with a history of colorectal cancer or missing information on screenings, the total population sample included 80,220 participants 50-75 years old.

The researchers considered a person as having been screened if they received at least one recommended screening test within the year covered by the survey, regardless of why they underwent the test.

Recommended tests included sigmoidoscopy, colonoscopy, and stool-based tests for all survey years. In addition, the surveys for 2010, 2015, and 2018 included CT colonography, and the 2018 survey included FIT-DNA.
 

Screening across population groups

Colorectal cancer screening rates have doubled in the past 2 decades, from 36.7% in 2000 to 66.1% in 2018.

Rates are considerably lower, however, for several key groups, including the youngest group. Less than half (47.6%) of those aged 50-54 years received screenings in 2018, though this was still a nearly 20-point improvement over the 28.2% in this age group who were screened in 2000.

Separate from age, several other groups continue to have low screening rates in general, including Hispanics (56.5%, up from 25.9% in 2000), Asians (57.1%, up from 22.6% in 2000), those who have not received a high school degree (53.6%, up from 26.8% in 2000), and those from low income families (56.6%, up from 30.2% in 2000).

The group with the greatest need for more outreach and screenings are people without insurance, only 39.7% of whom were screened in 2018, a modest increase from 30.2% in 2000.

The biggest increase in screenings over time occurred in those aged 70-75 years, from 46.4% in 2000 to 78% in 2018 overall.

Racial/ethnic, economic, education, and insurance-based disparities were particularly evident the younger people were, including in terms of progress made over time.

For example, screenings of non-Hispanic White people aged 50-54 years improved 21 points (30.3% to 51%) between 2000 and 2018, compared with 19 points in Hispanics (16.7% to 35.5%) and 15 points in Asians (17.3% to 32.3%). Fortunately, Black Americans made even greater strides than White Americans with a 27-point increase during that time (23.4% to 50%). 

Similarly, income correlated with expansion in screening rates for 50- to 54-year-olds: Those earning at least 400% over the federal poverty line improved 20 points (from 33.5% to 53.8%), compared with a 16-point improvement in those earning less than 200% above the poverty line (from 19.3% to 35%).

Those with private insurance likewise improved 21 points (from 30.7% to 51.7%), while those in this age group without insurance declined, with just 21.2% getting screened in 2018, compared with 28.2% in 2000. Those on public insurance saw a 15-point improvement, from 27.8% in 2000 to 43.1% in 2018.

“The individual and societal burden of colorectal cancer is especially great among younger adults,” the authors wrote.

The reasons for the much lower prevalence of screening in those under 55, the authors suggested, is likely due to less concern about colorectal cancer, less access to medical care (including being underinsured or uninsured), and the barriers created by competing priorities, such as work schedules, family responsibilities, and caregiving. The latter may be particularly true in underserved populations, the authors noted.

“Screening programs must consider the barriers unique to younger adults, ensuring the benefits of screening are equally realized by all population groups,” the authors concluded.

The research was funded by the National Institutes of Health and the Cancer Prevention and Research Institute of Texas. One author reported grants from Epigenomics and Freenome and personal fees from Guardant Health. Another author reported personal fees from Freenome, and a third author reported personal fees from Exact Sciences. No other authors had industry disclosures.

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

Kami, a mother of one daughter in central Texas, lost three pregnancies in 2008. The third one nearly killed her.

The embryo became implanted in one of the fallopian tubes connecting her ovaries to her uterus. Because fallopian tubes can’t stretch to accommodate a fetus, patients must undergo surgery to remove the embryo before the tube ruptures. Failure to do so can result in internal bleeding and death.

But when Kami – who did not want to use her last name to avoid harassment – underwent an ultrasound to start the process of extracting the embryo, her doctor miscalculated how far along in the pregnancy she was and told her to come back in a few weeks.

She eventually did return, but only after passing out in the bathtub and waking up in a pool of her own blood. The tube had ruptured, and to remove it, emergency surgery was necessary.

Stories such as Kami’s could become more common in the aftermath of the U.S. Supreme Court’s decision to overturn Roe v. Wade, the 1973 case that created a right to an abortion.

Experts fear that antiabortion laws that take effect in the United States following the court’s decision will lead to a medical and legal limbo for thousands of people like Kami – people with uncommon reproductive conditions whose treatments involve the termination of pregnancies or the destruction of embryos.
 

Vague exceptions prompt concerns

According to the Guttmacher Institute, a nonprofit group for reproductive health, 13 states currently have trigger laws on the books that make abortion illegal in the absence of Roe. Nine other states have laws that would outlaw or severely restrict abortion without a federal right to the procedure.

Each of these laws carves out exceptions that allow the termination of a pregnancy to prevent the death of the pregnant individual. But the language of the provisions is not always precise in describing what those exceptions mean in practice, according to Elizabeth Nash, the principal policy associate for state issues at the Guttmacher Institute.

“These exceptions are designed to be extraordinarily narrow. These aren’t really designed to be usable exceptions,” Ms. Nash said. “There’s so much misinformation about abortion that there are probably legislators out there who think that it’s never needed to save a life.”
 

Tubal pregnancies

One of the best examples of a pregnancy termination that’s necessary to avoid death is in the case of an ectopic pregnancy such as Kami experienced. Without treatment to end the pregnancy, the embryo will eventually grow so large that the tube ruptures, causing massive bleeding that can kill the mother.

Most state laws regarding abortion exclude treatment of ectopic pregnancy, according to Ms. Nash. But, “if the state does not exclude ectopic pregnancy from all the regulations, then people might not be able to get the care that they need when they need it.”

The current abortion law in Texas, for example, prohibits ending a pregnancy after 6 weeks, or after cardiac activity becomes present. Cardiac activity can be present in cases of ectopic pregnancies, which account for between 1% and 2% of all pregnancies and are the leading cause of maternal deaths in the first trimester. And treatment definitely ends the life of the embryo or fetus in the fallopian tube, said Lisa Harris, MD, PhD, an ob.gyn. and medical ethicist at the University of Michigan, Ann Arbor.

Dr. Harris said she has never doubted that an ectopic pregnancy cannot possibly result in a live birth. But she recalled an encounter with another clinician on a surgical team for an ectopic pregnancy who said: “So you’re going to take it out of the tube and put it in the uterus, right?”

“It was a startling moment,” Dr. Harris recalled. She regarded the procedure as a “lifesaving, obvious surgery,” but her colleague, whose suggestion was a medical impossibility since the window of implantation is very brief after fertilization, viewed it “as an abortion, as killing an embryo or fetus.”

Dr. Harris said she isn’t concerned that physicians would stop treating ectopic pregnancies in a post-Roe world. Rather, she worries about two other possibilities: an overzealous prosecutor might not believe it was an ectopic pregnancy and press charges; or laws will cause physicians to second guess their clinical decisions for patients.

“What it means, in the middle of the night, when someone comes in with a 10-week ectopic pregnancy with a heartbeat, is the doctor may hesitate,” Dr. Harris said. Despite knowing the appropriate treatment, the doctor may want to speak with a lawyer or ethicist first to ensure they are covered legally. “And as that process unfolds, which could take hours or days, the person might have a complication.” s

Not treating an ectopic pregnancy would be malpractice, but “some doctors may not provide the standard of care that they would have ordinarily provided because they don’t want to risk breaking the law,” she said.

Even more ambiguous are cornual ectopic pregnancies, in which the implantation occurs at the junction of a fallopian tube and the uterus. These pregnancies, which make up 2%-4% of all tubal pregnancies, are immediately adjacent to the uterus. If an abortion is defined as the termination of an embryo or fetus in the womb, how such a legal definition would apply to these pregnancies is unclear.

An ob.gyn. wouldn’t regard ending an ectopic pregnancy as an abortion, but “this is not about logic or clinical meaning,” Dr. Harris said. “This is people outside of medicine making determinations that all pregnancies must continue, and when you think of a ban that way, you could see why a doctor would be frightened to end a pregnancy, whether it might be viable in the future or not.”

That’s true even if the pregnancy is located fully in the uterus. Dr. Harris described a pregnant patient she saw who had traveled from Texas to Michigan with a fetus that had a lethal defect.

The fetus had “an anomaly where the lungs couldn’t develop, where there were no kidneys. There was no chance this baby could be born and live. Her doctors were very clear that there will never be a baby that [she could] take home at the end of this pregnancy, yet they would not end her pregnancy because that would be an abortion,” Dr. Harris said.

Texas law “doesn’t make any allowances for whether a pregnancy will ever actually result in a baby or not,” Dr. Harris said. “The law, in effect, just says all pregnancies must continue.”
 

Selective reduction

How abortion laws in different states might affect selective reduction, which is used in some pregnancies to reduce the total number of fetuses a person is carrying, is even more ambiguous. The goal of selective reduction is to decrease health risks to the pregnant individual and increase the likelihood of survival for the remaining fetuses. Current Texas law prohibits these procedures.

Someone pregnant with quintuplets, for example, might seek selection reduction to reduce the pregnancy outcome to triplets or twins. A related procedure, selective termination, is used to terminate the life of a fetus with abnormalities while the pregnancy of the fetus’ in utero siblings continues.

The advent of assisted reproduction methods, such as in vitro fertilization (IVF), greatly increased the incidence of higher-order multiples, those with three or more fetuses. The first IVF baby was born in 1978. By 1998, the rate of higher-order multiple births was 1.9 per 1,000 births, five times the figure in 1980. The rate has since decreased by nearly half, to 1 per 1,000 births, but with 3.75 million live births a year, that’s still a lot of pregnancies with higher-order multiples.

The American College of Obstetricians and Gynecologists does not provide explicit guidance on when selective reduction is warranted, but its committee opinion on multifetal pregnancy reduction provides an ethical framework for providers to use when counseling people with pregnancies of three or more fetuses. How would various state laws that outlaw abortion affect these decisions? No one knows.

“Selective reduction ends the life of a fetus or embryo, but it doesn’t end the pregnancy,” Dr. Harris said. “So, if the pregnancy continues but it kills an embryo or fetus, is that an abortion?”
 

‘The question of the hour’

Dr. Harris and other doctors are haunted by potential medical cases in which continuing a pregnancy may result in the death of the person carrying the fetus but in which such death may not be so imminent that the law would allow immediate termination of the pregnancy.

Michael Northrup, MD, an intensive care pediatrician in Winston-Salem, N.C., recalled a particularly harrowing case that illustrates the peril in deciding when someone’s life is “enough” in danger to qualify as an exception to abortion bans.

The 14-year-old girl had severe lupus and kidney failure that required treatment with methotrexate and immediate dialysis to replace her electrolytes. A standard pretreatment pregnancy test revealed that she had been carrying a child for at least 10 weeks. Her pregnancy presented two problems. Methotrexate is so severely toxic that it’s sometimes used to end pregnancies. Even at low doses, fetuses that survive usually have severe deformities. In addition, dialysis requires administration of a blood thinner. If the teen miscarried while taking a blood thinner during dialysis, she risked bleeding to death.

Treatment could be delayed until week 24 of pregnancy, at which time delivery could be attempted, but the patient likely wouldn’t have any kidney function left by then. In addition, at 24 weeks, it was unlikely that the baby would survive anyway.

Dr. Northrup said that, had she chosen that route, “I’m not sure she would have made it. This was a religious family, people who very much were believers. They had their head of church come in, who fairly quickly determined that the best thing for her health was to terminate this pregnancy immediately and get the treatment she needed for her body.”

Would such a situation qualify for an emergency termination? The girl wasn’t going to die within 24 or 48 hours, but it may not have been possible to pinpoint the time of death within a day or 2.

“The family was sad, but they made that choice, and I wonder, would we have to justify that with these new laws?” Dr. Northrup said. “You definitely worry, being in the hot seat, ‘Does this count enough? Is she close enough to death?’ ”

The same question comes up when someone’s water breaks early in the second trimester. Since a live-birth delivery would be highly unlikely, given the age of the fetus, the standard of care is to offer to terminate the pregnancy to avoid a serious infection, Dr. Harris said. But if the infection hasn’t yet developed – even if it’s likely to develop soon – doctors in a state that outlaws abortion would not be able to offer termination. But as providers wait for an infection to develop, the person’s risk of dying from infection rapidly increases.

“How likely does someone need to be to die for it to count to get a life-preserving abortion?” Dr. Harris asked. “That, I think, is the question of the hour.”

Different institutions may decide to determine their own risk thresholds. One hospital, for example, may decide that any health threat that is associated with a 10% risk of death qualifies for a lifesaving abortion. But for many people, a 1 in 10 chance of dying is quite high.

“Who gets to decide what’s meaningful?” Dr. Harris asked, especially if the patient is already a parent of living children and doesn’t want to take any risk at all of orphaning them for a pregnancy with severe complications.

“The point is that this is way more complicated than anybody really knows, way more complicated than any legislator or justice could possibly know, and it creates all kinds of complicated ambiguities, some of which could result in harm to women,” she said. “I’ve been a doctor almost 30 years, and every week, sometimes every day, I’m humbled by how complicated pregnancy is and how complicated people’s bodies and life situations are.”

That’s what makes it so dangerous for policymakers to “insert themselves into medical practice,” Ms. Nash said. She worries about the legal ramifications of overturning Roe, such as prosecution of people who illegally undergo an abortion or of physicians who perform a procedure that a judge deems to be in violation of abortion law.

“There are already local prosecutors who have misused the law to go after people who have managed their own abortions,” Ms. Nash said. “Criminal abortion law, fetal homicide, child neglect, practicing medicine without a license – these are things people have actually been arrested and convicted under.”

Some laws may target the person seeking an abortion, whereas others may target clinicians providing abortions, or even people who simply help someone obtain an abortion, as the Texas law does. In Dr. Harris’s own state of Michigan, a group of Republican lawmakers recently introduced a bill that would imprison abortion providers for up to 10 years and anyone creating or distributing abortion medication for up to 20 years.

Michigan Gov. Gretchen Whitmer, a Democrat who called the proposed legislation “disturbing” and “infuriating,” would almost certainly veto the bill, but it’s just one of dozens already filed or that are expected to be filed across the United States.

The antiabortion organization National Right to Life has published a “post-Roe model abortion law” for states to adopt. The model includes an exemption for abortions that, “based on reasonable medical judgment, [were] necessary to prevent the death of the pregnant woman” – but, again, it does not clarify what that means in practice.
 

Lectures from strangers

Four years after nearly dying, Kami gave birth to a healthy girl following an uncomplicated pregnancy. But her journey to having more children presented more challenges.

Two years after the birth of her child, she had another ectopic pregnancy. Her doctor sent her prescriptions for medication that would end this pregnancy, but a pharmacist refused to fill the prescription.

“Do you know these are very serious medications?” the pharmacist asked her. She did – she had taken them once before for another ectopic pregnancy. She was with her daughter, feeling devastated about losing yet another desired pregnancy. She simply wanted to get the medication and go home.

