Despite the improved outcomes in rheumatoid arthritis (RA) observed in clinical trials from early use of biologic disease-modifying antirheumatic drugs (bDMARD) in a treat-to-target strategy, real-world use may be limited by stopping medications for various reasons. Burkard and colleagues used the Swiss RA registry to examine potential reasons for discontinuation of bDMARD and targeted synthetic disease-modifying antirheumatic drugs (tsDMARD) among over 2500 adults with RA who stopped these medications from 1999 through 2018. In this cohort study, patients were followed from date of discontinuation of their medication until restarting a bDMARD or tsDMARD. The most common reasons for discontinuation were nonresponse and adverse events; of these patients, over 80% restarted a bDMARD or tsDMARD. Only 8% of patients stopped due to remission; of these, nearly half restarted. The authors found a higher proportion of fibromyalgia among patients who stopped due to nonresponse and adverse events vs due to remission. Oddly, though 40%-50% of patients stopped for "unknown reasons" between 2002 and 2006, this proportion dropped to close to 0 after 2010; during the first time period, the proportions stopping medication due to adverse events and nonresponse were also low, suggesting possible misattribution of the reason for treatment cessation. As such, drawing further conclusions on association of different patient characteristics with reasons for treatment cessation is difficult.

The gap between control of inflammatory joint pain in RA and overall patient outcomes has come up frequently in recent studies. Gwinnutt and colleagues looked at patients participating in three European RA registries, comprising over 2500 patients followed over 8-10 years, and classified them as having high or low inflammation on the basis of Disease Activity Score (DAS28) and analyzed Health Assessment Questionnaire (HAQ) score trajectories as low vs high as a measure of disability. Overall, patients in the three registries had different trajectory patterns, though it appears clear, in keeping with other studies, that a subset of patients remain with high HAQ scores despite decreases in DAS28 scores. Older age; being a woman; and more pain, fatigue, and depressive symptoms were associated with higher HAQ trajectory in both the high and low inflammation pairs, suggesting that this phenomenon is not quite "excess disability" solely in patients with low inflammation.

An additional factor that increases morbidity as well as mortality in RA is frailty, which is associated with age as well as with RA (including people < 65 years old). Hanlon and colleagues examined the change in the "frailty phenotype" over time and its association with adverse clinical outcomes in people with early RA in the Scottish Early Rheumatoid Arthritis (SERA) and UK Biobank cohorts. Frailty was defined by different measures in the two cohorts, including elements of the HAQ disability index for SERA and self-reported fatigue, depression, and poor health for UK Biobank. The computed frailty index was higher in people with higher DAS28 scores and increased with age. Of note, frailty index values were higher prior to treatment initiation and improved somewhat with lower disease activity over time, though those with higher baseline frailty index values tended to have poorer physical function and disease activity over time. Understanding frailty in RA may allow us to better predict and prevent functional limitation, disease progression, and mortality in people with RA.

Of current interest is an observational study by van der Togt and colleagues on the response to COVID-19 vaccines in people with RA being treated with rituximab. Of patients who had previously been treated with 200, 500, or 1000 mg of rituximab prior to COVID-19 vaccination, those who received 200 mg  rituximab as well as those who had longer intervals between rituximab dose and vaccination had a better response to vaccination as defined by immunoglobulins (total, IgG, and IgM) against SARS-CoV-2. Although this study lacked a control arm of people being treated with other disease-modifying antirheumatic drugs and did not evaluate COVID-19 infections or outcomes, its findings do suggest that dosage and timing of rituximab in people with RA should be studied further in regard to vaccine response and infection risk.

Despite the improved outcomes in rheumatoid arthritis (RA) observed in clinical trials from early use of biologic disease-modifying antirheumatic drugs (bDMARD) in a treat-to-target strategy, real-world use may be limited by stopping medications for various reasons. Burkard and colleagues used the Swiss RA registry to examine potential reasons for discontinuation of bDMARD and targeted synthetic disease-modifying antirheumatic drugs (tsDMARD) among over 2500 adults with RA who stopped these medications from 1999 through 2018. In this cohort study, patients were followed from date of discontinuation of their medication until restarting a bDMARD or tsDMARD. The most common reasons for discontinuation were nonresponse and adverse events; of these patients, over 80% restarted a bDMARD or tsDMARD. Only 8% of patients stopped due to remission; of these, nearly half restarted. The authors found a higher proportion of fibromyalgia among patients who stopped due to nonresponse and adverse events vs due to remission. Oddly, though 40%-50% of patients stopped for "unknown reasons" between 2002 and 2006, this proportion dropped to close to 0 after 2010; during the first time period, the proportions stopping medication due to adverse events and nonresponse were also low, suggesting possible misattribution of the reason for treatment cessation. As such, drawing further conclusions on association of different patient characteristics with reasons for treatment cessation is difficult.

The gap between control of inflammatory joint pain in RA and overall patient outcomes has come up frequently in recent studies. Gwinnutt and colleagues looked at patients participating in three European RA registries, comprising over 2500 patients followed over 8-10 years, and classified them as having high or low inflammation on the basis of Disease Activity Score (DAS28) and analyzed Health Assessment Questionnaire (HAQ) score trajectories as low vs high as a measure of disability. Overall, patients in the three registries had different trajectory patterns, though it appears clear, in keeping with other studies, that a subset of patients remain with high HAQ scores despite decreases in DAS28 scores. Older age; being a woman; and more pain, fatigue, and depressive symptoms were associated with higher HAQ trajectory in both the high and low inflammation pairs, suggesting that this phenomenon is not quite "excess disability" solely in patients with low inflammation.

An additional factor that increases morbidity as well as mortality in RA is frailty, which is associated with age as well as with RA (including people < 65 years old). Hanlon and colleagues examined the change in the "frailty phenotype" over time and its association with adverse clinical outcomes in people with early RA in the Scottish Early Rheumatoid Arthritis (SERA) and UK Biobank cohorts. Frailty was defined by different measures in the two cohorts, including elements of the HAQ disability index for SERA and self-reported fatigue, depression, and poor health for UK Biobank. The computed frailty index was higher in people with higher DAS28 scores and increased with age. Of note, frailty index values were higher prior to treatment initiation and improved somewhat with lower disease activity over time, though those with higher baseline frailty index values tended to have poorer physical function and disease activity over time. Understanding frailty in RA may allow us to better predict and prevent functional limitation, disease progression, and mortality in people with RA.

Of current interest is an observational study by van der Togt and colleagues on the response to COVID-19 vaccines in people with RA being treated with rituximab. Of patients who had previously been treated with 200, 500, or 1000 mg of rituximab prior to COVID-19 vaccination, those who received 200 mg  rituximab as well as those who had longer intervals between rituximab dose and vaccination had a better response to vaccination as defined by immunoglobulins (total, IgG, and IgM) against SARS-CoV-2. Although this study lacked a control arm of people being treated with other disease-modifying antirheumatic drugs and did not evaluate COVID-19 infections or outcomes, its findings do suggest that dosage and timing of rituximab in people with RA should be studied further in regard to vaccine response and infection risk.

Despite the improved outcomes in rheumatoid arthritis (RA) observed in clinical trials from early use of biologic disease-modifying antirheumatic drugs (bDMARD) in a treat-to-target strategy, real-world use may be limited by stopping medications for various reasons. Burkard and colleagues used the Swiss RA registry to examine potential reasons for discontinuation of bDMARD and targeted synthetic disease-modifying antirheumatic drugs (tsDMARD) among over 2500 adults with RA who stopped these medications from 1999 through 2018. In this cohort study, patients were followed from date of discontinuation of their medication until restarting a bDMARD or tsDMARD. The most common reasons for discontinuation were nonresponse and adverse events; of these patients, over 80% restarted a bDMARD or tsDMARD. Only 8% of patients stopped due to remission; of these, nearly half restarted. The authors found a higher proportion of fibromyalgia among patients who stopped due to nonresponse and adverse events vs due to remission. Oddly, though 40%-50% of patients stopped for "unknown reasons" between 2002 and 2006, this proportion dropped to close to 0 after 2010; during the first time period, the proportions stopping medication due to adverse events and nonresponse were also low, suggesting possible misattribution of the reason for treatment cessation. As such, drawing further conclusions on association of different patient characteristics with reasons for treatment cessation is difficult.

The gap between control of inflammatory joint pain in RA and overall patient outcomes has come up frequently in recent studies. Gwinnutt and colleagues looked at patients participating in three European RA registries, comprising over 2500 patients followed over 8-10 years, and classified them as having high or low inflammation on the basis of Disease Activity Score (DAS28) and analyzed Health Assessment Questionnaire (HAQ) score trajectories as low vs high as a measure of disability. Overall, patients in the three registries had different trajectory patterns, though it appears clear, in keeping with other studies, that a subset of patients remain with high HAQ scores despite decreases in DAS28 scores. Older age; being a woman; and more pain, fatigue, and depressive symptoms were associated with higher HAQ trajectory in both the high and low inflammation pairs, suggesting that this phenomenon is not quite "excess disability" solely in patients with low inflammation.

An additional factor that increases morbidity as well as mortality in RA is frailty, which is associated with age as well as with RA (including people < 65 years old). Hanlon and colleagues examined the change in the "frailty phenotype" over time and its association with adverse clinical outcomes in people with early RA in the Scottish Early Rheumatoid Arthritis (SERA) and UK Biobank cohorts. Frailty was defined by different measures in the two cohorts, including elements of the HAQ disability index for SERA and self-reported fatigue, depression, and poor health for UK Biobank. The computed frailty index was higher in people with higher DAS28 scores and increased with age. Of note, frailty index values were higher prior to treatment initiation and improved somewhat with lower disease activity over time, though those with higher baseline frailty index values tended to have poorer physical function and disease activity over time. Understanding frailty in RA may allow us to better predict and prevent functional limitation, disease progression, and mortality in people with RA.