“‘So you’re trying to have a cheap abortion,’ he said, and 30 heads turned and looked at me. The whole pharmacy heard,” Kami said.

She told the pharmacist that she’d miscarried. She said he responded with: “So you have a dead baby in your body.”

Even after her doctor called to insist on filling the order, the man refused to fill it.

Kami left without the prescription, and her doctor performed a surgical dilation and curettage to remove the embryo from her fallopian tube for no fee.

Kami later tried again to have more children. She experienced another ruptured tube that she said nearly killed her.

“There was such a sense of pain knowing that I couldn’t have any more kids, but also the relief of knowing that I don’t have to go through this again,” Kami said. Now, however, with the Supreme Court having overturned Roe v. Wade, she has a new worry: “That my daughter will not have the same rights and access to health care that I did.”

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

Kami, a mother of one daughter in central Texas, lost three pregnancies in 2008. The third one nearly killed her.

The embryo became implanted in one of the fallopian tubes connecting her ovaries to her uterus. Because fallopian tubes can’t stretch to accommodate a fetus, patients must undergo surgery to remove the embryo before the tube ruptures. Failure to do so can result in internal bleeding and death.

But when Kami – who did not want to use her last name to avoid harassment – underwent an ultrasound to start the process of extracting the embryo, her doctor miscalculated how far along in the pregnancy she was and told her to come back in a few weeks.

She eventually did return, but only after passing out in the bathtub and waking up in a pool of her own blood. The tube had ruptured, and to remove it, emergency surgery was necessary.

Stories such as Kami’s could become more common in the aftermath of the U.S. Supreme Court’s decision to overturn Roe v. Wade, the 1973 case that created a right to an abortion.

Experts fear that antiabortion laws that take effect in the United States following the court’s decision will lead to a medical and legal limbo for thousands of people like Kami – people with uncommon reproductive conditions whose treatments involve the termination of pregnancies or the destruction of embryos.
 

Vague exceptions prompt concerns

According to the Guttmacher Institute, a nonprofit group for reproductive health, 13 states currently have trigger laws on the books that make abortion illegal in the absence of Roe. Nine other states have laws that would outlaw or severely restrict abortion without a federal right to the procedure.

Each of these laws carves out exceptions that allow the termination of a pregnancy to prevent the death of the pregnant individual. But the language of the provisions is not always precise in describing what those exceptions mean in practice, according to Elizabeth Nash, the principal policy associate for state issues at the Guttmacher Institute.

“These exceptions are designed to be extraordinarily narrow. These aren’t really designed to be usable exceptions,” Ms. Nash said. “There’s so much misinformation about abortion that there are probably legislators out there who think that it’s never needed to save a life.”
 

Tubal pregnancies

One of the best examples of a pregnancy termination that’s necessary to avoid death is in the case of an ectopic pregnancy such as Kami experienced. Without treatment to end the pregnancy, the embryo will eventually grow so large that the tube ruptures, causing massive bleeding that can kill the mother.

Most state laws regarding abortion exclude treatment of ectopic pregnancy, according to Ms. Nash. But, “if the state does not exclude ectopic pregnancy from all the regulations, then people might not be able to get the care that they need when they need it.”

The current abortion law in Texas, for example, prohibits ending a pregnancy after 6 weeks, or after cardiac activity becomes present. Cardiac activity can be present in cases of ectopic pregnancies, which account for between 1% and 2% of all pregnancies and are the leading cause of maternal deaths in the first trimester. And treatment definitely ends the life of the embryo or fetus in the fallopian tube, said Lisa Harris, MD, PhD, an ob.gyn. and medical ethicist at the University of Michigan, Ann Arbor.

Dr. Harris said she has never doubted that an ectopic pregnancy cannot possibly result in a live birth. But she recalled an encounter with another clinician on a surgical team for an ectopic pregnancy who said: “So you’re going to take it out of the tube and put it in the uterus, right?”

“It was a startling moment,” Dr. Harris recalled. She regarded the procedure as a “lifesaving, obvious surgery,” but her colleague, whose suggestion was a medical impossibility since the window of implantation is very brief after fertilization, viewed it “as an abortion, as killing an embryo or fetus.”

Dr. Harris said she isn’t concerned that physicians would stop treating ectopic pregnancies in a post-Roe world. Rather, she worries about two other possibilities: an overzealous prosecutor might not believe it was an ectopic pregnancy and press charges; or laws will cause physicians to second guess their clinical decisions for patients.

“What it means, in the middle of the night, when someone comes in with a 10-week ectopic pregnancy with a heartbeat, is the doctor may hesitate,” Dr. Harris said. Despite knowing the appropriate treatment, the doctor may want to speak with a lawyer or ethicist first to ensure they are covered legally. “And as that process unfolds, which could take hours or days, the person might have a complication.” s

Not treating an ectopic pregnancy would be malpractice, but “some doctors may not provide the standard of care that they would have ordinarily provided because they don’t want to risk breaking the law,” she said.

Even more ambiguous are cornual ectopic pregnancies, in which the implantation occurs at the junction of a fallopian tube and the uterus. These pregnancies, which make up 2%-4% of all tubal pregnancies, are immediately adjacent to the uterus. If an abortion is defined as the termination of an embryo or fetus in the womb, how such a legal definition would apply to these pregnancies is unclear.

An ob.gyn. wouldn’t regard ending an ectopic pregnancy as an abortion, but “this is not about logic or clinical meaning,” Dr. Harris said. “This is people outside of medicine making determinations that all pregnancies must continue, and when you think of a ban that way, you could see why a doctor would be frightened to end a pregnancy, whether it might be viable in the future or not.”

That’s true even if the pregnancy is located fully in the uterus. Dr. Harris described a pregnant patient she saw who had traveled from Texas to Michigan with a fetus that had a lethal defect.

The fetus had “an anomaly where the lungs couldn’t develop, where there were no kidneys. There was no chance this baby could be born and live. Her doctors were very clear that there will never be a baby that [she could] take home at the end of this pregnancy, yet they would not end her pregnancy because that would be an abortion,” Dr. Harris said.

Texas law “doesn’t make any allowances for whether a pregnancy will ever actually result in a baby or not,” Dr. Harris said. “The law, in effect, just says all pregnancies must continue.”
 

Selective reduction

How abortion laws in different states might affect selective reduction, which is used in some pregnancies to reduce the total number of fetuses a person is carrying, is even more ambiguous. The goal of selective reduction is to decrease health risks to the pregnant individual and increase the likelihood of survival for the remaining fetuses. Current Texas law prohibits these procedures.

Someone pregnant with quintuplets, for example, might seek selection reduction to reduce the pregnancy outcome to triplets or twins. A related procedure, selective termination, is used to terminate the life of a fetus with abnormalities while the pregnancy of the fetus’ in utero siblings continues.

The advent of assisted reproduction methods, such as in vitro fertilization (IVF), greatly increased the incidence of higher-order multiples, those with three or more fetuses. The first IVF baby was born in 1978. By 1998, the rate of higher-order multiple births was 1.9 per 1,000 births, five times the figure in 1980. The rate has since decreased by nearly half, to 1 per 1,000 births, but with 3.75 million live births a year, that’s still a lot of pregnancies with higher-order multiples.

The American College of Obstetricians and Gynecologists does not provide explicit guidance on when selective reduction is warranted, but its committee opinion on multifetal pregnancy reduction provides an ethical framework for providers to use when counseling people with pregnancies of three or more fetuses. How would various state laws that outlaw abortion affect these decisions? No one knows.

“Selective reduction ends the life of a fetus or embryo, but it doesn’t end the pregnancy,” Dr. Harris said. “So, if the pregnancy continues but it kills an embryo or fetus, is that an abortion?”
 

‘The question of the hour’

Dr. Harris and other doctors are haunted by potential medical cases in which continuing a pregnancy may result in the death of the person carrying the fetus but in which such death may not be so imminent that the law would allow immediate termination of the pregnancy.

Michael Northrup, MD, an intensive care pediatrician in Winston-Salem, N.C., recalled a particularly harrowing case that illustrates the peril in deciding when someone’s life is “enough” in danger to qualify as an exception to abortion bans.

The 14-year-old girl had severe lupus and kidney failure that required treatment with methotrexate and immediate dialysis to replace her electrolytes. A standard pretreatment pregnancy test revealed that she had been carrying a child for at least 10 weeks. Her pregnancy presented two problems. Methotrexate is so severely toxic that it’s sometimes used to end pregnancies. Even at low doses, fetuses that survive usually have severe deformities. In addition, dialysis requires administration of a blood thinner. If the teen miscarried while taking a blood thinner during dialysis, she risked bleeding to death.

Treatment could be delayed until week 24 of pregnancy, at which time delivery could be attempted, but the patient likely wouldn’t have any kidney function left by then. In addition, at 24 weeks, it was unlikely that the baby would survive anyway.

Dr. Northrup said that, had she chosen that route, “I’m not sure she would have made it. This was a religious family, people who very much were believers. They had their head of church come in, who fairly quickly determined that the best thing for her health was to terminate this pregnancy immediately and get the treatment she needed for her body.”

Would such a situation qualify for an emergency termination? The girl wasn’t going to die within 24 or 48 hours, but it may not have been possible to pinpoint the time of death within a day or 2.

“The family was sad, but they made that choice, and I wonder, would we have to justify that with these new laws?” Dr. Northrup said. “You definitely worry, being in the hot seat, ‘Does this count enough? Is she close enough to death?’ ”

The same question comes up when someone’s water breaks early in the second trimester. Since a live-birth delivery would be highly unlikely, given the age of the fetus, the standard of care is to offer to terminate the pregnancy to avoid a serious infection, Dr. Harris said. But if the infection hasn’t yet developed – even if it’s likely to develop soon – doctors in a state that outlaws abortion would not be able to offer termination. But as providers wait for an infection to develop, the person’s risk of dying from infection rapidly increases.

“How likely does someone need to be to die for it to count to get a life-preserving abortion?” Dr. Harris asked. “That, I think, is the question of the hour.”

Different institutions may decide to determine their own risk thresholds. One hospital, for example, may decide that any health threat that is associated with a 10% risk of death qualifies for a lifesaving abortion. But for many people, a 1 in 10 chance of dying is quite high.

“Who gets to decide what’s meaningful?” Dr. Harris asked, especially if the patient is already a parent of living children and doesn’t want to take any risk at all of orphaning them for a pregnancy with severe complications.

“The point is that this is way more complicated than anybody really knows, way more complicated than any legislator or justice could possibly know, and it creates all kinds of complicated ambiguities, some of which could result in harm to women,” she said. “I’ve been a doctor almost 30 years, and every week, sometimes every day, I’m humbled by how complicated pregnancy is and how complicated people’s bodies and life situations are.”

That’s what makes it so dangerous for policymakers to “insert themselves into medical practice,” Ms. Nash said. She worries about the legal ramifications of overturning Roe, such as prosecution of people who illegally undergo an abortion or of physicians who perform a procedure that a judge deems to be in violation of abortion law.

“There are already local prosecutors who have misused the law to go after people who have managed their own abortions,” Ms. Nash said. “Criminal abortion law, fetal homicide, child neglect, practicing medicine without a license – these are things people have actually been arrested and convicted under.”

Some laws may target the person seeking an abortion, whereas others may target clinicians providing abortions, or even people who simply help someone obtain an abortion, as the Texas law does. In Dr. Harris’s own state of Michigan, a group of Republican lawmakers recently introduced a bill that would imprison abortion providers for up to 10 years and anyone creating or distributing abortion medication for up to 20 years.

Michigan Gov. Gretchen Whitmer, a Democrat who called the proposed legislation “disturbing” and “infuriating,” would almost certainly veto the bill, but it’s just one of dozens already filed or that are expected to be filed across the United States.

The antiabortion organization National Right to Life has published a “post-Roe model abortion law” for states to adopt. The model includes an exemption for abortions that, “based on reasonable medical judgment, [were] necessary to prevent the death of the pregnant woman” – but, again, it does not clarify what that means in practice.
 

Lectures from strangers

Four years after nearly dying, Kami gave birth to a healthy girl following an uncomplicated pregnancy. But her journey to having more children presented more challenges.

Two years after the birth of her child, she had another ectopic pregnancy. Her doctor sent her prescriptions for medication that would end this pregnancy, but a pharmacist refused to fill the prescription.

“Do you know these are very serious medications?” the pharmacist asked her. She did – she had taken them once before for another ectopic pregnancy. She was with her daughter, feeling devastated about losing yet another desired pregnancy. She simply wanted to get the medication and go home.

“‘So you’re trying to have a cheap abortion,’ he said, and 30 heads turned and looked at me. The whole pharmacy heard,” Kami said.

She told the pharmacist that she’d miscarried. She said he responded with: “So you have a dead baby in your body.”

Even after her doctor called to insist on filling the order, the man refused to fill it.

Kami left without the prescription, and her doctor performed a surgical dilation and curettage to remove the embryo from her fallopian tube for no fee.

Kami later tried again to have more children. She experienced another ruptured tube that she said nearly killed her.

“There was such a sense of pain knowing that I couldn’t have any more kids, but also the relief of knowing that I don’t have to go through this again,” Kami said. Now, however, with the Supreme Court having overturned Roe v. Wade, she has a new worry: “That my daughter will not have the same rights and access to health care that I did.”

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

Kami, a mother of one daughter in central Texas, lost three pregnancies in 2008. The third one nearly killed her.

The embryo became implanted in one of the fallopian tubes connecting her ovaries to her uterus. Because fallopian tubes can’t stretch to accommodate a fetus, patients must undergo surgery to remove the embryo before the tube ruptures. Failure to do so can result in internal bleeding and death.

But when Kami – who did not want to use her last name to avoid harassment – underwent an ultrasound to start the process of extracting the embryo, her doctor miscalculated how far along in the pregnancy she was and told her to come back in a few weeks.

She eventually did return, but only after passing out in the bathtub and waking up in a pool of her own blood. The tube had ruptured, and to remove it, emergency surgery was necessary.

Stories such as Kami’s could become more common in the aftermath of the U.S. Supreme Court’s decision to overturn Roe v. Wade, the 1973 case that created a right to an abortion.

Experts fear that antiabortion laws that take effect in the United States following the court’s decision will lead to a medical and legal limbo for thousands of people like Kami – people with uncommon reproductive conditions whose treatments involve the termination of pregnancies or the destruction of embryos.
 

Vague exceptions prompt concerns

According to the Guttmacher Institute, a nonprofit group for reproductive health, 13 states currently have trigger laws on the books that make abortion illegal in the absence of Roe. Nine other states have laws that would outlaw or severely restrict abortion without a federal right to the procedure.

Each of these laws carves out exceptions that allow the termination of a pregnancy to prevent the death of the pregnant individual. But the language of the provisions is not always precise in describing what those exceptions mean in practice, according to Elizabeth Nash, the principal policy associate for state issues at the Guttmacher Institute.

“These exceptions are designed to be extraordinarily narrow. These aren’t really designed to be usable exceptions,” Ms. Nash said. “There’s so much misinformation about abortion that there are probably legislators out there who think that it’s never needed to save a life.”
 

Tubal pregnancies

One of the best examples of a pregnancy termination that’s necessary to avoid death is in the case of an ectopic pregnancy such as Kami experienced. Without treatment to end the pregnancy, the embryo will eventually grow so large that the tube ruptures, causing massive bleeding that can kill the mother.

Most state laws regarding abortion exclude treatment of ectopic pregnancy, according to Ms. Nash. But, “if the state does not exclude ectopic pregnancy from all the regulations, then people might not be able to get the care that they need when they need it.”

The current abortion law in Texas, for example, prohibits ending a pregnancy after 6 weeks, or after cardiac activity becomes present. Cardiac activity can be present in cases of ectopic pregnancies, which account for between 1% and 2% of all pregnancies and are the leading cause of maternal deaths in the first trimester. And treatment definitely ends the life of the embryo or fetus in the fallopian tube, said Lisa Harris, MD, PhD, an ob.gyn. and medical ethicist at the University of Michigan, Ann Arbor.

Dr. Harris said she has never doubted that an ectopic pregnancy cannot possibly result in a live birth. But she recalled an encounter with another clinician on a surgical team for an ectopic pregnancy who said: “So you’re going to take it out of the tube and put it in the uterus, right?”

“It was a startling moment,” Dr. Harris recalled. She regarded the procedure as a “lifesaving, obvious surgery,” but her colleague, whose suggestion was a medical impossibility since the window of implantation is very brief after fertilization, viewed it “as an abortion, as killing an embryo or fetus.”

Dr. Harris said she isn’t concerned that physicians would stop treating ectopic pregnancies in a post-Roe world. Rather, she worries about two other possibilities: an overzealous prosecutor might not believe it was an ectopic pregnancy and press charges; or laws will cause physicians to second guess their clinical decisions for patients.

“What it means, in the middle of the night, when someone comes in with a 10-week ectopic pregnancy with a heartbeat, is the doctor may hesitate,” Dr. Harris said. Despite knowing the appropriate treatment, the doctor may want to speak with a lawyer or ethicist first to ensure they are covered legally. “And as that process unfolds, which could take hours or days, the person might have a complication.” s

Not treating an ectopic pregnancy would be malpractice, but “some doctors may not provide the standard of care that they would have ordinarily provided because they don’t want to risk breaking the law,” she said.

Even more ambiguous are cornual ectopic pregnancies, in which the implantation occurs at the junction of a fallopian tube and the uterus. These pregnancies, which make up 2%-4% of all tubal pregnancies, are immediately adjacent to the uterus. If an abortion is defined as the termination of an embryo or fetus in the womb, how such a legal definition would apply to these pregnancies is unclear.

An ob.gyn. wouldn’t regard ending an ectopic pregnancy as an abortion, but “this is not about logic or clinical meaning,” Dr. Harris said. “This is people outside of medicine making determinations that all pregnancies must continue, and when you think of a ban that way, you could see why a doctor would be frightened to end a pregnancy, whether it might be viable in the future or not.”

That’s true even if the pregnancy is located fully in the uterus. Dr. Harris described a pregnant patient she saw who had traveled from Texas to Michigan with a fetus that had a lethal defect.

The fetus had “an anomaly where the lungs couldn’t develop, where there were no kidneys. There was no chance this baby could be born and live. Her doctors were very clear that there will never be a baby that [she could] take home at the end of this pregnancy, yet they would not end her pregnancy because that would be an abortion,” Dr. Harris said.

Texas law “doesn’t make any allowances for whether a pregnancy will ever actually result in a baby or not,” Dr. Harris said. “The law, in effect, just says all pregnancies must continue.”
 

Selective reduction

How abortion laws in different states might affect selective reduction, which is used in some pregnancies to reduce the total number of fetuses a person is carrying, is even more ambiguous. The goal of selective reduction is to decrease health risks to the pregnant individual and increase the likelihood of survival for the remaining fetuses. Current Texas law prohibits these procedures.

Someone pregnant with quintuplets, for example, might seek selection reduction to reduce the pregnancy outcome to triplets or twins. A related procedure, selective termination, is used to terminate the life of a fetus with abnormalities while the pregnancy of the fetus’ in utero siblings continues.

The advent of assisted reproduction methods, such as in vitro fertilization (IVF), greatly increased the incidence of higher-order multiples, those with three or more fetuses. The first IVF baby was born in 1978. By 1998, the rate of higher-order multiple births was 1.9 per 1,000 births, five times the figure in 1980. The rate has since decreased by nearly half, to 1 per 1,000 births, but with 3.75 million live births a year, that’s still a lot of pregnancies with higher-order multiples.

The American College of Obstetricians and Gynecologists does not provide explicit guidance on when selective reduction is warranted, but its committee opinion on multifetal pregnancy reduction provides an ethical framework for providers to use when counseling people with pregnancies of three or more fetuses. How would various state laws that outlaw abortion affect these decisions? No one knows.

“Selective reduction ends the life of a fetus or embryo, but it doesn’t end the pregnancy,” Dr. Harris said. “So, if the pregnancy continues but it kills an embryo or fetus, is that an abortion?”
 

‘The question of the hour’

Dr. Harris and other doctors are haunted by potential medical cases in which continuing a pregnancy may result in the death of the person carrying the fetus but in which such death may not be so imminent that the law would allow immediate termination of the pregnancy.

Michael Northrup, MD, an intensive care pediatrician in Winston-Salem, N.C., recalled a particularly harrowing case that illustrates the peril in deciding when someone’s life is “enough” in danger to qualify as an exception to abortion bans.

The 14-year-old girl had severe lupus and kidney failure that required treatment with methotrexate and immediate dialysis to replace her electrolytes. A standard pretreatment pregnancy test revealed that she had been carrying a child for at least 10 weeks. Her pregnancy presented two problems. Methotrexate is so severely toxic that it’s sometimes used to end pregnancies. Even at low doses, fetuses that survive usually have severe deformities. In addition, dialysis requires administration of a blood thinner. If the teen miscarried while taking a blood thinner during dialysis, she risked bleeding to death.

Treatment could be delayed until week 24 of pregnancy, at which time delivery could be attempted, but the patient likely wouldn’t have any kidney function left by then. In addition, at 24 weeks, it was unlikely that the baby would survive anyway.

Dr. Northrup said that, had she chosen that route, “I’m not sure she would have made it. This was a religious family, people who very much were believers. They had their head of church come in, who fairly quickly determined that the best thing for her health was to terminate this pregnancy immediately and get the treatment she needed for her body.”

Would such a situation qualify for an emergency termination? The girl wasn’t going to die within 24 or 48 hours, but it may not have been possible to pinpoint the time of death within a day or 2.

“The family was sad, but they made that choice, and I wonder, would we have to justify that with these new laws?” Dr. Northrup said. “You definitely worry, being in the hot seat, ‘Does this count enough? Is she close enough to death?’ ”

The same question comes up when someone’s water breaks early in the second trimester. Since a live-birth delivery would be highly unlikely, given the age of the fetus, the standard of care is to offer to terminate the pregnancy to avoid a serious infection, Dr. Harris said. But if the infection hasn’t yet developed – even if it’s likely to develop soon – doctors in a state that outlaws abortion would not be able to offer termination. But as providers wait for an infection to develop, the person’s risk of dying from infection rapidly increases.

“How likely does someone need to be to die for it to count to get a life-preserving abortion?” Dr. Harris asked. “That, I think, is the question of the hour.”

Different institutions may decide to determine their own risk thresholds. One hospital, for example, may decide that any health threat that is associated with a 10% risk of death qualifies for a lifesaving abortion. But for many people, a 1 in 10 chance of dying is quite high.

“Who gets to decide what’s meaningful?” Dr. Harris asked, especially if the patient is already a parent of living children and doesn’t want to take any risk at all of orphaning them for a pregnancy with severe complications.

“The point is that this is way more complicated than anybody really knows, way more complicated than any legislator or justice could possibly know, and it creates all kinds of complicated ambiguities, some of which could result in harm to women,” she said. “I’ve been a doctor almost 30 years, and every week, sometimes every day, I’m humbled by how complicated pregnancy is and how complicated people’s bodies and life situations are.”

That’s what makes it so dangerous for policymakers to “insert themselves into medical practice,” Ms. Nash said. She worries about the legal ramifications of overturning Roe, such as prosecution of people who illegally undergo an abortion or of physicians who perform a procedure that a judge deems to be in violation of abortion law.

“There are already local prosecutors who have misused the law to go after people who have managed their own abortions,” Ms. Nash said. “Criminal abortion law, fetal homicide, child neglect, practicing medicine without a license – these are things people have actually been arrested and convicted under.”

Some laws may target the person seeking an abortion, whereas others may target clinicians providing abortions, or even people who simply help someone obtain an abortion, as the Texas law does. In Dr. Harris’s own state of Michigan, a group of Republican lawmakers recently introduced a bill that would imprison abortion providers for up to 10 years and anyone creating or distributing abortion medication for up to 20 years.

Michigan Gov. Gretchen Whitmer, a Democrat who called the proposed legislation “disturbing” and “infuriating,” would almost certainly veto the bill, but it’s just one of dozens already filed or that are expected to be filed across the United States.

The antiabortion organization National Right to Life has published a “post-Roe model abortion law” for states to adopt. The model includes an exemption for abortions that, “based on reasonable medical judgment, [were] necessary to prevent the death of the pregnant woman” – but, again, it does not clarify what that means in practice.
 

Lectures from strangers

Four years after nearly dying, Kami gave birth to a healthy girl following an uncomplicated pregnancy. But her journey to having more children presented more challenges.

Two years after the birth of her child, she had another ectopic pregnancy. Her doctor sent her prescriptions for medication that would end this pregnancy, but a pharmacist refused to fill the prescription.

“Do you know these are very serious medications?” the pharmacist asked her. She did – she had taken them once before for another ectopic pregnancy. She was with her daughter, feeling devastated about losing yet another desired pregnancy. She simply wanted to get the medication and go home.

“‘So you’re trying to have a cheap abortion,’ he said, and 30 heads turned and looked at me. The whole pharmacy heard,” Kami said.

She told the pharmacist that she’d miscarried. She said he responded with: “So you have a dead baby in your body.”

Even after her doctor called to insist on filling the order, the man refused to fill it.

Kami left without the prescription, and her doctor performed a surgical dilation and curettage to remove the embryo from her fallopian tube for no fee.

Kami later tried again to have more children. She experienced another ruptured tube that she said nearly killed her.

“There was such a sense of pain knowing that I couldn’t have any more kids, but also the relief of knowing that I don’t have to go through this again,” Kami said. Now, however, with the Supreme Court having overturned Roe v. Wade, she has a new worry: “That my daughter will not have the same rights and access to health care that I did.”

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

Ongoing research in patients with oligoarticular juvenile idiopathic arthritis (JIA) so far suggests that a set of biomarkers in synovial fluid may help to predict which patients may be more likely to stay with persistent oligoarticular disease rather than progress to polyarticular disease, according to new research presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance, held virtually this year. Identifying biomarkers in synovial fluid or possibly serum could aid families and physicians in being more proactive in treatment protocols, said AnneMarie C. Brescia, MD, of Nemours Children’s Hospital in Wilmington, Del.

“JIA carries the risk of permanent joint damage and disability, which can result when joint involvement evolves from oligoarticular into a polyarticular course, termed extended oligoarticular disease,” Dr. Brescia told attendees. “Since disease progression increases the risk for disability, early prediction of this course is essential.”

This group – those whose oligoarticular disease will begin recruiting joints and ultimately become extended oligoarticular JIA – is “very important because they have been shown to have worse health-related quality of life and greater risk of needing a joint replacement than even polyarticular [JIA],” Dr. Brescia said. “So, our lab has really focused on trying to predict who will fall in this group.”

Melissa Oliver, MD, assistant professor of clinical pediatrics in the division of pediatric rheumatology at Indiana University in Indianapolis, was not involved in the study but agreed that having highly sensitive and specific biomarkers could be particularly helpful in clinical care.

“Biomarkers can help guide treatment decisions and help physicians and their patients share the decision-making about next choices and when to change,” Dr. Oliver told this news organization. “If a provider and parent know that their child has these markers in their serum or synovial fluid that may predict extension of their disease, then they may be more aggressive upfront with therapy.”

The study aimed to determine whether differential levels of synovial fluid proteins could be used to predict whether JIA would evolve into an extended course before it became clinically evident. Although early aggressive treatment is common with rheumatoid arthritis and can lead to remission, JIA treatment paradigms tend to be more reactive, Dr. Brescia said.

“It would be better to switch to proactive, that if we’re able to predict that this patient may have a more difficult course with extension to polyarticular, we could be prepared, we could inform the parents, and it would just help us have a more proactive approach,” she said.

The researchers used antibody arrays to detect the following inflammatory mediators in blinded samples: CD14, interleukin (IL)-1-alpha, IL-3, IL-5, IL-6, vascular endothelial growth factor (VEGF), and angiogenin. They analyzed 37 samples with persistent disease and 32 samples from disease that had not yet extended but would become extended in that patient. The samples came from patients who were taking no medicines or only NSAIDs. The researchers assessed the sensitivity and specificity of each biomarker. Sensitivity referred the biomarker’s ability to correctly indicate that the sample would extend, and specificity referred to the biomarker’s accuracy in determining that the disease in the sample would remain persistent.

Combining samples from cohorts at Nemours Children’s Health (14 persistent and 7 extended-to-be) and Cincinnati Children’s Hospital (23 persistent and 25 extended-to-be) yielded the following results:

“This is a work in progress,” Dr. Brescia said, “so hopefully you’ll hear about it next year.” In response to an attendee’s question, she said she believes identifying reliable biomarkers will eventually lead to refining treatment paradigms.

“I think it will at least change the guidance we can provide parents about making next choices and how quickly to accelerate to those next choices,” Dr. Brescia said. For example, if a child’s serum or synovial fluid has markers that show a very high likelihood of extension, the parent may decide to proceed to the next level medication sooner. “I do think it will push both parents and doctors to be a little more proactive instead of reactive when the poor patient comes back with 13 joints involved when they had just been an oligo for years.”

Dr. Oliver noted the promise of CD14 and IL-6 in potentially predicting which patients’ disease will stay persistent but cautioned that it’s still early in evaluating these biomarkers, especially with the limited patient samples in this study.

“I think these results are promising, and it’s great that there are groups out there working on this,” Dr. Oliver said. “Once we have a reliable, highly sensitive and specific biomarker, that will definitely help providers, parents, and patients be more informed.”