Of current interest is an observational study by van der Togt and colleagues on the response to COVID-19 vaccines in people with RA being treated with rituximab. Of patients who had previously been treated with 200, 500, or 1000 mg of rituximab prior to COVID-19 vaccination, those who received 200 mg  rituximab as well as those who had longer intervals between rituximab dose and vaccination had a better response to vaccination as defined by immunoglobulins (total, IgG, and IgM) against SARS-CoV-2. Although this study lacked a control arm of people being treated with other disease-modifying antirheumatic drugs and did not evaluate COVID-19 infections or outcomes, its findings do suggest that dosage and timing of rituximab in people with RA should be studied further in regard to vaccine response and infection risk.

Detection of fetal heart defects is an important aspect of prenatal diagnostic ultrasound. A recent study by Haberer and colleagues in the Journal of the American Society of Echocardiography investigated the diagnostic accuracy of fetal echocardiography. They looked at all of the fetuses with major cardiac anomalies diagnosed at a single institution over an 11-year period and compared the fetal echocardiogram reports with postnatal imaging, surgical reports, and autopsies. Of the almost 600 cases examined, 90% of the diagnoses were accurate. The highest rate of accuracy was for univentricular hearts defects (97.6%) and the lowest was with heterotaxy (71.1%). This article is important because findings show that diagnostic accuracy of fetal echocardiography was high for major fetal cardiac defects.

The ability to accurately diagnose placenta accreta prenatally is important to obstetricians because of the increased risk it poses for maternal morbidity and mortality. This issue is considered in a recent systematic review and meta-analysis by Hong and colleagues in the journal Insights into Imaging. They compared ultrasound to MRI for diagnostic accuracy of placenta accreta spectrum disorder (PAS). In the studies they examined, the diagnostic accuracy of ultrasound for PAS had a sensitivity of 0.9 and a specificity of 0.83, while the diagnostic accuracy of MRI had a sensitivity of 0.89 and a specificity of 0.87. This shows that the diagnostic accuracy of PAS is similar for both ultrasound and MRI. Given the significant expense of an MRI, this raises the question of its importance in the role of evaluating patients suspected of placenta accreta.

Precise prenatal diagnosis of estimated fetal weight (EFW) is central to the care of pregnant patients. It allows for appropriate timing of delivery to decrease the risk for stillbirth. A recent article by Visentin and colleagues evaluates prenatal methods for estimation of fetal weight and prediction of small-for-gestational-age (SGA) fetuses. The researchers performed a retrospective review of singleton gestations that were at increased risk for fetal growth restriction from two hospitals. They found that EFW z-scores derived from either the Hadlock method or the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) assessment were similar and more accurate than abdominal circumference (AC) z-scores for detecting SGA infants. This study should open the debate again on how to best measure estimated fetal weight: EFW alone or assessment of both EFW and AC.

Detection of fetal heart defects is an important aspect of prenatal diagnostic ultrasound. A recent study by Haberer and colleagues in the Journal of the American Society of Echocardiography investigated the diagnostic accuracy of fetal echocardiography. They looked at all of the fetuses with major cardiac anomalies diagnosed at a single institution over an 11-year period and compared the fetal echocardiogram reports with postnatal imaging, surgical reports, and autopsies. Of the almost 600 cases examined, 90% of the diagnoses were accurate. The highest rate of accuracy was for univentricular hearts defects (97.6%) and the lowest was with heterotaxy (71.1%). This article is important because findings show that diagnostic accuracy of fetal echocardiography was high for major fetal cardiac defects.

The ability to accurately diagnose placenta accreta prenatally is important to obstetricians because of the increased risk it poses for maternal morbidity and mortality. This issue is considered in a recent systematic review and meta-analysis by Hong and colleagues in the journal Insights into Imaging. They compared ultrasound to MRI for diagnostic accuracy of placenta accreta spectrum disorder (PAS). In the studies they examined, the diagnostic accuracy of ultrasound for PAS had a sensitivity of 0.9 and a specificity of 0.83, while the diagnostic accuracy of MRI had a sensitivity of 0.89 and a specificity of 0.87. This shows that the diagnostic accuracy of PAS is similar for both ultrasound and MRI. Given the significant expense of an MRI, this raises the question of its importance in the role of evaluating patients suspected of placenta accreta.

Precise prenatal diagnosis of estimated fetal weight (EFW) is central to the care of pregnant patients. It allows for appropriate timing of delivery to decrease the risk for stillbirth. A recent article by Visentin and colleagues evaluates prenatal methods for estimation of fetal weight and prediction of small-for-gestational-age (SGA) fetuses. The researchers performed a retrospective review of singleton gestations that were at increased risk for fetal growth restriction from two hospitals. They found that EFW z-scores derived from either the Hadlock method or the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) assessment were similar and more accurate than abdominal circumference (AC) z-scores for detecting SGA infants. This study should open the debate again on how to best measure estimated fetal weight: EFW alone or assessment of both EFW and AC.

Detection of fetal heart defects is an important aspect of prenatal diagnostic ultrasound. A recent study by Haberer and colleagues in the Journal of the American Society of Echocardiography investigated the diagnostic accuracy of fetal echocardiography. They looked at all of the fetuses with major cardiac anomalies diagnosed at a single institution over an 11-year period and compared the fetal echocardiogram reports with postnatal imaging, surgical reports, and autopsies. Of the almost 600 cases examined, 90% of the diagnoses were accurate. The highest rate of accuracy was for univentricular hearts defects (97.6%) and the lowest was with heterotaxy (71.1%). This article is important because findings show that diagnostic accuracy of fetal echocardiography was high for major fetal cardiac defects.

The ability to accurately diagnose placenta accreta prenatally is important to obstetricians because of the increased risk it poses for maternal morbidity and mortality. This issue is considered in a recent systematic review and meta-analysis by Hong and colleagues in the journal Insights into Imaging. They compared ultrasound to MRI for diagnostic accuracy of placenta accreta spectrum disorder (PAS). In the studies they examined, the diagnostic accuracy of ultrasound for PAS had a sensitivity of 0.9 and a specificity of 0.83, while the diagnostic accuracy of MRI had a sensitivity of 0.89 and a specificity of 0.87. This shows that the diagnostic accuracy of PAS is similar for both ultrasound and MRI. Given the significant expense of an MRI, this raises the question of its importance in the role of evaluating patients suspected of placenta accreta.

Precise prenatal diagnosis of estimated fetal weight (EFW) is central to the care of pregnant patients. It allows for appropriate timing of delivery to decrease the risk for stillbirth. A recent article by Visentin and colleagues evaluates prenatal methods for estimation of fetal weight and prediction of small-for-gestational-age (SGA) fetuses. The researchers performed a retrospective review of singleton gestations that were at increased risk for fetal growth restriction from two hospitals. They found that EFW z-scores derived from either the Hadlock method or the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) assessment were similar and more accurate than abdominal circumference (AC) z-scores for detecting SGA infants. This study should open the debate again on how to best measure estimated fetal weight: EFW alone or assessment of both EFW and AC.

This study of antibiotic use in the first 2 years of life in a reasonably standardized primary care office raises issues about antibiotic stewardship that can be the basis for counseling against antibiotics for viral infections or mild uncomplicated acute otitis media (AOM) above 6 months of age. Even unintended and previously undescribed downstream effects of antibiotics should play a role in our decisions and are another nudge toward prudent antibiotic use – for example, watchful waiting (WW) for AOM. 

Some families ask for antibiotics for almost any infection while others may want antibiotics only if really necessary. But maybe patient family wishes are not the main driver, considering a report in Pediatrics (2022;150[1]:e2021055613). They analyzed over 2 million AOM episodes from billing/enrollment records from the MarketScan commercial claims research databases. They reported that, despite WW being the management of choice per American Academy of Pediatrics guidelines for uncomplicated AOM in children over 1 year of age, WW use had not increased between 2015 and 2019. Further, they noted that WW was not related to patient factors or demographics but was associated with specialty and provider. For example, WW use was five times more likely by otolaryngologists than pediatricians and less likely by nonpediatricians than pediatricians. Further, some clinicians used WW a lot, while others almost not at all (high-volume antibiotic prescribers). Of note, having a fever significantly lowered the chance of WW.

Maturing data on antibiotic-related alterations in species distribution and quantity within children’s microbiome plus potential effects on antibody responses to vaccines are ideas families need to hear. I suggest sharing these as part of anticipatory guidance at well-child checks as early in life as is feasible. 

Christopher J. Harrison, MD, is professor, University of Missouri Kansas City School of Medicine, department of medicine, infectious diseases section, Kansas City. He has no financial conflicts of interest.

This study of antibiotic use in the first 2 years of life in a reasonably standardized primary care office raises issues about antibiotic stewardship that can be the basis for counseling against antibiotics for viral infections or mild uncomplicated acute otitis media (AOM) above 6 months of age. Even unintended and previously undescribed downstream effects of antibiotics should play a role in our decisions and are another nudge toward prudent antibiotic use – for example, watchful waiting (WW) for AOM. 