The research was supported by the Open Net Foundation, the Arthritis Foundation, Delaware Community Foundation, the Delaware Clinical and Translational Research (DE-CTR) ACCEL Program, the Nancy Taylor Foundation for Chronic Diseases, and CARRA. Dr. Brescia and Dr. Oliver have disclosed no relevant financial relationships.

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

Ongoing research in patients with oligoarticular juvenile idiopathic arthritis (JIA) so far suggests that a set of biomarkers in synovial fluid may help to predict which patients may be more likely to stay with persistent oligoarticular disease rather than progress to polyarticular disease, according to new research presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance, held virtually this year. Identifying biomarkers in synovial fluid or possibly serum could aid families and physicians in being more proactive in treatment protocols, said AnneMarie C. Brescia, MD, of Nemours Children’s Hospital in Wilmington, Del.

“JIA carries the risk of permanent joint damage and disability, which can result when joint involvement evolves from oligoarticular into a polyarticular course, termed extended oligoarticular disease,” Dr. Brescia told attendees. “Since disease progression increases the risk for disability, early prediction of this course is essential.”

This group – those whose oligoarticular disease will begin recruiting joints and ultimately become extended oligoarticular JIA – is “very important because they have been shown to have worse health-related quality of life and greater risk of needing a joint replacement than even polyarticular [JIA],” Dr. Brescia said. “So, our lab has really focused on trying to predict who will fall in this group.”

Melissa Oliver, MD, assistant professor of clinical pediatrics in the division of pediatric rheumatology at Indiana University in Indianapolis, was not involved in the study but agreed that having highly sensitive and specific biomarkers could be particularly helpful in clinical care.

“Biomarkers can help guide treatment decisions and help physicians and their patients share the decision-making about next choices and when to change,” Dr. Oliver told this news organization. “If a provider and parent know that their child has these markers in their serum or synovial fluid that may predict extension of their disease, then they may be more aggressive upfront with therapy.”

The study aimed to determine whether differential levels of synovial fluid proteins could be used to predict whether JIA would evolve into an extended course before it became clinically evident. Although early aggressive treatment is common with rheumatoid arthritis and can lead to remission, JIA treatment paradigms tend to be more reactive, Dr. Brescia said.

“It would be better to switch to proactive, that if we’re able to predict that this patient may have a more difficult course with extension to polyarticular, we could be prepared, we could inform the parents, and it would just help us have a more proactive approach,” she said.

The researchers used antibody arrays to detect the following inflammatory mediators in blinded samples: CD14, interleukin (IL)-1-alpha, IL-3, IL-5, IL-6, vascular endothelial growth factor (VEGF), and angiogenin. They analyzed 37 samples with persistent disease and 32 samples from disease that had not yet extended but would become extended in that patient. The samples came from patients who were taking no medicines or only NSAIDs. The researchers assessed the sensitivity and specificity of each biomarker. Sensitivity referred the biomarker’s ability to correctly indicate that the sample would extend, and specificity referred to the biomarker’s accuracy in determining that the disease in the sample would remain persistent.

Combining samples from cohorts at Nemours Children’s Health (14 persistent and 7 extended-to-be) and Cincinnati Children’s Hospital (23 persistent and 25 extended-to-be) yielded the following results:

“This is a work in progress,” Dr. Brescia said, “so hopefully you’ll hear about it next year.” In response to an attendee’s question, she said she believes identifying reliable biomarkers will eventually lead to refining treatment paradigms.

“I think it will at least change the guidance we can provide parents about making next choices and how quickly to accelerate to those next choices,” Dr. Brescia said. For example, if a child’s serum or synovial fluid has markers that show a very high likelihood of extension, the parent may decide to proceed to the next level medication sooner. “I do think it will push both parents and doctors to be a little more proactive instead of reactive when the poor patient comes back with 13 joints involved when they had just been an oligo for years.”

Dr. Oliver noted the promise of CD14 and IL-6 in potentially predicting which patients’ disease will stay persistent but cautioned that it’s still early in evaluating these biomarkers, especially with the limited patient samples in this study.

“I think these results are promising, and it’s great that there are groups out there working on this,” Dr. Oliver said. “Once we have a reliable, highly sensitive and specific biomarker, that will definitely help providers, parents, and patients be more informed.”

The research was supported by the Open Net Foundation, the Arthritis Foundation, Delaware Community Foundation, the Delaware Clinical and Translational Research (DE-CTR) ACCEL Program, the Nancy Taylor Foundation for Chronic Diseases, and CARRA. Dr. Brescia and Dr. Oliver have disclosed no relevant financial relationships.

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

Ongoing research in patients with oligoarticular juvenile idiopathic arthritis (JIA) so far suggests that a set of biomarkers in synovial fluid may help to predict which patients may be more likely to stay with persistent oligoarticular disease rather than progress to polyarticular disease, according to new research presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance, held virtually this year. Identifying biomarkers in synovial fluid or possibly serum could aid families and physicians in being more proactive in treatment protocols, said AnneMarie C. Brescia, MD, of Nemours Children’s Hospital in Wilmington, Del.

“JIA carries the risk of permanent joint damage and disability, which can result when joint involvement evolves from oligoarticular into a polyarticular course, termed extended oligoarticular disease,” Dr. Brescia told attendees. “Since disease progression increases the risk for disability, early prediction of this course is essential.”

This group – those whose oligoarticular disease will begin recruiting joints and ultimately become extended oligoarticular JIA – is “very important because they have been shown to have worse health-related quality of life and greater risk of needing a joint replacement than even polyarticular [JIA],” Dr. Brescia said. “So, our lab has really focused on trying to predict who will fall in this group.”

Melissa Oliver, MD, assistant professor of clinical pediatrics in the division of pediatric rheumatology at Indiana University in Indianapolis, was not involved in the study but agreed that having highly sensitive and specific biomarkers could be particularly helpful in clinical care.

“Biomarkers can help guide treatment decisions and help physicians and their patients share the decision-making about next choices and when to change,” Dr. Oliver told this news organization. “If a provider and parent know that their child has these markers in their serum or synovial fluid that may predict extension of their disease, then they may be more aggressive upfront with therapy.”

The study aimed to determine whether differential levels of synovial fluid proteins could be used to predict whether JIA would evolve into an extended course before it became clinically evident. Although early aggressive treatment is common with rheumatoid arthritis and can lead to remission, JIA treatment paradigms tend to be more reactive, Dr. Brescia said.

“It would be better to switch to proactive, that if we’re able to predict that this patient may have a more difficult course with extension to polyarticular, we could be prepared, we could inform the parents, and it would just help us have a more proactive approach,” she said.

The researchers used antibody arrays to detect the following inflammatory mediators in blinded samples: CD14, interleukin (IL)-1-alpha, IL-3, IL-5, IL-6, vascular endothelial growth factor (VEGF), and angiogenin. They analyzed 37 samples with persistent disease and 32 samples from disease that had not yet extended but would become extended in that patient. The samples came from patients who were taking no medicines or only NSAIDs. The researchers assessed the sensitivity and specificity of each biomarker. Sensitivity referred the biomarker’s ability to correctly indicate that the sample would extend, and specificity referred to the biomarker’s accuracy in determining that the disease in the sample would remain persistent.

Combining samples from cohorts at Nemours Children’s Health (14 persistent and 7 extended-to-be) and Cincinnati Children’s Hospital (23 persistent and 25 extended-to-be) yielded the following results:

“This is a work in progress,” Dr. Brescia said, “so hopefully you’ll hear about it next year.” In response to an attendee’s question, she said she believes identifying reliable biomarkers will eventually lead to refining treatment paradigms.

“I think it will at least change the guidance we can provide parents about making next choices and how quickly to accelerate to those next choices,” Dr. Brescia said. For example, if a child’s serum or synovial fluid has markers that show a very high likelihood of extension, the parent may decide to proceed to the next level medication sooner. “I do think it will push both parents and doctors to be a little more proactive instead of reactive when the poor patient comes back with 13 joints involved when they had just been an oligo for years.”

Dr. Oliver noted the promise of CD14 and IL-6 in potentially predicting which patients’ disease will stay persistent but cautioned that it’s still early in evaluating these biomarkers, especially with the limited patient samples in this study.

“I think these results are promising, and it’s great that there are groups out there working on this,” Dr. Oliver said. “Once we have a reliable, highly sensitive and specific biomarker, that will definitely help providers, parents, and patients be more informed.”

The research was supported by the Open Net Foundation, the Arthritis Foundation, Delaware Community Foundation, the Delaware Clinical and Translational Research (DE-CTR) ACCEL Program, the Nancy Taylor Foundation for Chronic Diseases, and CARRA. Dr. Brescia and Dr. Oliver have disclosed no relevant financial relationships.

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

A person’s ‘genetic’ height – the height they are predicted to reach independent of environmental influences – may be an underappreciated risk factor for a wide range of chronic conditions, according to a study published in PLOS Genetics.

Prior studies have investigated height as a risk factor for chronic diseases, such as a higher risk for atrial fibrillation and a reduced risk of cardiovascular disease. It’s been consistently difficult, however, to eliminate the confounding influences of diet, socioeconomics, lifestyle behaviors, and other environmental factors that may interfere with a person’s reaching their expected height based on their genes.

This study, however, was able to better parse those differences by using Mendelian randomization within the comprehensive clinical and genetic dataset of a national health care system biobank. Mendelian randomization uses “genetic instruments for exposures of interest under the assumption that genotype is less susceptible to confounding than measured exposures,” the authors explained. The findings confirmed previously suspected associations between height and a range of cardiovascular and metabolic conditions as well as revealing new associations with several other conditions.
 

Prior associations confirmed, new associations uncovered

The results confirmed that being tall is linked to a higher risk of atrial fibrillation and varicose veins, and a lower risk of coronary heart disease, high blood pressure, and high cholesterol. The study also uncovered new associations between greater height and a higher risk of peripheral neuropathy, which is caused by damage to nerves on the extremities, as well as skin and bone infections, such as leg and foot ulcers.

The meta-analysis “identified five additional traits associated with genetically-predicted height,” wrote Sridharan Raghavan, MD, assistant professor of medicine at the University of Colorado Anschutz Medical Campus, and colleagues. “Two were genitourinary conditions – erectile dysfunction and urinary retention – that can be associated with neuropathy, and a third was a phecode for nonspecific skin disorders that may be related to skin infections – consistent with the race/ethnicity stratified results.”
 

Removing potential confounders

F. Perry Wilson, MD, associate professor of medicine at Yale University, New Haven, Conn., who was not involved in the study, said the findings were not particularly surprising overall, but it’s striking that the researchers had ”such a large cohort with such detailed electronic health records allowing for the comparison of genetic height with a variety of clinical outcomes.” He also noted the study’s strength in using Mendelian randomization so that the exposure is the predicted genetic height instead of a person’s measured height.

“This is key, since lots of things affect actual height – nutrition is an important one that could certainly be linked to disease as well,” Dr. Wilson said. ”By using genetic height, the authors remove these potential confounders. Since genetic height is “assigned” at birth (or conception), there is little opportunity for confounding. Of course, it is possible that some of the gene variants used to predict genetic height actually do something else, such as make you seek out less nutritious meals, but by and large this is how these types of studies need to be done.”
 

Height may impact over 100 clinical traits

The study relied on data from the U.S. Veteran Affairs Million Veteran Program with 222,300 non-Hispanic White and 58,151 non-Hispanic Black participants. The researchers first estimated the likelihood of participants’ genetic height based on 3,290 genetic variants determined to affect genetic height in a recent European-ancestry genome-wide meta-analysis. Then they compared these estimates with participants’ actual height in the VA medical record, adjusting for age, sex, and other genetic characteristics.

In doing so, the researchers found 345 clinical traits that were associated with the actual measured height in White participants plus another 17 clinical trials linked to actual measured height in Black participants. An overall 127 of these clinical traits were significantly associated with White participants’ genetically predicted height, and two of them were significantly associated with Black participants’ genetically predicted height.

In analyzing all these data together, the researchers were largely able to separate out those associations between genetically predicted height and certain health conditions from those associations between health conditions and a person’s actual measured height. They also determined that including body mass index as a covariate had little impact on the results. The researchers conducted the appropriate statistical correction to ensure the use of so many variables did not result in spurious statistical significance in some associations.

“Using genetic methods applied to the VA Million Veteran Program, we found evidence that adult height may impact over 100 clinical traits, including several conditions associated with poor outcomes and quality of life – peripheral neuropathy, lower extremity ulcers, and chronic venous insufficiency. We conclude that height may be an unrecognized nonmodifiable risk factor for several common conditions in adults.”
 

Height linked with health conditions

Genetically predicted height predicted a reduced risk of hyperlipidemia and hypertension independent of coronary heart disease, the analysis revealed. Genetically predicted height was also linked to an approximately 51% increased risk of atrial fibrillation in participants without coronary heart disease but, paradoxically, only a 39% increased risk in those with coronary heart disease, despite coronary heart disease being a risk factor for atrial fibrillation. Genetically predicted height was also associated with a greater risk of varicose veins in the legs and deep vein thrombosis.

Another novel association uncovered by the analysis was between women’s genetically predicted height and both asthma and nonspecific peripheral nerve disorders. “Whether these associations reflect differences by sex in disease pathophysiology related to height may warrant exploration in a sample with better balance between men and women,” the authors wrote. “In sum, our results suggest that an individual’s height may warrant consideration as a nonmodifiable predictor for several common conditions, particularly those affecting peripheral/distal extremities that are most physically impacted by tall stature.”

A substantial limitation of the study was its homogeneity of participants, who were 92% male with an average height of 176 cm and an average BMI of 30.1. The Black participants tended to be younger, with an average age of 58 compared with 64 years in the White participants, but the groups were otherwise similar in height and weight.* The database included data from Hispanic participants, but the researchers excluded these data because of the small sample size.

The smaller dataset for Black participants was a limitation as well as the fact that the genome-wide association study the researchers relied on came from a European population, which may not be as accurate in people with other ancestry, Dr. Wilson said. The bigger limitation, however, is what the findings’ clinical relevance is.
 

What does it all mean?

“Genetic height is in your genes – there is nothing to be done about it – so it is more of academic interest than clinical interest,” Dr. Wilson said. It’s not even clear whether incorporating a person’s height – actual or genetically predicted, if it could be easily determined for each person – into risk calculators. ”To know whether it would be beneficial to use height (or genetic height) as a risk factor, you’d need to examine each condition of interest, adjusting for all known risk factors, to see if height improved the prediction,” Dr. Wilson said. “I suspect for most conditions, the well-known risk factors would swamp height. For example, high genetic height might truly increase risk for neuropathy. But diabetes might increase the risk so much more that height is not particularly relevant.”

On the other hand, the fact that height in general has any potential influence at all on disease risk may inspire physicians to consider other risk factors in especially tall individuals.

”Physicians may find it interesting that we have some confirmation that height does increase the risk of certain conditions,” Dr. Wilson said. “While this is unlikely to dramatically change practice, they may be a bit more diligent in looking for other relevant risk factors for the diseases found in this study in their very tall patients.”

The research was funded by the U.S. Department of Veteran Affairs, the Boettcher Foundation’s Webb-Waring Biomedical Research Program, the National Institutes of Health, and a Linda Pechenik Montague Investigator award. One study coauthor is a full-time employee of Novartis Institutes of Biomedical Research. The other authors and Dr. Wilson had no disclosures.

*Correction, 6/29/22: An earlier version of this article misstated the average age of Black participants.

A person’s ‘genetic’ height – the height they are predicted to reach independent of environmental influences – may be an underappreciated risk factor for a wide range of chronic conditions, according to a study published in PLOS Genetics.

Prior studies have investigated height as a risk factor for chronic diseases, such as a higher risk for atrial fibrillation and a reduced risk of cardiovascular disease. It’s been consistently difficult, however, to eliminate the confounding influences of diet, socioeconomics, lifestyle behaviors, and other environmental factors that may interfere with a person’s reaching their expected height based on their genes.

This study, however, was able to better parse those differences by using Mendelian randomization within the comprehensive clinical and genetic dataset of a national health care system biobank. Mendelian randomization uses “genetic instruments for exposures of interest under the assumption that genotype is less susceptible to confounding than measured exposures,” the authors explained. The findings confirmed previously suspected associations between height and a range of cardiovascular and metabolic conditions as well as revealing new associations with several other conditions.
 

Prior associations confirmed, new associations uncovered

The results confirmed that being tall is linked to a higher risk of atrial fibrillation and varicose veins, and a lower risk of coronary heart disease, high blood pressure, and high cholesterol. The study also uncovered new associations between greater height and a higher risk of peripheral neuropathy, which is caused by damage to nerves on the extremities, as well as skin and bone infections, such as leg and foot ulcers.

The meta-analysis “identified five additional traits associated with genetically-predicted height,” wrote Sridharan Raghavan, MD, assistant professor of medicine at the University of Colorado Anschutz Medical Campus, and colleagues. “Two were genitourinary conditions – erectile dysfunction and urinary retention – that can be associated with neuropathy, and a third was a phecode for nonspecific skin disorders that may be related to skin infections – consistent with the race/ethnicity stratified results.”
 

Removing potential confounders

F. Perry Wilson, MD, associate professor of medicine at Yale University, New Haven, Conn., who was not involved in the study, said the findings were not particularly surprising overall, but it’s striking that the researchers had ”such a large cohort with such detailed electronic health records allowing for the comparison of genetic height with a variety of clinical outcomes.” He also noted the study’s strength in using Mendelian randomization so that the exposure is the predicted genetic height instead of a person’s measured height.

“This is key, since lots of things affect actual height – nutrition is an important one that could certainly be linked to disease as well,” Dr. Wilson said. ”By using genetic height, the authors remove these potential confounders. Since genetic height is “assigned” at birth (or conception), there is little opportunity for confounding. Of course, it is possible that some of the gene variants used to predict genetic height actually do something else, such as make you seek out less nutritious meals, but by and large this is how these types of studies need to be done.”
 

Height may impact over 100 clinical traits

The study relied on data from the U.S. Veteran Affairs Million Veteran Program with 222,300 non-Hispanic White and 58,151 non-Hispanic Black participants. The researchers first estimated the likelihood of participants’ genetic height based on 3,290 genetic variants determined to affect genetic height in a recent European-ancestry genome-wide meta-analysis. Then they compared these estimates with participants’ actual height in the VA medical record, adjusting for age, sex, and other genetic characteristics.

In doing so, the researchers found 345 clinical traits that were associated with the actual measured height in White participants plus another 17 clinical trials linked to actual measured height in Black participants. An overall 127 of these clinical traits were significantly associated with White participants’ genetically predicted height, and two of them were significantly associated with Black participants’ genetically predicted height.

In analyzing all these data together, the researchers were largely able to separate out those associations between genetically predicted height and certain health conditions from those associations between health conditions and a person’s actual measured height. They also determined that including body mass index as a covariate had little impact on the results. The researchers conducted the appropriate statistical correction to ensure the use of so many variables did not result in spurious statistical significance in some associations.

“Using genetic methods applied to the VA Million Veteran Program, we found evidence that adult height may impact over 100 clinical traits, including several conditions associated with poor outcomes and quality of life – peripheral neuropathy, lower extremity ulcers, and chronic venous insufficiency. We conclude that height may be an unrecognized nonmodifiable risk factor for several common conditions in adults.”
 

Height linked with health conditions

Genetically predicted height predicted a reduced risk of hyperlipidemia and hypertension independent of coronary heart disease, the analysis revealed. Genetically predicted height was also linked to an approximately 51% increased risk of atrial fibrillation in participants without coronary heart disease but, paradoxically, only a 39% increased risk in those with coronary heart disease, despite coronary heart disease being a risk factor for atrial fibrillation. Genetically predicted height was also associated with a greater risk of varicose veins in the legs and deep vein thrombosis.

Another novel association uncovered by the analysis was between women’s genetically predicted height and both asthma and nonspecific peripheral nerve disorders. “Whether these associations reflect differences by sex in disease pathophysiology related to height may warrant exploration in a sample with better balance between men and women,” the authors wrote. “In sum, our results suggest that an individual’s height may warrant consideration as a nonmodifiable predictor for several common conditions, particularly those affecting peripheral/distal extremities that are most physically impacted by tall stature.”

A substantial limitation of the study was its homogeneity of participants, who were 92% male with an average height of 176 cm and an average BMI of 30.1. The Black participants tended to be younger, with an average age of 58 compared with 64 years in the White participants, but the groups were otherwise similar in height and weight.* The database included data from Hispanic participants, but the researchers excluded these data because of the small sample size.

The smaller dataset for Black participants was a limitation as well as the fact that the genome-wide association study the researchers relied on came from a European population, which may not be as accurate in people with other ancestry, Dr. Wilson said. The bigger limitation, however, is what the findings’ clinical relevance is.
 

What does it all mean?

“Genetic height is in your genes – there is nothing to be done about it – so it is more of academic interest than clinical interest,” Dr. Wilson said. It’s not even clear whether incorporating a person’s height – actual or genetically predicted, if it could be easily determined for each person – into risk calculators. ”To know whether it would be beneficial to use height (or genetic height) as a risk factor, you’d need to examine each condition of interest, adjusting for all known risk factors, to see if height improved the prediction,” Dr. Wilson said. “I suspect for most conditions, the well-known risk factors would swamp height. For example, high genetic height might truly increase risk for neuropathy. But diabetes might increase the risk so much more that height is not particularly relevant.”

On the other hand, the fact that height in general has any potential influence at all on disease risk may inspire physicians to consider other risk factors in especially tall individuals.

”Physicians may find it interesting that we have some confirmation that height does increase the risk of certain conditions,” Dr. Wilson said. “While this is unlikely to dramatically change practice, they may be a bit more diligent in looking for other relevant risk factors for the diseases found in this study in their very tall patients.”

The research was funded by the U.S. Department of Veteran Affairs, the Boettcher Foundation’s Webb-Waring Biomedical Research Program, the National Institutes of Health, and a Linda Pechenik Montague Investigator award. One study coauthor is a full-time employee of Novartis Institutes of Biomedical Research. The other authors and Dr. Wilson had no disclosures.

*Correction, 6/29/22: An earlier version of this article misstated the average age of Black participants.

A person’s ‘genetic’ height – the height they are predicted to reach independent of environmental influences – may be an underappreciated risk factor for a wide range of chronic conditions, according to a study published in PLOS Genetics.

Prior studies have investigated height as a risk factor for chronic diseases, such as a higher risk for atrial fibrillation and a reduced risk of cardiovascular disease. It’s been consistently difficult, however, to eliminate the confounding influences of diet, socioeconomics, lifestyle behaviors, and other environmental factors that may interfere with a person’s reaching their expected height based on their genes.

This study, however, was able to better parse those differences by using Mendelian randomization within the comprehensive clinical and genetic dataset of a national health care system biobank. Mendelian randomization uses “genetic instruments for exposures of interest under the assumption that genotype is less susceptible to confounding than measured exposures,” the authors explained. The findings confirmed previously suspected associations between height and a range of cardiovascular and metabolic conditions as well as revealing new associations with several other conditions.
 

Prior associations confirmed, new associations uncovered

The results confirmed that being tall is linked to a higher risk of atrial fibrillation and varicose veins, and a lower risk of coronary heart disease, high blood pressure, and high cholesterol. The study also uncovered new associations between greater height and a higher risk of peripheral neuropathy, which is caused by damage to nerves on the extremities, as well as skin and bone infections, such as leg and foot ulcers.

The meta-analysis “identified five additional traits associated with genetically-predicted height,” wrote Sridharan Raghavan, MD, assistant professor of medicine at the University of Colorado Anschutz Medical Campus, and colleagues. “Two were genitourinary conditions – erectile dysfunction and urinary retention – that can be associated with neuropathy, and a third was a phecode for nonspecific skin disorders that may be related to skin infections – consistent with the race/ethnicity stratified results.”
 

Removing potential confounders

F. Perry Wilson, MD, associate professor of medicine at Yale University, New Haven, Conn., who was not involved in the study, said the findings were not particularly surprising overall, but it’s striking that the researchers had ”such a large cohort with such detailed electronic health records allowing for the comparison of genetic height with a variety of clinical outcomes.” He also noted the study’s strength in using Mendelian randomization so that the exposure is the predicted genetic height instead of a person’s measured height.

“This is key, since lots of things affect actual height – nutrition is an important one that could certainly be linked to disease as well,” Dr. Wilson said. ”By using genetic height, the authors remove these potential confounders. Since genetic height is “assigned” at birth (or conception), there is little opportunity for confounding. Of course, it is possible that some of the gene variants used to predict genetic height actually do something else, such as make you seek out less nutritious meals, but by and large this is how these types of studies need to be done.”
 

Height may impact over 100 clinical traits

The study relied on data from the U.S. Veteran Affairs Million Veteran Program with 222,300 non-Hispanic White and 58,151 non-Hispanic Black participants. The researchers first estimated the likelihood of participants’ genetic height based on 3,290 genetic variants determined to affect genetic height in a recent European-ancestry genome-wide meta-analysis. Then they compared these estimates with participants’ actual height in the VA medical record, adjusting for age, sex, and other genetic characteristics.

In doing so, the researchers found 345 clinical traits that were associated with the actual measured height in White participants plus another 17 clinical trials linked to actual measured height in Black participants. An overall 127 of these clinical traits were significantly associated with White participants’ genetically predicted height, and two of them were significantly associated with Black participants’ genetically predicted height.

In analyzing all these data together, the researchers were largely able to separate out those associations between genetically predicted height and certain health conditions from those associations between health conditions and a person’s actual measured height. They also determined that including body mass index as a covariate had little impact on the results. The researchers conducted the appropriate statistical correction to ensure the use of so many variables did not result in spurious statistical significance in some associations.

“Using genetic methods applied to the VA Million Veteran Program, we found evidence that adult height may impact over 100 clinical traits, including several conditions associated with poor outcomes and quality of life – peripheral neuropathy, lower extremity ulcers, and chronic venous insufficiency. We conclude that height may be an unrecognized nonmodifiable risk factor for several common conditions in adults.”
 

Height linked with health conditions

Genetically predicted height predicted a reduced risk of hyperlipidemia and hypertension independent of coronary heart disease, the analysis revealed. Genetically predicted height was also linked to an approximately 51% increased risk of atrial fibrillation in participants without coronary heart disease but, paradoxically, only a 39% increased risk in those with coronary heart disease, despite coronary heart disease being a risk factor for atrial fibrillation. Genetically predicted height was also associated with a greater risk of varicose veins in the legs and deep vein thrombosis.

Another novel association uncovered by the analysis was between women’s genetically predicted height and both asthma and nonspecific peripheral nerve disorders. “Whether these associations reflect differences by sex in disease pathophysiology related to height may warrant exploration in a sample with better balance between men and women,” the authors wrote. “In sum, our results suggest that an individual’s height may warrant consideration as a nonmodifiable predictor for several common conditions, particularly those affecting peripheral/distal extremities that are most physically impacted by tall stature.”

A substantial limitation of the study was its homogeneity of participants, who were 92% male with an average height of 176 cm and an average BMI of 30.1. The Black participants tended to be younger, with an average age of 58 compared with 64 years in the White participants, but the groups were otherwise similar in height and weight.* The database included data from Hispanic participants, but the researchers excluded these data because of the small sample size.

The smaller dataset for Black participants was a limitation as well as the fact that the genome-wide association study the researchers relied on came from a European population, which may not be as accurate in people with other ancestry, Dr. Wilson said. The bigger limitation, however, is what the findings’ clinical relevance is.
 

What does it all mean?

“Genetic height is in your genes – there is nothing to be done about it – so it is more of academic interest than clinical interest,” Dr. Wilson said. It’s not even clear whether incorporating a person’s height – actual or genetically predicted, if it could be easily determined for each person – into risk calculators. ”To know whether it would be beneficial to use height (or genetic height) as a risk factor, you’d need to examine each condition of interest, adjusting for all known risk factors, to see if height improved the prediction,” Dr. Wilson said. “I suspect for most conditions, the well-known risk factors would swamp height. For example, high genetic height might truly increase risk for neuropathy. But diabetes might increase the risk so much more that height is not particularly relevant.”

On the other hand, the fact that height in general has any potential influence at all on disease risk may inspire physicians to consider other risk factors in especially tall individuals.

”Physicians may find it interesting that we have some confirmation that height does increase the risk of certain conditions,” Dr. Wilson said. “While this is unlikely to dramatically change practice, they may be a bit more diligent in looking for other relevant risk factors for the diseases found in this study in their very tall patients.”

The research was funded by the U.S. Department of Veteran Affairs, the Boettcher Foundation’s Webb-Waring Biomedical Research Program, the National Institutes of Health, and a Linda Pechenik Montague Investigator award. One study coauthor is a full-time employee of Novartis Institutes of Biomedical Research. The other authors and Dr. Wilson had no disclosures.

*Correction, 6/29/22: An earlier version of this article misstated the average age of Black participants.

Scientists have confirmed that a receptor long suspected to be linked to lupus is, in fact, a major driver of the autoimmune disease for at least some subset of patients, according to a study recently published in Nature. Researchers discovered the crucial role of toll-like receptor 7 (TLR7) because of a rare mutation in a pediatric patient with systemic lupus erythematosus (SLE) who had a particularly severe presentation.