Some families ask for antibiotics for almost any infection while others may want antibiotics only if really necessary. But maybe patient family wishes are not the main driver, considering a report in Pediatrics (2022;150[1]:e2021055613). They analyzed over 2 million AOM episodes from billing/enrollment records from the MarketScan commercial claims research databases. They reported that, despite WW being the management of choice per American Academy of Pediatrics guidelines for uncomplicated AOM in children over 1 year of age, WW use had not increased between 2015 and 2019. Further, they noted that WW was not related to patient factors or demographics but was associated with specialty and provider. For example, WW use was five times more likely by otolaryngologists than pediatricians and less likely by nonpediatricians than pediatricians. Further, some clinicians used WW a lot, while others almost not at all (high-volume antibiotic prescribers). Of note, having a fever significantly lowered the chance of WW.

Maturing data on antibiotic-related alterations in species distribution and quantity within children’s microbiome plus potential effects on antibody responses to vaccines are ideas families need to hear. I suggest sharing these as part of anticipatory guidance at well-child checks as early in life as is feasible. 

Christopher J. Harrison, MD, is professor, University of Missouri Kansas City School of Medicine, department of medicine, infectious diseases section, Kansas City. He has no financial conflicts of interest.

This study of antibiotic use in the first 2 years of life in a reasonably standardized primary care office raises issues about antibiotic stewardship that can be the basis for counseling against antibiotics for viral infections or mild uncomplicated acute otitis media (AOM) above 6 months of age. Even unintended and previously undescribed downstream effects of antibiotics should play a role in our decisions and are another nudge toward prudent antibiotic use – for example, watchful waiting (WW) for AOM. 

Some families ask for antibiotics for almost any infection while others may want antibiotics only if really necessary. But maybe patient family wishes are not the main driver, considering a report in Pediatrics (2022;150[1]:e2021055613). They analyzed over 2 million AOM episodes from billing/enrollment records from the MarketScan commercial claims research databases. They reported that, despite WW being the management of choice per American Academy of Pediatrics guidelines for uncomplicated AOM in children over 1 year of age, WW use had not increased between 2015 and 2019. Further, they noted that WW was not related to patient factors or demographics but was associated with specialty and provider. For example, WW use was five times more likely by otolaryngologists than pediatricians and less likely by nonpediatricians than pediatricians. Further, some clinicians used WW a lot, while others almost not at all (high-volume antibiotic prescribers). Of note, having a fever significantly lowered the chance of WW.

Maturing data on antibiotic-related alterations in species distribution and quantity within children’s microbiome plus potential effects on antibody responses to vaccines are ideas families need to hear. I suggest sharing these as part of anticipatory guidance at well-child checks as early in life as is feasible. 

Christopher J. Harrison, MD, is professor, University of Missouri Kansas City School of Medicine, department of medicine, infectious diseases section, Kansas City. He has no financial conflicts of interest.

In this column I have previously discussed the microbiome and its importance to health, especially as it relates to infections in children. Given the appreciated connection between microbiome and immunity, my group in Rochester, N.Y., recently undertook a study of the effect of antibiotic usage on the immune response to routine early childhood vaccines. In mouse models, it was previously shown that antibiotic exposure induced a reduction in the abundance and diversity of gut microbiota that in turn negatively affected the generation and maintenance of vaccine-induced immunity.^1,2 A study from Stanford University was the first experimental human trial of antibiotic effects on vaccine responses. Adult volunteers were given an antibiotic or not before seasonal influenza vaccination and the researchers identified specific bacteria in the gut that were reduced by the antibiotics given. Those normal bacteria in the gut microbiome were shown to provide positive immunity signals to the systemic immune system that potentiated vaccine responses.³

My group conducted the first-ever study in children to explore whether an association existed between antibiotic use and vaccine-induced antibody levels. In the May issue of Pediatrics we report results from 560 children studied.⁴ From these children, 11,888 serum antibody levels to vaccine antigens were measured. Vaccine-induced antibody levels were determined at various time points after primary vaccination at child age 2, 4, and 6 months and boosters at age 12-18 months for 10 antigens included in four vaccines: DTaP, Hib, IPV, and PCV. The antibody levels to vaccine components were measured to DTaP (diphtheria toxoid, pertussis toxoid, tetanus toxoid, pertactin, and filamentous hemagglutinin), Hib conjugate (polyribosylribitol phosphate), IPV (polio 2), and PCV (serotypes 6B, 14, and 23F). A total of 342 children with 1,678 antibiotic courses prescribed were compared with 218 children with no antibiotic exposures. The predominant antibiotics prescribed were amoxicillin, cefdinir, amoxicillin/clavulanate, and ceftriaxone, since most treatments were for acute otitis media.

Of possible high clinical relevance, we found that from 9 to 24 months of age, children with antibiotic exposure had a higher frequency of vaccine-induced antibody levels below protection compared with children with no antibiotic use, placing them at risk of contracting a vaccine-preventable infection for DTaP antigens DT, TT, and PT and for PCV serotype 14.

For time points where antibody levels were determined within 30 days of completion of a course of antibiotics (recent antibiotic use), individual antibiotics were analyzed for effect on antibody levels below protective levels. Across all vaccine antigens measured, we found that all antibiotics had a negative effect on antibody levels and percentage of children achieving the protective antibody level threshold. Amoxicillin use had a lower association with lower antibody levels than the broader spectrum antibiotics, amoxicillin clavulanate (Augmentin), cefdinir, and ceftriaxone. For children receiving amoxicillin/clavulanate prescriptions, it was possible to compare the effect of shorter versus longer courses and we found that a 5-day course was associated with subprotective antibody levels similar to 10 days of amoxicillin, whereas 10-day amoxicillin/clavulanate was associated with higher frequency of children having subprotective antibody levels (Figure).

We examined whether accumulation of antibiotic courses in the first year of life had an association with subsequent vaccine-induced antibody levels and found that each antibiotic prescription was associated with a reduction in the median antibody level. For DTaP, each prescription was associated with 5.8% drop in antibody level to the vaccine components. For Hib the drop was 6.8%, IPV was 11.3%, and PCV was 10.4% – all statistically significant. To determine if booster vaccination influenced this association, a second analysis was performed using antibiotic prescriptions up to 15 months of age. We found each antibiotic prescription was associated with a reduction in median vaccine-induced antibody levels for DTaP by 18%, Hib by 21%, IPV by 19%, and PCV by 12% – all statistically significant.

Our study is the first in young children during the early age window where vaccine-induced immunity is established. Antibiotic use was associated with increased frequency of subprotective antibody levels for several vaccines used in children up to 2 years of age. The lower antibody levels could leave children vulnerable to vaccine preventable diseases. Perhaps outbreaks of vaccine-preventable diseases, such as pertussis, may be a consequence of multiple courses of antibiotics suppressing vaccine-induced immunity.

A goal of this study was to explore potential acute and long-term effects of antibiotic exposure on vaccine-induced antibody levels. Accumulated antibiotic courses up to booster immunization was associated with decreased vaccine antibody levels both before and after booster, suggesting that booster immunization was not sufficient to change the negative association with antibiotic exposure. The results were similar for all vaccines tested, suggesting that the specific vaccine formulation was not a factor.

The study has several limitations. The antibiotic prescription data and measurements of vaccine-induced antibody levels were recorded and measured prospectively; however, our analysis was done retrospectively. The group of study children was derived from my private practice in Rochester, N.Y., and may not be broadly representative of all children. The number of vaccine antibody measurements was limited by serum availability at some sampling time points in some children; and sometimes, the serum samples were collected far apart, which weakened our ability to perform longitudinal analyses. We did not collect stool samples from the children so we could not directly study the effect of antibiotic courses on the gut microbiome.

Our study adds new reasons to be cautious about overprescribing antibiotics on an individual child basis because an adverse effect extends to reduction in vaccine responses. This should be explained to parents requesting unnecessary antibiotics for colds and coughs. When antibiotics are necessary, the judicious choice of a narrow-spectrum antibiotic or a shorter duration of a broader spectrum antibiotic may reduce adverse effects on vaccine-induced immunity.

References

1. Valdez Y et al. Influence of the microbiota on vaccine effectiveness. Trends Immunol. 2014;35(11):526-37.

2. Lynn MA et al. Early-life antibiotic-driven dysbiosis leads to dysregulated vaccine immune responses in mice. Cell Host Microbe. 2018;23(5):653-60.e5.

3. Hagan T et al. Antibiotics-driven gut microbiome perturbation alters immunity to vaccines in humans. Cell. 2019;178(6):1313-28.e13.

4. Chapman T et al. Antibiotic use and vaccine antibody levels. Pediatrics. 2022;149(5);1-17. doi: 10.1542/peds.2021-052061.

In this column I have previously discussed the microbiome and its importance to health, especially as it relates to infections in children. Given the appreciated connection between microbiome and immunity, my group in Rochester, N.Y., recently undertook a study of the effect of antibiotic usage on the immune response to routine early childhood vaccines. In mouse models, it was previously shown that antibiotic exposure induced a reduction in the abundance and diversity of gut microbiota that in turn negatively affected the generation and maintenance of vaccine-induced immunity.^1,2 A study from Stanford University was the first experimental human trial of antibiotic effects on vaccine responses. Adult volunteers were given an antibiotic or not before seasonal influenza vaccination and the researchers identified specific bacteria in the gut that were reduced by the antibiotics given. Those normal bacteria in the gut microbiome were shown to provide positive immunity signals to the systemic immune system that potentiated vaccine responses.³

My group conducted the first-ever study in children to explore whether an association existed between antibiotic use and vaccine-induced antibody levels. In the May issue of Pediatrics we report results from 560 children studied.⁴ From these children, 11,888 serum antibody levels to vaccine antigens were measured. Vaccine-induced antibody levels were determined at various time points after primary vaccination at child age 2, 4, and 6 months and boosters at age 12-18 months for 10 antigens included in four vaccines: DTaP, Hib, IPV, and PCV. The antibody levels to vaccine components were measured to DTaP (diphtheria toxoid, pertussis toxoid, tetanus toxoid, pertactin, and filamentous hemagglutinin), Hib conjugate (polyribosylribitol phosphate), IPV (polio 2), and PCV (serotypes 6B, 14, and 23F). A total of 342 children with 1,678 antibiotic courses prescribed were compared with 218 children with no antibiotic exposures. The predominant antibiotics prescribed were amoxicillin, cefdinir, amoxicillin/clavulanate, and ceftriaxone, since most treatments were for acute otitis media.