“Sometimes it’s valuable to find these very severe cases where there is one mutation that has a strong effect because if we understand how those mutations work, the lessons we learn can generally tell us about disease mechanisms,” explained senior author Carola G. Vinuesa, MD, PhD, of the Centre for Personalised Immunology at Australian National University in Canberra and The Francis Crick Institute in London.

courtesy Michael Bowles

“It’s quite difficult to find one mutation that can alone cause the entire disease,” Dr. Vinuesa added, but what it reveals about how the disease develops may lead to more effective targeted therapies than the immune suppressants most often used to treat lupus currently.

The mutation they found was in the TLR7 gene that encodes the TLR7 protein. TLR7 is a receptor used by immune cells to identify viral RNA so they can fight off viral infections, including COVID-19. But if the body’s own genetic material binds to TLR7 in susceptible individuals, it can lead to an overproduction of type 1 interferons, which are cytokines that trigger or exacerbate the immune reactions that lead to lupus symptoms. The TLR7 gene occurs on the X chromosome, which may explain men’s greater susceptibility to COVID-19 and the greater incidence of lupus in women, who have two X chromosomes instead of the one that men have, Dr. Vinuesa said.

Previous research had shown an association between TLR7 and lupus, but this new study is the first to provide definitive proof that a TLR7 mutation by itself can directly cause human lupus. After discovering the variant in the patient, Dr. Vinuesa’s team used CRISPR to edit the genome of a mouse model and introduce the same mutation the patient had. “And they developed full-blown disease, just with this one single base-pair substitution – 1 letter in the 3 billion letters of the genome,” Dr. Vinuesa said. “It tells us that these receptors are not just there to recognize viral RNA, that in some circumstances, they could be triggered by our own nucleic acids.”
 

One pathway among many?

The finding does not mean that every lupus patient has this mutation, which remains rare, but suggests that overactivity in this receptor already reported in many lupus patients may be causally related to disease, Dr. Vinuesa said.

Noa Schwartz, MD, an assistant professor of medicine at Albert Einstein College of Medicine, New York, and director of the Montefiore-Einstein Institute for Lupus Care and Research, said in an interview that lupus is thought of as a syndrome, a collection of different but similar diseases that don’t necessarily have a single cause. But finding a single gene mutation that could potentially lead to lupus is an important piece of the puzzle, said Dr. Schwartz, who was not involved in the study. Based on past research in mice models, “we’ve hypothesized that TLR7 is important in humans as well, but this is the last nail in the coffin.”

One of the key questions this finding has prompted is how many patients’ disease results from TLR7 activity. “Because of the evidence from Ignacio Sanz’s group demonstrating TLR7 overactivity in a significant fraction of SLE patients, we believe that it is probably going to be pretty important,” Dr. Vinuesa said. “My feeling is that it is going to be quite a central pathway in lupus pathogenesis, if not the central pathway.”

Dr. Schwartz was more cautious, noting that it is probably important for a subset of patients but may “have a limited effect on the general lupus population.” While it’s not yet clear how large that subset is, it is possible it will include people with cutaneous lupus, those with primarily dermatologic symptoms.

“Hydroxychloroquine works particularly well for cutaneous manifestations of lupus, and one of the ways that works is by inhibiting TLR7 and TLR9, so this [finding] potentially matters for skin disease and lupus, but it’s very early,” Dr. Schwartz said. If it does turn out that TLR7 activity is particularly associated with cutaneous lupus, it may mean therapies with fewer side effects, she said. “Specifically for cutaneous lupus, the concept of suppressing the entire immune system for skin illness sometimes feels, especially to patients, very extreme, so they are [patients] who directed therapy could be so especially relevant for.”

Laura Lewandowski, MD, an assistant clinical investigator and head of the lupus genomics and global health disparities unit at the National Institute of Arthritis and Musculoskeletal and Skin Disease, described this study as particularly remarkable in the way it revealed the mechanism leading to lupus symptoms.

“As whole genome sequencing becomes faster and less expensive, more and more people are employing them in their studies,” most of which report changes in certain genes, Dr. Lewandowski said. “One of the most striking findings about this paper was that they took it to the next step and did a really elegant study on the exact way this gain-of-function TLR7 mutation leads to the autoimmunity that we see in lupus. The detail of mechanism in this paper is really unique.”
 

A step toward personalized medicine

Dr. Lewandowski is part of a team that recently presented a poster related to genomic sequencing in lupus patients at the annual meeting of the Childhood Arthritis and Rheumatology Research Alliance. Her study reported on the whole genome sequencing of patients with childhood-onset SLE who were already enrolled in the CARRA Lupus Registry. Children with lupus may be more likely than adults to have rare genetic variants, so a registry of childhood-onset SLE patients with fully sequenced genomes provides an opportunity to look for single-gene mutations specifically linked to lupus, said Dr. Lewandowski, who has recently begun a research collaboration with Dr. Vinuesa.

“As we move forward and more and more patients are included in these studies, we will understand a little bit more about the genetic architecture of patients who have rare variations leading to disease, or even common variations,” Dr. Lewandowski said about the intersection between her research and Dr. Vinuesa’s study. The more data they gather, the more they can explore the possible interactions of rare and common variants that play a role in SLE as well as what environmental triggers, such as viral infection or pollution exposure, might tip someone into having an autoimmune disease. “We’re just starting to peek under the hood,” Dr. Lewandowski said.

If further research can reveal the relative contribution of genetics to the disease and what those genetic drivers are, it may allow for greater precision in therapies and “ultimately improve the quality of life for our patients, the ultimate goal of all of these studies,” Dr. Lewandowski said.

Drugs that target TLR7 already exist for other indications, and clinical trials have already begun to see if these TLR7 inhibitors benefit lupus patients.

“If the clinical trials work, this will be quite a nice, targeted therapy with potentially much less side effects than other therapies on the market at the moment,” Dr. Vinuesa said. She is cautiously hopeful, saying it’s likely to make an impact on lupus treatment, but it’s too early to say precisely how much.

“It allows us to understand the disease mechanisms a little bit better and to try and assess what percentage of patients’ disease can be explained by overactivity in this receptor,” Dr. Vinuesa said. She thinks it’s possible that TLR7 over activation may be relevant to other systemic autoimmune diseases as well, such as Sjögren’s syndrome, rheumatoid arthritis, or juvenile dermatomyositis, but it will take more studies to find out.

“Right now, we have medicines that broadly inhibit the immune system and aren’t as targeted, but we have a lot more clinical and scientific work to do before we move this field forward for lupus patients,” Dr. Lewandowski said. “This is one case where they were able to find the exact molecular defect, and it’s not the end of the path of precision medicine — it’s the beginning.”

Dr. Vinuesa, Dr. Schwartz, and Dr. Lewandowski reported no disclosures.

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

Scientists have confirmed that a receptor long suspected to be linked to lupus is, in fact, a major driver of the autoimmune disease for at least some subset of patients, according to a study recently published in Nature. Researchers discovered the crucial role of toll-like receptor 7 (TLR7) because of a rare mutation in a pediatric patient with systemic lupus erythematosus (SLE) who had a particularly severe presentation.

“Sometimes it’s valuable to find these very severe cases where there is one mutation that has a strong effect because if we understand how those mutations work, the lessons we learn can generally tell us about disease mechanisms,” explained senior author Carola G. Vinuesa, MD, PhD, of the Centre for Personalised Immunology at Australian National University in Canberra and The Francis Crick Institute in London.

courtesy Michael Bowles

“It’s quite difficult to find one mutation that can alone cause the entire disease,” Dr. Vinuesa added, but what it reveals about how the disease develops may lead to more effective targeted therapies than the immune suppressants most often used to treat lupus currently.

The mutation they found was in the TLR7 gene that encodes the TLR7 protein. TLR7 is a receptor used by immune cells to identify viral RNA so they can fight off viral infections, including COVID-19. But if the body’s own genetic material binds to TLR7 in susceptible individuals, it can lead to an overproduction of type 1 interferons, which are cytokines that trigger or exacerbate the immune reactions that lead to lupus symptoms. The TLR7 gene occurs on the X chromosome, which may explain men’s greater susceptibility to COVID-19 and the greater incidence of lupus in women, who have two X chromosomes instead of the one that men have, Dr. Vinuesa said.

Previous research had shown an association between TLR7 and lupus, but this new study is the first to provide definitive proof that a TLR7 mutation by itself can directly cause human lupus. After discovering the variant in the patient, Dr. Vinuesa’s team used CRISPR to edit the genome of a mouse model and introduce the same mutation the patient had. “And they developed full-blown disease, just with this one single base-pair substitution – 1 letter in the 3 billion letters of the genome,” Dr. Vinuesa said. “It tells us that these receptors are not just there to recognize viral RNA, that in some circumstances, they could be triggered by our own nucleic acids.”
 

One pathway among many?

The finding does not mean that every lupus patient has this mutation, which remains rare, but suggests that overactivity in this receptor already reported in many lupus patients may be causally related to disease, Dr. Vinuesa said.

Noa Schwartz, MD, an assistant professor of medicine at Albert Einstein College of Medicine, New York, and director of the Montefiore-Einstein Institute for Lupus Care and Research, said in an interview that lupus is thought of as a syndrome, a collection of different but similar diseases that don’t necessarily have a single cause. But finding a single gene mutation that could potentially lead to lupus is an important piece of the puzzle, said Dr. Schwartz, who was not involved in the study. Based on past research in mice models, “we’ve hypothesized that TLR7 is important in humans as well, but this is the last nail in the coffin.”

One of the key questions this finding has prompted is how many patients’ disease results from TLR7 activity. “Because of the evidence from Ignacio Sanz’s group demonstrating TLR7 overactivity in a significant fraction of SLE patients, we believe that it is probably going to be pretty important,” Dr. Vinuesa said. “My feeling is that it is going to be quite a central pathway in lupus pathogenesis, if not the central pathway.”

Dr. Schwartz was more cautious, noting that it is probably important for a subset of patients but may “have a limited effect on the general lupus population.” While it’s not yet clear how large that subset is, it is possible it will include people with cutaneous lupus, those with primarily dermatologic symptoms.

“Hydroxychloroquine works particularly well for cutaneous manifestations of lupus, and one of the ways that works is by inhibiting TLR7 and TLR9, so this [finding] potentially matters for skin disease and lupus, but it’s very early,” Dr. Schwartz said. If it does turn out that TLR7 activity is particularly associated with cutaneous lupus, it may mean therapies with fewer side effects, she said. “Specifically for cutaneous lupus, the concept of suppressing the entire immune system for skin illness sometimes feels, especially to patients, very extreme, so they are [patients] who directed therapy could be so especially relevant for.”

Laura Lewandowski, MD, an assistant clinical investigator and head of the lupus genomics and global health disparities unit at the National Institute of Arthritis and Musculoskeletal and Skin Disease, described this study as particularly remarkable in the way it revealed the mechanism leading to lupus symptoms.

“As whole genome sequencing becomes faster and less expensive, more and more people are employing them in their studies,” most of which report changes in certain genes, Dr. Lewandowski said. “One of the most striking findings about this paper was that they took it to the next step and did a really elegant study on the exact way this gain-of-function TLR7 mutation leads to the autoimmunity that we see in lupus. The detail of mechanism in this paper is really unique.”
 

A step toward personalized medicine

Dr. Lewandowski is part of a team that recently presented a poster related to genomic sequencing in lupus patients at the annual meeting of the Childhood Arthritis and Rheumatology Research Alliance. Her study reported on the whole genome sequencing of patients with childhood-onset SLE who were already enrolled in the CARRA Lupus Registry. Children with lupus may be more likely than adults to have rare genetic variants, so a registry of childhood-onset SLE patients with fully sequenced genomes provides an opportunity to look for single-gene mutations specifically linked to lupus, said Dr. Lewandowski, who has recently begun a research collaboration with Dr. Vinuesa.

“As we move forward and more and more patients are included in these studies, we will understand a little bit more about the genetic architecture of patients who have rare variations leading to disease, or even common variations,” Dr. Lewandowski said about the intersection between her research and Dr. Vinuesa’s study. The more data they gather, the more they can explore the possible interactions of rare and common variants that play a role in SLE as well as what environmental triggers, such as viral infection or pollution exposure, might tip someone into having an autoimmune disease. “We’re just starting to peek under the hood,” Dr. Lewandowski said.

If further research can reveal the relative contribution of genetics to the disease and what those genetic drivers are, it may allow for greater precision in therapies and “ultimately improve the quality of life for our patients, the ultimate goal of all of these studies,” Dr. Lewandowski said.

Drugs that target TLR7 already exist for other indications, and clinical trials have already begun to see if these TLR7 inhibitors benefit lupus patients.

“If the clinical trials work, this will be quite a nice, targeted therapy with potentially much less side effects than other therapies on the market at the moment,” Dr. Vinuesa said. She is cautiously hopeful, saying it’s likely to make an impact on lupus treatment, but it’s too early to say precisely how much.

“It allows us to understand the disease mechanisms a little bit better and to try and assess what percentage of patients’ disease can be explained by overactivity in this receptor,” Dr. Vinuesa said. She thinks it’s possible that TLR7 over activation may be relevant to other systemic autoimmune diseases as well, such as Sjögren’s syndrome, rheumatoid arthritis, or juvenile dermatomyositis, but it will take more studies to find out.

“Right now, we have medicines that broadly inhibit the immune system and aren’t as targeted, but we have a lot more clinical and scientific work to do before we move this field forward for lupus patients,” Dr. Lewandowski said. “This is one case where they were able to find the exact molecular defect, and it’s not the end of the path of precision medicine — it’s the beginning.”

Dr. Vinuesa, Dr. Schwartz, and Dr. Lewandowski reported no disclosures.

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

Scientists have confirmed that a receptor long suspected to be linked to lupus is, in fact, a major driver of the autoimmune disease for at least some subset of patients, according to a study recently published in Nature. Researchers discovered the crucial role of toll-like receptor 7 (TLR7) because of a rare mutation in a pediatric patient with systemic lupus erythematosus (SLE) who had a particularly severe presentation.

“Sometimes it’s valuable to find these very severe cases where there is one mutation that has a strong effect because if we understand how those mutations work, the lessons we learn can generally tell us about disease mechanisms,” explained senior author Carola G. Vinuesa, MD, PhD, of the Centre for Personalised Immunology at Australian National University in Canberra and The Francis Crick Institute in London.

courtesy Michael Bowles

“It’s quite difficult to find one mutation that can alone cause the entire disease,” Dr. Vinuesa added, but what it reveals about how the disease develops may lead to more effective targeted therapies than the immune suppressants most often used to treat lupus currently.

The mutation they found was in the TLR7 gene that encodes the TLR7 protein. TLR7 is a receptor used by immune cells to identify viral RNA so they can fight off viral infections, including COVID-19. But if the body’s own genetic material binds to TLR7 in susceptible individuals, it can lead to an overproduction of type 1 interferons, which are cytokines that trigger or exacerbate the immune reactions that lead to lupus symptoms. The TLR7 gene occurs on the X chromosome, which may explain men’s greater susceptibility to COVID-19 and the greater incidence of lupus in women, who have two X chromosomes instead of the one that men have, Dr. Vinuesa said.