Of possible high clinical relevance, we found that from 9 to 24 months of age, children with antibiotic exposure had a higher frequency of vaccine-induced antibody levels below protection compared with children with no antibiotic use, placing them at risk of contracting a vaccine-preventable infection for DTaP antigens DT, TT, and PT and for PCV serotype 14.

For time points where antibody levels were determined within 30 days of completion of a course of antibiotics (recent antibiotic use), individual antibiotics were analyzed for effect on antibody levels below protective levels. Across all vaccine antigens measured, we found that all antibiotics had a negative effect on antibody levels and percentage of children achieving the protective antibody level threshold. Amoxicillin use had a lower association with lower antibody levels than the broader spectrum antibiotics, amoxicillin clavulanate (Augmentin), cefdinir, and ceftriaxone. For children receiving amoxicillin/clavulanate prescriptions, it was possible to compare the effect of shorter versus longer courses and we found that a 5-day course was associated with subprotective antibody levels similar to 10 days of amoxicillin, whereas 10-day amoxicillin/clavulanate was associated with higher frequency of children having subprotective antibody levels (Figure).

We examined whether accumulation of antibiotic courses in the first year of life had an association with subsequent vaccine-induced antibody levels and found that each antibiotic prescription was associated with a reduction in the median antibody level. For DTaP, each prescription was associated with 5.8% drop in antibody level to the vaccine components. For Hib the drop was 6.8%, IPV was 11.3%, and PCV was 10.4% – all statistically significant. To determine if booster vaccination influenced this association, a second analysis was performed using antibiotic prescriptions up to 15 months of age. We found each antibiotic prescription was associated with a reduction in median vaccine-induced antibody levels for DTaP by 18%, Hib by 21%, IPV by 19%, and PCV by 12% – all statistically significant.

Our study is the first in young children during the early age window where vaccine-induced immunity is established. Antibiotic use was associated with increased frequency of subprotective antibody levels for several vaccines used in children up to 2 years of age. The lower antibody levels could leave children vulnerable to vaccine preventable diseases. Perhaps outbreaks of vaccine-preventable diseases, such as pertussis, may be a consequence of multiple courses of antibiotics suppressing vaccine-induced immunity.

A goal of this study was to explore potential acute and long-term effects of antibiotic exposure on vaccine-induced antibody levels. Accumulated antibiotic courses up to booster immunization was associated with decreased vaccine antibody levels both before and after booster, suggesting that booster immunization was not sufficient to change the negative association with antibiotic exposure. The results were similar for all vaccines tested, suggesting that the specific vaccine formulation was not a factor.

The study has several limitations. The antibiotic prescription data and measurements of vaccine-induced antibody levels were recorded and measured prospectively; however, our analysis was done retrospectively. The group of study children was derived from my private practice in Rochester, N.Y., and may not be broadly representative of all children. The number of vaccine antibody measurements was limited by serum availability at some sampling time points in some children; and sometimes, the serum samples were collected far apart, which weakened our ability to perform longitudinal analyses. We did not collect stool samples from the children so we could not directly study the effect of antibiotic courses on the gut microbiome.

Our study adds new reasons to be cautious about overprescribing antibiotics on an individual child basis because an adverse effect extends to reduction in vaccine responses. This should be explained to parents requesting unnecessary antibiotics for colds and coughs. When antibiotics are necessary, the judicious choice of a narrow-spectrum antibiotic or a shorter duration of a broader spectrum antibiotic may reduce adverse effects on vaccine-induced immunity.

References

1. Valdez Y et al. Influence of the microbiota on vaccine effectiveness. Trends Immunol. 2014;35(11):526-37.

2. Lynn MA et al. Early-life antibiotic-driven dysbiosis leads to dysregulated vaccine immune responses in mice. Cell Host Microbe. 2018;23(5):653-60.e5.

3. Hagan T et al. Antibiotics-driven gut microbiome perturbation alters immunity to vaccines in humans. Cell. 2019;178(6):1313-28.e13.

4. Chapman T et al. Antibiotic use and vaccine antibody levels. Pediatrics. 2022;149(5);1-17. doi: 10.1542/peds.2021-052061.

In this column I have previously discussed the microbiome and its importance to health, especially as it relates to infections in children. Given the appreciated connection between microbiome and immunity, my group in Rochester, N.Y., recently undertook a study of the effect of antibiotic usage on the immune response to routine early childhood vaccines. In mouse models, it was previously shown that antibiotic exposure induced a reduction in the abundance and diversity of gut microbiota that in turn negatively affected the generation and maintenance of vaccine-induced immunity.^1,2 A study from Stanford University was the first experimental human trial of antibiotic effects on vaccine responses. Adult volunteers were given an antibiotic or not before seasonal influenza vaccination and the researchers identified specific bacteria in the gut that were reduced by the antibiotics given. Those normal bacteria in the gut microbiome were shown to provide positive immunity signals to the systemic immune system that potentiated vaccine responses.³

My group conducted the first-ever study in children to explore whether an association existed between antibiotic use and vaccine-induced antibody levels. In the May issue of Pediatrics we report results from 560 children studied.⁴ From these children, 11,888 serum antibody levels to vaccine antigens were measured. Vaccine-induced antibody levels were determined at various time points after primary vaccination at child age 2, 4, and 6 months and boosters at age 12-18 months for 10 antigens included in four vaccines: DTaP, Hib, IPV, and PCV. The antibody levels to vaccine components were measured to DTaP (diphtheria toxoid, pertussis toxoid, tetanus toxoid, pertactin, and filamentous hemagglutinin), Hib conjugate (polyribosylribitol phosphate), IPV (polio 2), and PCV (serotypes 6B, 14, and 23F). A total of 342 children with 1,678 antibiotic courses prescribed were compared with 218 children with no antibiotic exposures. The predominant antibiotics prescribed were amoxicillin, cefdinir, amoxicillin/clavulanate, and ceftriaxone, since most treatments were for acute otitis media.

Of possible high clinical relevance, we found that from 9 to 24 months of age, children with antibiotic exposure had a higher frequency of vaccine-induced antibody levels below protection compared with children with no antibiotic use, placing them at risk of contracting a vaccine-preventable infection for DTaP antigens DT, TT, and PT and for PCV serotype 14.

For time points where antibody levels were determined within 30 days of completion of a course of antibiotics (recent antibiotic use), individual antibiotics were analyzed for effect on antibody levels below protective levels. Across all vaccine antigens measured, we found that all antibiotics had a negative effect on antibody levels and percentage of children achieving the protective antibody level threshold. Amoxicillin use had a lower association with lower antibody levels than the broader spectrum antibiotics, amoxicillin clavulanate (Augmentin), cefdinir, and ceftriaxone. For children receiving amoxicillin/clavulanate prescriptions, it was possible to compare the effect of shorter versus longer courses and we found that a 5-day course was associated with subprotective antibody levels similar to 10 days of amoxicillin, whereas 10-day amoxicillin/clavulanate was associated with higher frequency of children having subprotective antibody levels (Figure).

We examined whether accumulation of antibiotic courses in the first year of life had an association with subsequent vaccine-induced antibody levels and found that each antibiotic prescription was associated with a reduction in the median antibody level. For DTaP, each prescription was associated with 5.8% drop in antibody level to the vaccine components. For Hib the drop was 6.8%, IPV was 11.3%, and PCV was 10.4% – all statistically significant. To determine if booster vaccination influenced this association, a second analysis was performed using antibiotic prescriptions up to 15 months of age. We found each antibiotic prescription was associated with a reduction in median vaccine-induced antibody levels for DTaP by 18%, Hib by 21%, IPV by 19%, and PCV by 12% – all statistically significant.

Our study is the first in young children during the early age window where vaccine-induced immunity is established. Antibiotic use was associated with increased frequency of subprotective antibody levels for several vaccines used in children up to 2 years of age. The lower antibody levels could leave children vulnerable to vaccine preventable diseases. Perhaps outbreaks of vaccine-preventable diseases, such as pertussis, may be a consequence of multiple courses of antibiotics suppressing vaccine-induced immunity.

A goal of this study was to explore potential acute and long-term effects of antibiotic exposure on vaccine-induced antibody levels. Accumulated antibiotic courses up to booster immunization was associated with decreased vaccine antibody levels both before and after booster, suggesting that booster immunization was not sufficient to change the negative association with antibiotic exposure. The results were similar for all vaccines tested, suggesting that the specific vaccine formulation was not a factor.