Previous research had shown an association between TLR7 and lupus, but this new study is the first to provide definitive proof that a TLR7 mutation by itself can directly cause human lupus. After discovering the variant in the patient, Dr. Vinuesa’s team used CRISPR to edit the genome of a mouse model and introduce the same mutation the patient had. “And they developed full-blown disease, just with this one single base-pair substitution – 1 letter in the 3 billion letters of the genome,” Dr. Vinuesa said. “It tells us that these receptors are not just there to recognize viral RNA, that in some circumstances, they could be triggered by our own nucleic acids.”
 

One pathway among many?

The finding does not mean that every lupus patient has this mutation, which remains rare, but suggests that overactivity in this receptor already reported in many lupus patients may be causally related to disease, Dr. Vinuesa said.

Noa Schwartz, MD, an assistant professor of medicine at Albert Einstein College of Medicine, New York, and director of the Montefiore-Einstein Institute for Lupus Care and Research, said in an interview that lupus is thought of as a syndrome, a collection of different but similar diseases that don’t necessarily have a single cause. But finding a single gene mutation that could potentially lead to lupus is an important piece of the puzzle, said Dr. Schwartz, who was not involved in the study. Based on past research in mice models, “we’ve hypothesized that TLR7 is important in humans as well, but this is the last nail in the coffin.”

One of the key questions this finding has prompted is how many patients’ disease results from TLR7 activity. “Because of the evidence from Ignacio Sanz’s group demonstrating TLR7 overactivity in a significant fraction of SLE patients, we believe that it is probably going to be pretty important,” Dr. Vinuesa said. “My feeling is that it is going to be quite a central pathway in lupus pathogenesis, if not the central pathway.”

Dr. Schwartz was more cautious, noting that it is probably important for a subset of patients but may “have a limited effect on the general lupus population.” While it’s not yet clear how large that subset is, it is possible it will include people with cutaneous lupus, those with primarily dermatologic symptoms.

“Hydroxychloroquine works particularly well for cutaneous manifestations of lupus, and one of the ways that works is by inhibiting TLR7 and TLR9, so this [finding] potentially matters for skin disease and lupus, but it’s very early,” Dr. Schwartz said. If it does turn out that TLR7 activity is particularly associated with cutaneous lupus, it may mean therapies with fewer side effects, she said. “Specifically for cutaneous lupus, the concept of suppressing the entire immune system for skin illness sometimes feels, especially to patients, very extreme, so they are [patients] who directed therapy could be so especially relevant for.”

Laura Lewandowski, MD, an assistant clinical investigator and head of the lupus genomics and global health disparities unit at the National Institute of Arthritis and Musculoskeletal and Skin Disease, described this study as particularly remarkable in the way it revealed the mechanism leading to lupus symptoms.

“As whole genome sequencing becomes faster and less expensive, more and more people are employing them in their studies,” most of which report changes in certain genes, Dr. Lewandowski said. “One of the most striking findings about this paper was that they took it to the next step and did a really elegant study on the exact way this gain-of-function TLR7 mutation leads to the autoimmunity that we see in lupus. The detail of mechanism in this paper is really unique.”
 

A step toward personalized medicine

Dr. Lewandowski is part of a team that recently presented a poster related to genomic sequencing in lupus patients at the annual meeting of the Childhood Arthritis and Rheumatology Research Alliance. Her study reported on the whole genome sequencing of patients with childhood-onset SLE who were already enrolled in the CARRA Lupus Registry. Children with lupus may be more likely than adults to have rare genetic variants, so a registry of childhood-onset SLE patients with fully sequenced genomes provides an opportunity to look for single-gene mutations specifically linked to lupus, said Dr. Lewandowski, who has recently begun a research collaboration with Dr. Vinuesa.

“As we move forward and more and more patients are included in these studies, we will understand a little bit more about the genetic architecture of patients who have rare variations leading to disease, or even common variations,” Dr. Lewandowski said about the intersection between her research and Dr. Vinuesa’s study. The more data they gather, the more they can explore the possible interactions of rare and common variants that play a role in SLE as well as what environmental triggers, such as viral infection or pollution exposure, might tip someone into having an autoimmune disease. “We’re just starting to peek under the hood,” Dr. Lewandowski said.

If further research can reveal the relative contribution of genetics to the disease and what those genetic drivers are, it may allow for greater precision in therapies and “ultimately improve the quality of life for our patients, the ultimate goal of all of these studies,” Dr. Lewandowski said.

Drugs that target TLR7 already exist for other indications, and clinical trials have already begun to see if these TLR7 inhibitors benefit lupus patients.

“If the clinical trials work, this will be quite a nice, targeted therapy with potentially much less side effects than other therapies on the market at the moment,” Dr. Vinuesa said. She is cautiously hopeful, saying it’s likely to make an impact on lupus treatment, but it’s too early to say precisely how much.

“It allows us to understand the disease mechanisms a little bit better and to try and assess what percentage of patients’ disease can be explained by overactivity in this receptor,” Dr. Vinuesa said. She thinks it’s possible that TLR7 over activation may be relevant to other systemic autoimmune diseases as well, such as Sjögren’s syndrome, rheumatoid arthritis, or juvenile dermatomyositis, but it will take more studies to find out.

“Right now, we have medicines that broadly inhibit the immune system and aren’t as targeted, but we have a lot more clinical and scientific work to do before we move this field forward for lupus patients,” Dr. Lewandowski said. “This is one case where they were able to find the exact molecular defect, and it’s not the end of the path of precision medicine — it’s the beginning.”

Dr. Vinuesa, Dr. Schwartz, and Dr. Lewandowski reported no disclosures.

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

The Pfizer-BioNTech mRNA vaccine (Comirnaty) showed a good safety profile with minimal short-term side effects and no negative impact on disease activity in a cohort of adolescents and young adults with rheumatic diseases, according to research presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance, held virtually this year.

Only 3% of patients experience a severe transient adverse event, according to Merav Heshin-Bekenstein, MD, of Dana-Dwek Children’s Hospital at the Tel Aviv Sourasky Medical Center in Israel. The findings were published in Rheumatology.

Courtesy Dr. Heshin-Bekenstein

“We found that the mRNA Pfizer vaccine was immunogenic and induced an adequate humoral immune response in adolescent patients,” Dr. Heshin-Bekenstein told CARRA attendees. “It was definitely comparable to healthy controls and practically all patients were seropositive following the second vaccine, except for one patient with long-standing systemic sclerosis.”

The findings were not necessarily surprising but were encouraging to Melissa S. Oliver, MD, assistant professor of clinical pediatrics in the division of pediatric rheumatology at Indiana University, Indianapolis. Dr. Oliver wasn’t part of the study team.

“We know that the COVID vaccines in healthy adolescents have shown good efficacy with minimal side effects, and it’s good to see that this study showed that in those with rheumatic diseases on immunosuppressive therapy,” Dr. Oliver told this news organization.

Until now, the data on COVID-19 vaccines in teens with rheumatic illnesses has been limited, she said, so “many pediatric rheumatologists only have the data from adult studies to go on or personal experience with their own cohort of patients.”

But the high immunogenicity seen in the study was a pleasant surprise to Beth H. Rutstein, MD, assistant professor of clinical pediatrics in the division of rheumatology at Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania.

“I was both surprised and thrilled with Dr. Heshin-Bekenstein’s findings suggesting near-universal seroconversion for patients with rheumatic disease regardless of underlying diagnosis or immunomodulatory therapy regimen, as much of the adult data has suggested a poorer seroconversion rate” and lower antibody titers in adults with similar illnesses, Dr. Rutstein said in an interview.

The study “provides essential reassurance that vaccination against COVID-19 does not increase the risk of disease flare or worsen disease severity scores,” said Dr. Rutstein, who was not associated with the research. “Rather than speaking purely anecdotally with our patients and their families, we can refer to the science – which is always more reassuring for both our patients and ourselves.”
 

Study included diverse conditions and therapies

Risk factors for poor outcomes with COVID-19 in children include obesity, cardiovascular disease, chronic lung disease, diabetes, and asthma, Dr. Heshin-Bekenstein told CARRA attendees. Multisystem inflammatory syndrome in children (MIS-C) and long COVID are also potential complications of COVID-19 with less understood risk factors.

Although COVID-19 is most often mild in children, certain severe, systemic rheumatic diseases increase hospitalization risk, including systemic lupus erythematosus (SLE) and vasculitis. Evidence has also shown that COVID-19 infection increases the risk of disease flare in teens with juvenile-onset rheumatic diseases, so it’s “crucial to prevent COVID-19 disease in this population,” Dr. Heshin-Bekenstein said.

Her study therefore aimed to assess the safety and immunogenicity of the Pfizer mRNA vaccine for teens with juvenile-onset rheumatic diseases and those taking immunomodulatory medications. The international prospective multicenter study ran from April to November 2021 at three pediatric rheumatology clinics in Israel and one in Slovenia. Endpoints included short-term side effects, vaccination impact on clinical disease activity, immunogenicity at 2-9 weeks after the second dose, and, secondarily, efficacy against COVID-19 infection.

The 91 participants included adolescents aged 12-18 and young adults aged 18-21. Nearly half of the participants (46%) had juvenile idiopathic arthritis (JIA), and 14% had SLE. Other participants’ conditions included systemic vasculitis, idiopathic uveitis, inflammatory bowel disease–related arthritis, systemic or localized scleroderma, juvenile dermatomyositis, or an autoinflammatory disease. Participants’ mean disease duration was 4.8 years.  

The researchers compared the patients with a control group of 40 individuals with similar demographics but without rheumatic disease. The researchers used the LIAISON quantitative assay to assess serum IgG antibody levels against the SARS-CoV-2 spike protein in both groups.

Eight in 10 participants with rheumatic disease were taking an immunomodulatory medication, including a conventional synthetic disease-modifying antirheumatic drug (csDMARD) in 40%, a biologic DMARD in 37%, tumor necrosis factor (TNF) inhibitors in 32%, hydroxychloroquine (HCQ) in 19%, glucocorticoids in 14%, and mycophenolate in 11%. A smaller proportion were on other biologics: JAK inhibitors in 6.6%, anti-CD20 drugs in 4.4%, and an IL-6 inhibitor in 1%.
 

Side effects similar in both groups

None of the side effects reported by participants were statistically different between those with rheumatic disease and the control group. Localized pain was the most common side effect, reported by 73%-79% of participants after each dose. About twice as many participants with rheumatic disease experienced muscle aches and joint pains, compared with the control group, but the differences were not significant. Fever occurred more often in those with rheumatic disease (6%, five cases) than without (3%, one case). One-third of those with rheumatic disease felt tiredness, compared with 20% of the control group.

None of the healthy controls were hospitalized after vaccination, but three rheumatic patients were, including two after the first dose. Both were 17 years old, had systemic vasculitis with granulomatosis with polyangiitis (GPA), and were taking rituximab (Rituxan). One patient experienced acute onset of chronic renal failure, fever, dehydration, and high C-reactive protein within hours of vaccination. The other experienced new onset of pulmonary hemorrhage a week after vaccination.

In addition, a 14-year-old female with lupus, taking only HCQ, went to the emergency department with fever, headache, vomiting, and joint pain 1 day after the second vaccine dose. She had normal inflammatory markers and no change in disease activity score, and she was discharged with low-dose steroids tapered after 2 weeks.
 

Immune response high in patients with rheumatic disease

Immunogenicity was similar in both groups, with 97% seropositivity in the rheumatic disease group and 100% in the control group. Average IgG titers were 242 in the rheumatic group and 388 in the control group (P < .0001). Seropositivity was 88% in those taking mycophenolate with another drug (100% with mycophenolate monotherapy), 90% with HCQ, 94% with any csDMARDs and another drug (100% with csDMARD monotherapy), and 100% for all other drugs. During 3 months’ follow-up after vaccination, there were no COVID-19 cases among the participants.

Dr. Heshin-Bekenstein noted that their results showed better immunogenicity in teens, compared with adults, for two specific drugs. Seropositivity in teens taking methotrexate (Rheumatrex, Trexall) or rituximab was 100% in this study, compared with 84% in adults taking methotrexate and 39% in adults taking rituximab in a previous study. However, only three patients in this study were taking rituximab, and only seven were taking methotrexate.

The study’s heterogenous population was both a strength and a weakness of the study. “Due to the diversity of rheumatic diseases and medications included in this cohort, it was not possible to draw significant conclusions regarding the impact of the immunomodulatory medications and type of disease” on titers, Dr. Heshin-Bekenstein told attendees.

Still, “I think as pediatric rheumatologists, we can feel reassured in recommending the COVID-19 vaccine to our patients,” Dr. Oliver said. “I will add that every patient is different, and everyone should have a conversation with their physician about receiving the COVID-19 vaccine.” Dr. Oliver said she discusses vaccination, including COVID vaccination, with every patient, and it’s been challenging to address concerns in the midst of so much misinformation circulating about the vaccine.

These findings do raise questions about whether it’s still necessary to hold immunomodulatory medications to get the vaccine,” Dr. Rutstein said.

“Many families are nervous to pause their medications before and after the vaccine as is currently recommended for many therapies by the American College of Rheumatology, and I do share that concern for some of my patients with more clinically unstable disease, so I try to work with each family to decide on best timing and have delayed or deferred the series until some patients are on a steady dose of a new immunomodulatory medication if it has been recently started,” Dr. Rutstein said. “This is one of the reasons why Dr. Heshin-Bekenstein’s study is so important – we may be holding medications that can be safely continued and even further decrease the risk of disease flare.”

None of the physicians have disclosed any relevant financial relationships.

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

The Pfizer-BioNTech mRNA vaccine (Comirnaty) showed a good safety profile with minimal short-term side effects and no negative impact on disease activity in a cohort of adolescents and young adults with rheumatic diseases, according to research presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance, held virtually this year.

Only 3% of patients experience a severe transient adverse event, according to Merav Heshin-Bekenstein, MD, of Dana-Dwek Children’s Hospital at the Tel Aviv Sourasky Medical Center in Israel. The findings were published in Rheumatology.

Courtesy Dr. Heshin-Bekenstein

“We found that the mRNA Pfizer vaccine was immunogenic and induced an adequate humoral immune response in adolescent patients,” Dr. Heshin-Bekenstein told CARRA attendees. “It was definitely comparable to healthy controls and practically all patients were seropositive following the second vaccine, except for one patient with long-standing systemic sclerosis.”

The findings were not necessarily surprising but were encouraging to Melissa S. Oliver, MD, assistant professor of clinical pediatrics in the division of pediatric rheumatology at Indiana University, Indianapolis. Dr. Oliver wasn’t part of the study team.

“We know that the COVID vaccines in healthy adolescents have shown good efficacy with minimal side effects, and it’s good to see that this study showed that in those with rheumatic diseases on immunosuppressive therapy,” Dr. Oliver told this news organization.