The study has several limitations. The antibiotic prescription data and measurements of vaccine-induced antibody levels were recorded and measured prospectively; however, our analysis was done retrospectively. The group of study children was derived from my private practice in Rochester, N.Y., and may not be broadly representative of all children. The number of vaccine antibody measurements was limited by serum availability at some sampling time points in some children; and sometimes, the serum samples were collected far apart, which weakened our ability to perform longitudinal analyses. We did not collect stool samples from the children so we could not directly study the effect of antibiotic courses on the gut microbiome.

Our study adds new reasons to be cautious about overprescribing antibiotics on an individual child basis because an adverse effect extends to reduction in vaccine responses. This should be explained to parents requesting unnecessary antibiotics for colds and coughs. When antibiotics are necessary, the judicious choice of a narrow-spectrum antibiotic or a shorter duration of a broader spectrum antibiotic may reduce adverse effects on vaccine-induced immunity.

References

1. Valdez Y et al. Influence of the microbiota on vaccine effectiveness. Trends Immunol. 2014;35(11):526-37.

2. Lynn MA et al. Early-life antibiotic-driven dysbiosis leads to dysregulated vaccine immune responses in mice. Cell Host Microbe. 2018;23(5):653-60.e5.

3. Hagan T et al. Antibiotics-driven gut microbiome perturbation alters immunity to vaccines in humans. Cell. 2019;178(6):1313-28.e13.

4. Chapman T et al. Antibiotic use and vaccine antibody levels. Pediatrics. 2022;149(5);1-17. doi: 10.1542/peds.2021-052061.

I attended my inaugural Digestive Disease Week^® (DDW) in Orlando in 2013 as a first-year fellow, both excited and somewhat intimidated to be giving my first oral abstract presentation on an international stage. At that time, the only familiar faces at the conference were my co-fellows and faculty, along with a few welcoming faces from the fellowship interview trail. My attendings, on the other hand, couldn’t walk more than 100 feet in the conference hall without bumping into a smiling colleague! Now nearly a decade later, I am pleased to say that there are many more familiar faces in the crowd as I walk the halls of DDW. Each May, I look forward to meeting up with friends and colleagues across the country and the world while learning from an outstanding group of GI thought-leaders. While the COVID pandemic has disrupted this annual tradition in recent years, for the first time since 2019 those who feel comfortable will convene in San Diego to see old colleagues and meet new ones, learn about exciting, practice-changing innovations in our field, and enjoy the California sunshine. For those who cannot travel, robust DDW virtual offerings are planned as well.

A quick look at the 2022 conference schedule reveals an astonishing 3,300 oral abstract and poster presentations, 400 original lectures, and a variety of professional networking events on the agenda. The conference weekend will open with the AGA Post-Graduate Course, which offers a great opportunity to efficiently brush up on your clinical knowledge, guided by leading experts in the field. Monday, May 23 will feature the AGA Presidential Plenary, with AGA Institute President John Inadomi, MD, AGAF, and an exciting lineup of speakers discussing how best to address health care disparities impacting our patients and outlining AGA’s recent efforts to promote diversity, equity, and inclusion in our field. While it is nearly impossible to attend all sessions of interest during this whirlwind 4-day conference, you can rely on GI & Hepatology News to bring you key conference highlights over the coming months to ensure you don’t miss a beat!

Megan A. Adams, MD, JD, MSc
Editor in chief

I attended my inaugural Digestive Disease Week^® (DDW) in Orlando in 2013 as a first-year fellow, both excited and somewhat intimidated to be giving my first oral abstract presentation on an international stage. At that time, the only familiar faces at the conference were my co-fellows and faculty, along with a few welcoming faces from the fellowship interview trail. My attendings, on the other hand, couldn’t walk more than 100 feet in the conference hall without bumping into a smiling colleague! Now nearly a decade later, I am pleased to say that there are many more familiar faces in the crowd as I walk the halls of DDW. Each May, I look forward to meeting up with friends and colleagues across the country and the world while learning from an outstanding group of GI thought-leaders. While the COVID pandemic has disrupted this annual tradition in recent years, for the first time since 2019 those who feel comfortable will convene in San Diego to see old colleagues and meet new ones, learn about exciting, practice-changing innovations in our field, and enjoy the California sunshine. For those who cannot travel, robust DDW virtual offerings are planned as well.

A quick look at the 2022 conference schedule reveals an astonishing 3,300 oral abstract and poster presentations, 400 original lectures, and a variety of professional networking events on the agenda. The conference weekend will open with the AGA Post-Graduate Course, which offers a great opportunity to efficiently brush up on your clinical knowledge, guided by leading experts in the field. Monday, May 23 will feature the AGA Presidential Plenary, with AGA Institute President John Inadomi, MD, AGAF, and an exciting lineup of speakers discussing how best to address health care disparities impacting our patients and outlining AGA’s recent efforts to promote diversity, equity, and inclusion in our field. While it is nearly impossible to attend all sessions of interest during this whirlwind 4-day conference, you can rely on GI & Hepatology News to bring you key conference highlights over the coming months to ensure you don’t miss a beat!

Megan A. Adams, MD, JD, MSc
Editor in chief

I attended my inaugural Digestive Disease Week^® (DDW) in Orlando in 2013 as a first-year fellow, both excited and somewhat intimidated to be giving my first oral abstract presentation on an international stage. At that time, the only familiar faces at the conference were my co-fellows and faculty, along with a few welcoming faces from the fellowship interview trail. My attendings, on the other hand, couldn’t walk more than 100 feet in the conference hall without bumping into a smiling colleague! Now nearly a decade later, I am pleased to say that there are many more familiar faces in the crowd as I walk the halls of DDW. Each May, I look forward to meeting up with friends and colleagues across the country and the world while learning from an outstanding group of GI thought-leaders. While the COVID pandemic has disrupted this annual tradition in recent years, for the first time since 2019 those who feel comfortable will convene in San Diego to see old colleagues and meet new ones, learn about exciting, practice-changing innovations in our field, and enjoy the California sunshine. For those who cannot travel, robust DDW virtual offerings are planned as well.

A quick look at the 2022 conference schedule reveals an astonishing 3,300 oral abstract and poster presentations, 400 original lectures, and a variety of professional networking events on the agenda. The conference weekend will open with the AGA Post-Graduate Course, which offers a great opportunity to efficiently brush up on your clinical knowledge, guided by leading experts in the field. Monday, May 23 will feature the AGA Presidential Plenary, with AGA Institute President John Inadomi, MD, AGAF, and an exciting lineup of speakers discussing how best to address health care disparities impacting our patients and outlining AGA’s recent efforts to promote diversity, equity, and inclusion in our field. While it is nearly impossible to attend all sessions of interest during this whirlwind 4-day conference, you can rely on GI & Hepatology News to bring you key conference highlights over the coming months to ensure you don’t miss a beat!

Megan A. Adams, MD, JD, MSc
Editor in chief

Knee and shoulder pain are common complaints for patients in the primary care office.

But identifying the source of the pain can be complicated,

and an accurate diagnosis of the underlying cause of discomfort is key to appropriate management – whether that involves simple home care options of ice and rest or a recommendation for a follow-up with a specialist.

Speaking at the annual meeting of the American College of Physicians, Greg Nakamoto, MD, department of orthopedics, Virginia Mason Medical Center, Seattle, discussed common knee and shoulder problems that patients often present with in the primary care setting, and offered tips on diagnosis and appropriate management.

The most common conditions causing knee pain are osteoarthritis and meniscal tears. “The differential for knee pain is broad,” Dr. Nakamoto said. “You have to have a way to divide it down, such as if it’s acute or chronic.”

The initial workup has several key components. The first steps: Determine the location of the pain – anterior, medial, lateral, posterior – and then whether it stems from an injury or is atraumatic.

“If you have to ask one question – ask where it hurts,” he said. “And is it from an injury or just wear and tear? That helps me when deciding if surgery is needed.”

Pain in the knee generally localizes well to the site of pathology, and knee pain of acute traumatic onset requires more scrutiny for problems best treated with early surgery. “This also helps establish whether radiographic findings are due to injury or degeneration,” Dr. Nakamoto said. “The presence of swelling guides the need for anti-inflammatories or cortisone.”

Palpating for tenderness along the joint line is important, as is palpating above and below the joint line, Dr. Nakamoto said.

“Tenderness limited to the joint line, combined with a meniscal exam maneuver that reproduces joint-line pain, is suggestive of pain from meniscal pathology,” he said.

Imaging is an important component of evaluating knee symptoms, and the question often arises as to when to order an MRI.

Dr. Nakamoto offered the following scenario: If significant osteoarthritis is evident on weight-bearing x-ray, treat the patient for the condition. However, if little or no osteoarthritis appears on x-ray, and if the onset of symptoms was traumatic and both patient history and physical examination suggest a meniscal tear, order an MRI.

An early MRI also is needed if the patient has had either atraumatic or traumatic onset of symptoms and their history and physical exams are suspicious for a mechanically locked or locking meniscus. For suspicion of a ruptured quadriceps or patellar tendon or a stress fracture, an MRI is needed urgently.

An MRI would be ordered later if the patient’s symptoms have not improved significantly after 3 months of conservative management.

Dr. Nakamoto stressed how common undiagnosed meniscus tears are in the general population. A third of men aged 50-59 years and nearly 20% of women in that age group have a tear, he said. “That number goes up to 56% and 51% in men and women aged 70-90 years, and 61% of these tears were in patients who were asymptomatic in the last month.”

In the setting of osteoarthritis, 76% of asymptomatic patients had a meniscus tear, and 91% of patients with symptomatic osteoarthritis had a meniscus tear, he added.

Treating knee pain

Treatment will vary depending on the underlying etiology of pain. For a possible meniscus tear, the recommendation is for a conservative intervention with ice, ibuprofen, knee immobilizer, and crutches, with a follow-up appointment in a week.

Three types of injections also can help:

• Cortisone for osteoarthritis or meniscus tears, swelling, and inflammation, and prophylaxis against inflammation.
• Viscosupplementation (intra‐articular hyaluronic acid) for chronic, baseline osteoarthritis symptoms.
• Regenerative therapies (platelet-rich plasma, stem cells, etc.) are used primarily for osteoarthritis (these do not regrow cartilage, but some patients report decreased pain).

The data on injections are mixed, Dr. Nakamoto said. For example, the results of a 2015 Cochrane review on cortisone injections for osteoarthritis reported that the benefits were small to moderate at 4‐6 weeks, and small to none at 13 weeks.  

“There is a lot of controversy for viscosupplementation despite all of the data on it,” he said. “But the recommendations from professional organizations are mixed.”

He noted that he has been using viscosupplementation since the 1990s, and some patients do benefit from it.

Shoulder pain

The most common causes of shoulder pain are adhesive capsulitis, rotator cuff tears and tendinopathy, and impingement.

As with knee pain, the same assessment routine largely applies.

First, pinpoint the location: Is the trouble spot the lateral shoulder and upper arm, the trapezial ridge, or the shoulder blade?

Next, assess pain on movement: Does the patient experience discomfort reaching overhead or behind the back, or moving at the glenohumeral joint/capsule and engaging the rotator cuff? Check for stiffness, weakness, and decreased range of motion in the rotator cuff.

Determine if the cause of the pain is traumatic or atraumatic and stems from an acute injury versus degeneration or overuse.

As with the knee, imaging is a major component of the assessment and typically involves the use of x-ray. An MRI may be required for evaluating full- and partial-thickness tears and when contemplating surgery.

MRI also is necessary for evaluating cases of acute, traumatic shoulder injury, and patients exhibiting disability suggestive of a rotator cuff tear in an otherwise healthy tendon.

Some pain can be treated with cortisone injections or regenerative therapies, which generally are given at the acromioclavicular or glenohumeral joints or in the subacromial space. A 2005 meta-analysis found that subacromial injections of corticosteroids are effective for improvement for rotator cuff tendinitis up to a 9‐month period.

Surgery may be warranted in some cases, Dr. Nakamoto said. These include adhesive capsulitis, rotator cuff tear, acute traumatic injury in an otherwise healthy tendon, and chronic (or acute-on-chronic) tears in a degenerative tendon following a trial of conservative therapy.

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

Knee and shoulder pain are common complaints for patients in the primary care office.

But identifying the source of the pain can be complicated,

and an accurate diagnosis of the underlying cause of discomfort is key to appropriate management – whether that involves simple home care options of ice and rest or a recommendation for a follow-up with a specialist.

Speaking at the annual meeting of the American College of Physicians, Greg Nakamoto, MD, department of orthopedics, Virginia Mason Medical Center, Seattle, discussed common knee and shoulder problems that patients often present with in the primary care setting, and offered tips on diagnosis and appropriate management.

The most common conditions causing knee pain are osteoarthritis and meniscal tears. “The differential for knee pain is broad,” Dr. Nakamoto said. “You have to have a way to divide it down, such as if it’s acute or chronic.”

The initial workup has several key components. The first steps: Determine the location of the pain – anterior, medial, lateral, posterior – and then whether it stems from an injury or is atraumatic.

“If you have to ask one question – ask where it hurts,” he said. “And is it from an injury or just wear and tear? That helps me when deciding if surgery is needed.”

Pain in the knee generally localizes well to the site of pathology, and knee pain of acute traumatic onset requires more scrutiny for problems best treated with early surgery. “This also helps establish whether radiographic findings are due to injury or degeneration,” Dr. Nakamoto said. “The presence of swelling guides the need for anti-inflammatories or cortisone.”

Palpating for tenderness along the joint line is important, as is palpating above and below the joint line, Dr. Nakamoto said.

“Tenderness limited to the joint line, combined with a meniscal exam maneuver that reproduces joint-line pain, is suggestive of pain from meniscal pathology,” he said.

Imaging is an important component of evaluating knee symptoms, and the question often arises as to when to order an MRI.

Dr. Nakamoto offered the following scenario: If significant osteoarthritis is evident on weight-bearing x-ray, treat the patient for the condition. However, if little or no osteoarthritis appears on x-ray, and if the onset of symptoms was traumatic and both patient history and physical examination suggest a meniscal tear, order an MRI.

An early MRI also is needed if the patient has had either atraumatic or traumatic onset of symptoms and their history and physical exams are suspicious for a mechanically locked or locking meniscus. For suspicion of a ruptured quadriceps or patellar tendon or a stress fracture, an MRI is needed urgently.

An MRI would be ordered later if the patient’s symptoms have not improved significantly after 3 months of conservative management.

Dr. Nakamoto stressed how common undiagnosed meniscus tears are in the general population. A third of men aged 50-59 years and nearly 20% of women in that age group have a tear, he said. “That number goes up to 56% and 51% in men and women aged 70-90 years, and 61% of these tears were in patients who were asymptomatic in the last month.”

In the setting of osteoarthritis, 76% of asymptomatic patients had a meniscus tear, and 91% of patients with symptomatic osteoarthritis had a meniscus tear, he added.

Treating knee pain

Treatment will vary depending on the underlying etiology of pain. For a possible meniscus tear, the recommendation is for a conservative intervention with ice, ibuprofen, knee immobilizer, and crutches, with a follow-up appointment in a week.

Three types of injections also can help:

• Cortisone for osteoarthritis or meniscus tears, swelling, and inflammation, and prophylaxis against inflammation.
• Viscosupplementation (intra‐articular hyaluronic acid) for chronic, baseline osteoarthritis symptoms.
• Regenerative therapies (platelet-rich plasma, stem cells, etc.) are used primarily for osteoarthritis (these do not regrow cartilage, but some patients report decreased pain).

The data on injections are mixed, Dr. Nakamoto said. For example, the results of a 2015 Cochrane review on cortisone injections for osteoarthritis reported that the benefits were small to moderate at 4‐6 weeks, and small to none at 13 weeks.  

“There is a lot of controversy for viscosupplementation despite all of the data on it,” he said. “But the recommendations from professional organizations are mixed.”

He noted that he has been using viscosupplementation since the 1990s, and some patients do benefit from it.

Shoulder pain

The most common causes of shoulder pain are adhesive capsulitis, rotator cuff tears and tendinopathy, and impingement.

As with knee pain, the same assessment routine largely applies.

First, pinpoint the location: Is the trouble spot the lateral shoulder and upper arm, the trapezial ridge, or the shoulder blade?

Next, assess pain on movement: Does the patient experience discomfort reaching overhead or behind the back, or moving at the glenohumeral joint/capsule and engaging the rotator cuff? Check for stiffness, weakness, and decreased range of motion in the rotator cuff.

Determine if the cause of the pain is traumatic or atraumatic and stems from an acute injury versus degeneration or overuse.

As with the knee, imaging is a major component of the assessment and typically involves the use of x-ray. An MRI may be required for evaluating full- and partial-thickness tears and when contemplating surgery.

MRI also is necessary for evaluating cases of acute, traumatic shoulder injury, and patients exhibiting disability suggestive of a rotator cuff tear in an otherwise healthy tendon.

Some pain can be treated with cortisone injections or regenerative therapies, which generally are given at the acromioclavicular or glenohumeral joints or in the subacromial space. A 2005 meta-analysis found that subacromial injections of corticosteroids are effective for improvement for rotator cuff tendinitis up to a 9‐month period.

Surgery may be warranted in some cases, Dr. Nakamoto said. These include adhesive capsulitis, rotator cuff tear, acute traumatic injury in an otherwise healthy tendon, and chronic (or acute-on-chronic) tears in a degenerative tendon following a trial of conservative therapy.

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

Knee and shoulder pain are common complaints for patients in the primary care office.

But identifying the source of the pain can be complicated,

and an accurate diagnosis of the underlying cause of discomfort is key to appropriate management – whether that involves simple home care options of ice and rest or a recommendation for a follow-up with a specialist.

Speaking at the annual meeting of the American College of Physicians, Greg Nakamoto, MD, department of orthopedics, Virginia Mason Medical Center, Seattle, discussed common knee and shoulder problems that patients often present with in the primary care setting, and offered tips on diagnosis and appropriate management.

The most common conditions causing knee pain are osteoarthritis and meniscal tears. “The differential for knee pain is broad,” Dr. Nakamoto said. “You have to have a way to divide it down, such as if it’s acute or chronic.”

The initial workup has several key components. The first steps: Determine the location of the pain – anterior, medial, lateral, posterior – and then whether it stems from an injury or is atraumatic.

“If you have to ask one question – ask where it hurts,” he said. “And is it from an injury or just wear and tear? That helps me when deciding if surgery is needed.”

Pain in the knee generally localizes well to the site of pathology, and knee pain of acute traumatic onset requires more scrutiny for problems best treated with early surgery. “This also helps establish whether radiographic findings are due to injury or degeneration,” Dr. Nakamoto said. “The presence of swelling guides the need for anti-inflammatories or cortisone.”

Palpating for tenderness along the joint line is important, as is palpating above and below the joint line, Dr. Nakamoto said.

“Tenderness limited to the joint line, combined with a meniscal exam maneuver that reproduces joint-line pain, is suggestive of pain from meniscal pathology,” he said.