Until now, the data on COVID-19 vaccines in teens with rheumatic illnesses has been limited, she said, so “many pediatric rheumatologists only have the data from adult studies to go on or personal experience with their own cohort of patients.”

But the high immunogenicity seen in the study was a pleasant surprise to Beth H. Rutstein, MD, assistant professor of clinical pediatrics in the division of rheumatology at Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania.

“I was both surprised and thrilled with Dr. Heshin-Bekenstein’s findings suggesting near-universal seroconversion for patients with rheumatic disease regardless of underlying diagnosis or immunomodulatory therapy regimen, as much of the adult data has suggested a poorer seroconversion rate” and lower antibody titers in adults with similar illnesses, Dr. Rutstein said in an interview.

The study “provides essential reassurance that vaccination against COVID-19 does not increase the risk of disease flare or worsen disease severity scores,” said Dr. Rutstein, who was not associated with the research. “Rather than speaking purely anecdotally with our patients and their families, we can refer to the science – which is always more reassuring for both our patients and ourselves.”
 

Study included diverse conditions and therapies

Risk factors for poor outcomes with COVID-19 in children include obesity, cardiovascular disease, chronic lung disease, diabetes, and asthma, Dr. Heshin-Bekenstein told CARRA attendees. Multisystem inflammatory syndrome in children (MIS-C) and long COVID are also potential complications of COVID-19 with less understood risk factors.

Although COVID-19 is most often mild in children, certain severe, systemic rheumatic diseases increase hospitalization risk, including systemic lupus erythematosus (SLE) and vasculitis. Evidence has also shown that COVID-19 infection increases the risk of disease flare in teens with juvenile-onset rheumatic diseases, so it’s “crucial to prevent COVID-19 disease in this population,” Dr. Heshin-Bekenstein said.

Her study therefore aimed to assess the safety and immunogenicity of the Pfizer mRNA vaccine for teens with juvenile-onset rheumatic diseases and those taking immunomodulatory medications. The international prospective multicenter study ran from April to November 2021 at three pediatric rheumatology clinics in Israel and one in Slovenia. Endpoints included short-term side effects, vaccination impact on clinical disease activity, immunogenicity at 2-9 weeks after the second dose, and, secondarily, efficacy against COVID-19 infection.

The 91 participants included adolescents aged 12-18 and young adults aged 18-21. Nearly half of the participants (46%) had juvenile idiopathic arthritis (JIA), and 14% had SLE. Other participants’ conditions included systemic vasculitis, idiopathic uveitis, inflammatory bowel disease–related arthritis, systemic or localized scleroderma, juvenile dermatomyositis, or an autoinflammatory disease. Participants’ mean disease duration was 4.8 years.  

The researchers compared the patients with a control group of 40 individuals with similar demographics but without rheumatic disease. The researchers used the LIAISON quantitative assay to assess serum IgG antibody levels against the SARS-CoV-2 spike protein in both groups.

Eight in 10 participants with rheumatic disease were taking an immunomodulatory medication, including a conventional synthetic disease-modifying antirheumatic drug (csDMARD) in 40%, a biologic DMARD in 37%, tumor necrosis factor (TNF) inhibitors in 32%, hydroxychloroquine (HCQ) in 19%, glucocorticoids in 14%, and mycophenolate in 11%. A smaller proportion were on other biologics: JAK inhibitors in 6.6%, anti-CD20 drugs in 4.4%, and an IL-6 inhibitor in 1%.
 

Side effects similar in both groups

None of the side effects reported by participants were statistically different between those with rheumatic disease and the control group. Localized pain was the most common side effect, reported by 73%-79% of participants after each dose. About twice as many participants with rheumatic disease experienced muscle aches and joint pains, compared with the control group, but the differences were not significant. Fever occurred more often in those with rheumatic disease (6%, five cases) than without (3%, one case). One-third of those with rheumatic disease felt tiredness, compared with 20% of the control group.

None of the healthy controls were hospitalized after vaccination, but three rheumatic patients were, including two after the first dose. Both were 17 years old, had systemic vasculitis with granulomatosis with polyangiitis (GPA), and were taking rituximab (Rituxan). One patient experienced acute onset of chronic renal failure, fever, dehydration, and high C-reactive protein within hours of vaccination. The other experienced new onset of pulmonary hemorrhage a week after vaccination.

In addition, a 14-year-old female with lupus, taking only HCQ, went to the emergency department with fever, headache, vomiting, and joint pain 1 day after the second vaccine dose. She had normal inflammatory markers and no change in disease activity score, and she was discharged with low-dose steroids tapered after 2 weeks.
 

Immune response high in patients with rheumatic disease

Immunogenicity was similar in both groups, with 97% seropositivity in the rheumatic disease group and 100% in the control group. Average IgG titers were 242 in the rheumatic group and 388 in the control group (P < .0001). Seropositivity was 88% in those taking mycophenolate with another drug (100% with mycophenolate monotherapy), 90% with HCQ, 94% with any csDMARDs and another drug (100% with csDMARD monotherapy), and 100% for all other drugs. During 3 months’ follow-up after vaccination, there were no COVID-19 cases among the participants.

Dr. Heshin-Bekenstein noted that their results showed better immunogenicity in teens, compared with adults, for two specific drugs. Seropositivity in teens taking methotrexate (Rheumatrex, Trexall) or rituximab was 100% in this study, compared with 84% in adults taking methotrexate and 39% in adults taking rituximab in a previous study. However, only three patients in this study were taking rituximab, and only seven were taking methotrexate.

The study’s heterogenous population was both a strength and a weakness of the study. “Due to the diversity of rheumatic diseases and medications included in this cohort, it was not possible to draw significant conclusions regarding the impact of the immunomodulatory medications and type of disease” on titers, Dr. Heshin-Bekenstein told attendees.

Still, “I think as pediatric rheumatologists, we can feel reassured in recommending the COVID-19 vaccine to our patients,” Dr. Oliver said. “I will add that every patient is different, and everyone should have a conversation with their physician about receiving the COVID-19 vaccine.” Dr. Oliver said she discusses vaccination, including COVID vaccination, with every patient, and it’s been challenging to address concerns in the midst of so much misinformation circulating about the vaccine.

These findings do raise questions about whether it’s still necessary to hold immunomodulatory medications to get the vaccine,” Dr. Rutstein said.

“Many families are nervous to pause their medications before and after the vaccine as is currently recommended for many therapies by the American College of Rheumatology, and I do share that concern for some of my patients with more clinically unstable disease, so I try to work with each family to decide on best timing and have delayed or deferred the series until some patients are on a steady dose of a new immunomodulatory medication if it has been recently started,” Dr. Rutstein said. “This is one of the reasons why Dr. Heshin-Bekenstein’s study is so important – we may be holding medications that can be safely continued and even further decrease the risk of disease flare.”

None of the physicians have disclosed any relevant financial relationships.

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

The Pfizer-BioNTech mRNA vaccine (Comirnaty) showed a good safety profile with minimal short-term side effects and no negative impact on disease activity in a cohort of adolescents and young adults with rheumatic diseases, according to research presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance, held virtually this year.

Only 3% of patients experience a severe transient adverse event, according to Merav Heshin-Bekenstein, MD, of Dana-Dwek Children’s Hospital at the Tel Aviv Sourasky Medical Center in Israel. The findings were published in Rheumatology.

Courtesy Dr. Heshin-Bekenstein

“We found that the mRNA Pfizer vaccine was immunogenic and induced an adequate humoral immune response in adolescent patients,” Dr. Heshin-Bekenstein told CARRA attendees. “It was definitely comparable to healthy controls and practically all patients were seropositive following the second vaccine, except for one patient with long-standing systemic sclerosis.”

The findings were not necessarily surprising but were encouraging to Melissa S. Oliver, MD, assistant professor of clinical pediatrics in the division of pediatric rheumatology at Indiana University, Indianapolis. Dr. Oliver wasn’t part of the study team.

“We know that the COVID vaccines in healthy adolescents have shown good efficacy with minimal side effects, and it’s good to see that this study showed that in those with rheumatic diseases on immunosuppressive therapy,” Dr. Oliver told this news organization.

Until now, the data on COVID-19 vaccines in teens with rheumatic illnesses has been limited, she said, so “many pediatric rheumatologists only have the data from adult studies to go on or personal experience with their own cohort of patients.”

But the high immunogenicity seen in the study was a pleasant surprise to Beth H. Rutstein, MD, assistant professor of clinical pediatrics in the division of rheumatology at Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania.

“I was both surprised and thrilled with Dr. Heshin-Bekenstein’s findings suggesting near-universal seroconversion for patients with rheumatic disease regardless of underlying diagnosis or immunomodulatory therapy regimen, as much of the adult data has suggested a poorer seroconversion rate” and lower antibody titers in adults with similar illnesses, Dr. Rutstein said in an interview.

The study “provides essential reassurance that vaccination against COVID-19 does not increase the risk of disease flare or worsen disease severity scores,” said Dr. Rutstein, who was not associated with the research. “Rather than speaking purely anecdotally with our patients and their families, we can refer to the science – which is always more reassuring for both our patients and ourselves.”
 

Study included diverse conditions and therapies

Risk factors for poor outcomes with COVID-19 in children include obesity, cardiovascular disease, chronic lung disease, diabetes, and asthma, Dr. Heshin-Bekenstein told CARRA attendees. Multisystem inflammatory syndrome in children (MIS-C) and long COVID are also potential complications of COVID-19 with less understood risk factors.

Although COVID-19 is most often mild in children, certain severe, systemic rheumatic diseases increase hospitalization risk, including systemic lupus erythematosus (SLE) and vasculitis. Evidence has also shown that COVID-19 infection increases the risk of disease flare in teens with juvenile-onset rheumatic diseases, so it’s “crucial to prevent COVID-19 disease in this population,” Dr. Heshin-Bekenstein said.

Her study therefore aimed to assess the safety and immunogenicity of the Pfizer mRNA vaccine for teens with juvenile-onset rheumatic diseases and those taking immunomodulatory medications. The international prospective multicenter study ran from April to November 2021 at three pediatric rheumatology clinics in Israel and one in Slovenia. Endpoints included short-term side effects, vaccination impact on clinical disease activity, immunogenicity at 2-9 weeks after the second dose, and, secondarily, efficacy against COVID-19 infection.

The 91 participants included adolescents aged 12-18 and young adults aged 18-21. Nearly half of the participants (46%) had juvenile idiopathic arthritis (JIA), and 14% had SLE. Other participants’ conditions included systemic vasculitis, idiopathic uveitis, inflammatory bowel disease–related arthritis, systemic or localized scleroderma, juvenile dermatomyositis, or an autoinflammatory disease. Participants’ mean disease duration was 4.8 years.  

The researchers compared the patients with a control group of 40 individuals with similar demographics but without rheumatic disease. The researchers used the LIAISON quantitative assay to assess serum IgG antibody levels against the SARS-CoV-2 spike protein in both groups.

Eight in 10 participants with rheumatic disease were taking an immunomodulatory medication, including a conventional synthetic disease-modifying antirheumatic drug (csDMARD) in 40%, a biologic DMARD in 37%, tumor necrosis factor (TNF) inhibitors in 32%, hydroxychloroquine (HCQ) in 19%, glucocorticoids in 14%, and mycophenolate in 11%. A smaller proportion were on other biologics: JAK inhibitors in 6.6%, anti-CD20 drugs in 4.4%, and an IL-6 inhibitor in 1%.
 

Side effects similar in both groups

None of the side effects reported by participants were statistically different between those with rheumatic disease and the control group. Localized pain was the most common side effect, reported by 73%-79% of participants after each dose. About twice as many participants with rheumatic disease experienced muscle aches and joint pains, compared with the control group, but the differences were not significant. Fever occurred more often in those with rheumatic disease (6%, five cases) than without (3%, one case). One-third of those with rheumatic disease felt tiredness, compared with 20% of the control group.

None of the healthy controls were hospitalized after vaccination, but three rheumatic patients were, including two after the first dose. Both were 17 years old, had systemic vasculitis with granulomatosis with polyangiitis (GPA), and were taking rituximab (Rituxan). One patient experienced acute onset of chronic renal failure, fever, dehydration, and high C-reactive protein within hours of vaccination. The other experienced new onset of pulmonary hemorrhage a week after vaccination.

In addition, a 14-year-old female with lupus, taking only HCQ, went to the emergency department with fever, headache, vomiting, and joint pain 1 day after the second vaccine dose. She had normal inflammatory markers and no change in disease activity score, and she was discharged with low-dose steroids tapered after 2 weeks.
 

Immune response high in patients with rheumatic disease

Immunogenicity was similar in both groups, with 97% seropositivity in the rheumatic disease group and 100% in the control group. Average IgG titers were 242 in the rheumatic group and 388 in the control group (P < .0001). Seropositivity was 88% in those taking mycophenolate with another drug (100% with mycophenolate monotherapy), 90% with HCQ, 94% with any csDMARDs and another drug (100% with csDMARD monotherapy), and 100% for all other drugs. During 3 months’ follow-up after vaccination, there were no COVID-19 cases among the participants.

Dr. Heshin-Bekenstein noted that their results showed better immunogenicity in teens, compared with adults, for two specific drugs. Seropositivity in teens taking methotrexate (Rheumatrex, Trexall) or rituximab was 100% in this study, compared with 84% in adults taking methotrexate and 39% in adults taking rituximab in a previous study. However, only three patients in this study were taking rituximab, and only seven were taking methotrexate.

The study’s heterogenous population was both a strength and a weakness of the study. “Due to the diversity of rheumatic diseases and medications included in this cohort, it was not possible to draw significant conclusions regarding the impact of the immunomodulatory medications and type of disease” on titers, Dr. Heshin-Bekenstein told attendees.

Still, “I think as pediatric rheumatologists, we can feel reassured in recommending the COVID-19 vaccine to our patients,” Dr. Oliver said. “I will add that every patient is different, and everyone should have a conversation with their physician about receiving the COVID-19 vaccine.” Dr. Oliver said she discusses vaccination, including COVID vaccination, with every patient, and it’s been challenging to address concerns in the midst of so much misinformation circulating about the vaccine.

These findings do raise questions about whether it’s still necessary to hold immunomodulatory medications to get the vaccine,” Dr. Rutstein said.

“Many families are nervous to pause their medications before and after the vaccine as is currently recommended for many therapies by the American College of Rheumatology, and I do share that concern for some of my patients with more clinically unstable disease, so I try to work with each family to decide on best timing and have delayed or deferred the series until some patients are on a steady dose of a new immunomodulatory medication if it has been recently started,” Dr. Rutstein said. “This is one of the reasons why Dr. Heshin-Bekenstein’s study is so important – we may be holding medications that can be safely continued and even further decrease the risk of disease flare.”

None of the physicians have disclosed any relevant financial relationships.

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