Imaging is an important component of evaluating knee symptoms, and the question often arises as to when to order an MRI.

Dr. Nakamoto offered the following scenario: If significant osteoarthritis is evident on weight-bearing x-ray, treat the patient for the condition. However, if little or no osteoarthritis appears on x-ray, and if the onset of symptoms was traumatic and both patient history and physical examination suggest a meniscal tear, order an MRI.

An early MRI also is needed if the patient has had either atraumatic or traumatic onset of symptoms and their history and physical exams are suspicious for a mechanically locked or locking meniscus. For suspicion of a ruptured quadriceps or patellar tendon or a stress fracture, an MRI is needed urgently.

An MRI would be ordered later if the patient’s symptoms have not improved significantly after 3 months of conservative management.

Dr. Nakamoto stressed how common undiagnosed meniscus tears are in the general population. A third of men aged 50-59 years and nearly 20% of women in that age group have a tear, he said. “That number goes up to 56% and 51% in men and women aged 70-90 years, and 61% of these tears were in patients who were asymptomatic in the last month.”

In the setting of osteoarthritis, 76% of asymptomatic patients had a meniscus tear, and 91% of patients with symptomatic osteoarthritis had a meniscus tear, he added.

Treating knee pain

Treatment will vary depending on the underlying etiology of pain. For a possible meniscus tear, the recommendation is for a conservative intervention with ice, ibuprofen, knee immobilizer, and crutches, with a follow-up appointment in a week.

Three types of injections also can help:

• Cortisone for osteoarthritis or meniscus tears, swelling, and inflammation, and prophylaxis against inflammation.
• Viscosupplementation (intra‐articular hyaluronic acid) for chronic, baseline osteoarthritis symptoms.
• Regenerative therapies (platelet-rich plasma, stem cells, etc.) are used primarily for osteoarthritis (these do not regrow cartilage, but some patients report decreased pain).

The data on injections are mixed, Dr. Nakamoto said. For example, the results of a 2015 Cochrane review on cortisone injections for osteoarthritis reported that the benefits were small to moderate at 4‐6 weeks, and small to none at 13 weeks.  

“There is a lot of controversy for viscosupplementation despite all of the data on it,” he said. “But the recommendations from professional organizations are mixed.”

He noted that he has been using viscosupplementation since the 1990s, and some patients do benefit from it.

Shoulder pain

The most common causes of shoulder pain are adhesive capsulitis, rotator cuff tears and tendinopathy, and impingement.

As with knee pain, the same assessment routine largely applies.

First, pinpoint the location: Is the trouble spot the lateral shoulder and upper arm, the trapezial ridge, or the shoulder blade?

Next, assess pain on movement: Does the patient experience discomfort reaching overhead or behind the back, or moving at the glenohumeral joint/capsule and engaging the rotator cuff? Check for stiffness, weakness, and decreased range of motion in the rotator cuff.

Determine if the cause of the pain is traumatic or atraumatic and stems from an acute injury versus degeneration or overuse.

As with the knee, imaging is a major component of the assessment and typically involves the use of x-ray. An MRI may be required for evaluating full- and partial-thickness tears and when contemplating surgery.

MRI also is necessary for evaluating cases of acute, traumatic shoulder injury, and patients exhibiting disability suggestive of a rotator cuff tear in an otherwise healthy tendon.

Some pain can be treated with cortisone injections or regenerative therapies, which generally are given at the acromioclavicular or glenohumeral joints or in the subacromial space. A 2005 meta-analysis found that subacromial injections of corticosteroids are effective for improvement for rotator cuff tendinitis up to a 9‐month period.

Surgery may be warranted in some cases, Dr. Nakamoto said. These include adhesive capsulitis, rotator cuff tear, acute traumatic injury in an otherwise healthy tendon, and chronic (or acute-on-chronic) tears in a degenerative tendon following a trial of conservative therapy.

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

CHICAGO – The COVID pandemic left hospitalist Ngozi Nwankwo, MD, with the most difficult patient interactions she had ever experienced.

“At my hospital, it was such a big thing to make sure that families are called,” said Dr. Nwankwo, in an interview following a session on compassionate communication at the annual meeting of the American College of Physicians. “So you have 19 patients, and you have to call almost every family to update them. And then you call, and they say, ‘Call this person as well.’ You feel like you’re at your wit’s end a lot of times.”

Sometimes, she has had to dig deep to find the empathy for patients that she knows her patients deserve.

“You really want to care by thinking about where is this patient coming from? What’s going on in their lives? And not just label them a difficult patient,” she said.

Become curious

Auguste Fortin, MD, MPH, offered advice for handling patient interactions under these kinds of circumstances, while serving as a moderator during the session.

“When the going gets tough, turn to wonder.” Become curious about why a patient might be feeling the way they are, he said.

Dr. Fortin, professor of internal medicine at Yale University, New Haven, Conn., said using the ADOBE acronym, has helped him more effectively communicate with his patients. This tool cues him to keep the following in mind: acknowledge, discover, opportunity, boundary setting, and extend.

He went on to explain to the audience why thinking about these terms is useful when interacting with patients.

First, acknowledge the feelings of the patient. Noting that a patient is angry, perhaps counterintuitively, helps, he said. In fact, not acknowledging the anger “throws gasoline on the fire.”

Then, discover the cause of their emotion. Saying "tell me more" and "help me understand" can be powerful tools, he noted.

Next, take this as an opportunity for empathy – especially important to remember when you’re being verbally attacked.

Boundary setting is important, because it lets the patient know that the conversation won’t continue unless they show the same respect the physician is showing, he said.

Finally, physicians can extend the system of support by asking others – such as colleagues or security – for help.

Use the NURS guide to show empathy

Dr. Fortin said he uses the “NURS” guide or calling to mind “name, express, respect, and support” to show empathy:

This involves naming a patient’s emotion; expressing understanding, with phrases like "I can see how you could be …"; showing respect, acknowledging a patient is going through a lot; and offering support, by saying something like, "Let’s see what we can do together to get to the bottom of this," he explained.

“My lived experience in using [these] in this order is that by the end of it, the patient cannot stay mad at me,” Dr. Fortin said.

“It’s really quite remarkable,” he added.

Steps for nonviolent communication

Rebecca Andrews, MD, MS, another moderator for the session, offered these steps for “nonviolent communication”:

• Observing the situation without blame or judgment.
• Telling the person how this situation makes you feel.
• Connecting with a need of the other person.
• Making a request that is specific and based on action, rather than a request not to do something, such as "Would you be willing to … ?"

Dr. Andrews, who is professor of medicine at the University of Connecticut, Farmington, said this approach has worked well for her, both in interactions with patients and in her personal life.

“It is evidence based that compassion actually makes care better,” she noted.

Varun Jain, MD, a member of the audience, expressed gratitude to the session’s speakers for teaching him something that he had not learned in medical school or residency.

“Every week you will have one or two people who will be labeled as ‘difficult,’ ” and it was nice to have some proven advice on how to handle these tough interactions, said the hospitalist at St. Francis Hospital in Hartford, Conn.

“We never got any actual training on this, and we were expected to know this because we are just physicians, and physicians are expected to be compassionate,” Dr. Jain said. “No one taught us how to have compassion.”

Dr. Fortin and Dr. Andrews disclosed no relevant financial relationships.

CHICAGO – The COVID pandemic left hospitalist Ngozi Nwankwo, MD, with the most difficult patient interactions she had ever experienced.

“At my hospital, it was such a big thing to make sure that families are called,” said Dr. Nwankwo, in an interview following a session on compassionate communication at the annual meeting of the American College of Physicians. “So you have 19 patients, and you have to call almost every family to update them. And then you call, and they say, ‘Call this person as well.’ You feel like you’re at your wit’s end a lot of times.”

Sometimes, she has had to dig deep to find the empathy for patients that she knows her patients deserve.

“You really want to care by thinking about where is this patient coming from? What’s going on in their lives? And not just label them a difficult patient,” she said.

Become curious

Auguste Fortin, MD, MPH, offered advice for handling patient interactions under these kinds of circumstances, while serving as a moderator during the session.

“When the going gets tough, turn to wonder.” Become curious about why a patient might be feeling the way they are, he said.

Dr. Fortin, professor of internal medicine at Yale University, New Haven, Conn., said using the ADOBE acronym, has helped him more effectively communicate with his patients. This tool cues him to keep the following in mind: acknowledge, discover, opportunity, boundary setting, and extend.

He went on to explain to the audience why thinking about these terms is useful when interacting with patients.

First, acknowledge the feelings of the patient. Noting that a patient is angry, perhaps counterintuitively, helps, he said. In fact, not acknowledging the anger “throws gasoline on the fire.”

Then, discover the cause of their emotion. Saying "tell me more" and "help me understand" can be powerful tools, he noted.

Next, take this as an opportunity for empathy – especially important to remember when you’re being verbally attacked.

Boundary setting is important, because it lets the patient know that the conversation won’t continue unless they show the same respect the physician is showing, he said.

Finally, physicians can extend the system of support by asking others – such as colleagues or security – for help.

Use the NURS guide to show empathy

Dr. Fortin said he uses the “NURS” guide or calling to mind “name, express, respect, and support” to show empathy:

This involves naming a patient’s emotion; expressing understanding, with phrases like "I can see how you could be …"; showing respect, acknowledging a patient is going through a lot; and offering support, by saying something like, "Let’s see what we can do together to get to the bottom of this," he explained.

“My lived experience in using [these] in this order is that by the end of it, the patient cannot stay mad at me,” Dr. Fortin said.

“It’s really quite remarkable,” he added.

Steps for nonviolent communication

Rebecca Andrews, MD, MS, another moderator for the session, offered these steps for “nonviolent communication”:

• Observing the situation without blame or judgment.
• Telling the person how this situation makes you feel.
• Connecting with a need of the other person.
• Making a request that is specific and based on action, rather than a request not to do something, such as "Would you be willing to … ?"

Dr. Andrews, who is professor of medicine at the University of Connecticut, Farmington, said this approach has worked well for her, both in interactions with patients and in her personal life.

“It is evidence based that compassion actually makes care better,” she noted.

Varun Jain, MD, a member of the audience, expressed gratitude to the session’s speakers for teaching him something that he had not learned in medical school or residency.

“Every week you will have one or two people who will be labeled as ‘difficult,’ ” and it was nice to have some proven advice on how to handle these tough interactions, said the hospitalist at St. Francis Hospital in Hartford, Conn.

“We never got any actual training on this, and we were expected to know this because we are just physicians, and physicians are expected to be compassionate,” Dr. Jain said. “No one taught us how to have compassion.”

Dr. Fortin and Dr. Andrews disclosed no relevant financial relationships.

CHICAGO – The COVID pandemic left hospitalist Ngozi Nwankwo, MD, with the most difficult patient interactions she had ever experienced.

“At my hospital, it was such a big thing to make sure that families are called,” said Dr. Nwankwo, in an interview following a session on compassionate communication at the annual meeting of the American College of Physicians. “So you have 19 patients, and you have to call almost every family to update them. And then you call, and they say, ‘Call this person as well.’ You feel like you’re at your wit’s end a lot of times.”

Sometimes, she has had to dig deep to find the empathy for patients that she knows her patients deserve.

“You really want to care by thinking about where is this patient coming from? What’s going on in their lives? And not just label them a difficult patient,” she said.

Become curious

Auguste Fortin, MD, MPH, offered advice for handling patient interactions under these kinds of circumstances, while serving as a moderator during the session.

“When the going gets tough, turn to wonder.” Become curious about why a patient might be feeling the way they are, he said.

Dr. Fortin, professor of internal medicine at Yale University, New Haven, Conn., said using the ADOBE acronym, has helped him more effectively communicate with his patients. This tool cues him to keep the following in mind: acknowledge, discover, opportunity, boundary setting, and extend.

He went on to explain to the audience why thinking about these terms is useful when interacting with patients.

First, acknowledge the feelings of the patient. Noting that a patient is angry, perhaps counterintuitively, helps, he said. In fact, not acknowledging the anger “throws gasoline on the fire.”

Then, discover the cause of their emotion. Saying "tell me more" and "help me understand" can be powerful tools, he noted.

Next, take this as an opportunity for empathy – especially important to remember when you’re being verbally attacked.

Boundary setting is important, because it lets the patient know that the conversation won’t continue unless they show the same respect the physician is showing, he said.

Finally, physicians can extend the system of support by asking others – such as colleagues or security – for help.

Use the NURS guide to show empathy

Dr. Fortin said he uses the “NURS” guide or calling to mind “name, express, respect, and support” to show empathy:

This involves naming a patient’s emotion; expressing understanding, with phrases like "I can see how you could be …"; showing respect, acknowledging a patient is going through a lot; and offering support, by saying something like, "Let’s see what we can do together to get to the bottom of this," he explained.

“My lived experience in using [these] in this order is that by the end of it, the patient cannot stay mad at me,” Dr. Fortin said.

“It’s really quite remarkable,” he added.

Steps for nonviolent communication

Rebecca Andrews, MD, MS, another moderator for the session, offered these steps for “nonviolent communication”:

• Observing the situation without blame or judgment.
• Telling the person how this situation makes you feel.
• Connecting with a need of the other person.
• Making a request that is specific and based on action, rather than a request not to do something, such as "Would you be willing to … ?"

Dr. Andrews, who is professor of medicine at the University of Connecticut, Farmington, said this approach has worked well for her, both in interactions with patients and in her personal life.

“It is evidence based that compassion actually makes care better,” she noted.

Varun Jain, MD, a member of the audience, expressed gratitude to the session’s speakers for teaching him something that he had not learned in medical school or residency.

“Every week you will have one or two people who will be labeled as ‘difficult,’ ” and it was nice to have some proven advice on how to handle these tough interactions, said the hospitalist at St. Francis Hospital in Hartford, Conn.

“We never got any actual training on this, and we were expected to know this because we are just physicians, and physicians are expected to be compassionate,” Dr. Jain said. “No one taught us how to have compassion.”

Dr. Fortin and Dr. Andrews disclosed no relevant financial relationships.

CHICAGO – Patrick Perri, MD, said during a talk that he frequently thinks about a group of people who were homeless and lived in a park about a hundred yards from the medical center in Boston where he did his training.

On a return visit about 10 years later, Dr. Perri went to the park and inquired about the men.

“I came to the horrible realization that all of these people were dead. All of them in 10 years,” he continued, speaking to an audience at the annual meeting of the American College of Physicians.

Thomas R. Collins/MDedge News

People experiencing homelessness don’t have to have such a grim health outlook, said Dr. Perri, who is medical director of the Center for Inclusion Health at the Allegheny Health Network in Pittsburgh.

During his talk, filled with jarring statistics on the health plight of those who struggle to stay sheltered, Dr. Perri said that many of the things that sicken and kill these people are the same things that sicken and kill others – liver disease, congestive heart failure, substance abuse. But the system isn’t equipped to handle the problems.

“Their needs are actually straightforward, they’re easy to describe,” he declared. “They’re known quantities. But the way that our systems respond, or don’t respond, to that creates the complexity. It’s the systems that are complex.”

Morbidity, mortality rates ‘go off a cliff’

A 2017 study in The Lancet compared morbidity and mortality in high-income countries, grouping people by their “level of deprivation.” The morbidity and mortality ticked higher with each deprivation level, but skyrocketed – nearly 10 times higher – for the group that included those experiencing homelessness or imprisonment, sex workers, and those with substance use disorders. As Dr. Perri put it, the rates “go off a cliff.”

Studies by the Boston Healthcare for the Homeless program have tracked mortality, and from 1988 to 1993 the average age at death was 47, so, “if you died while homeless, you probably died young.” Moreover, from their first contact to receive care through the program, to their death, only 25 months had elapsed.

“If there’s going to be an effective health care intervention, an acute one at least, you’ve got to get cracking,” Dr. Perri said.

Age at death has improved somewhat over time but drug overdose has become a much more common cause, Dr. Perri noted.

“There is utilitarian value in learning from people experiencing homelessness,” he said.

The same program looked at a high-risk cohort of 199 – those who went unsheltered for more than 6 months,were age 60 or older, or had certain serious health conditions, such as cirrhosis, substance abuse, and AIDS. A third of these people died within 5 years.

“There aren’t any other common diseases that I’m aware of that have statistics like that,” he said.

These people had an average of 31 emergency department visits a year and accounted for 871 hospitalizations. The estimated cost per-person, per-year was $22,000, while the average annual rent for a one-bedroom in Boston was $10,000.

“We’re hemorrhaging utilization around this population,” Dr. Perri said. “Maybe it makes sense to invest in something else other than acute health care. It’s not really yielding very much return on investment.”

Street medicine could be the answer

Housing First, a program to provide housing without the need to meet preconditions such as sobriety or passing background checks, has had a nonsignificant effect on mortality, substance use disorders, and mental health but has improved self-reported health status and quality of life. Analyses of the program suggest that better interventions are needed, Dr. Perri said.

Street medicine could be an answer, he said. Teams of medical staff go to where the people are, and the concept is intended as a continuous, cost-effective, flexible approach to care. Lehigh Valley Street Medicine in Pennsylvania has reported a reduction in emergency department visits and hospitalizations, Dr. Perri said. The programs are still too new to gauge the effect on actual health outcomes, but they hold the promise of being able to do so, he continued.

Curiosity about those experiencing homeless is a key first step in improving care, he said. The HOUSED BEDS tool, developed in Los Angeles, can help guide clinicians through their interactions with patients who do not have homes.

Dr. Perri said it is “enlightening” when you “express interest, genuine curiosity, about other people’s experiences.”

Catherine Kiley, MD, a retired internal medicine physician who volunteers as a preceptor for medical students in Cincinnati, said there is a void when it comes to teaching students about those experiencing homelessness.

“I don’t think there’s much of this type of discussion that they’re exposed to as part of medical education,” Dr. Kiley said. “Their experiences over time, as with most of medicine, will inform them.”

But the findings shared in the session show “how great the need is to speak out, speak up, about patients as people, and what they have to teach us.”

Dr. Perri disclosed no relevant financial relationships.

CHICAGO – Patrick Perri, MD, said during a talk that he frequently thinks about a group of people who were homeless and lived in a park about a hundred yards from the medical center in Boston where he did his training.

On a return visit about 10 years later, Dr. Perri went to the park and inquired about the men.

“I came to the horrible realization that all of these people were dead. All of them in 10 years,” he continued, speaking to an audience at the annual meeting of the American College of Physicians.

Thomas R. Collins/MDedge News

People experiencing homelessness don’t have to have such a grim health outlook, said Dr. Perri, who is medical director of the Center for Inclusion Health at the Allegheny Health Network in Pittsburgh.

During his talk, filled with jarring statistics on the health plight of those who struggle to stay sheltered, Dr. Perri said that many of the things that sicken and kill these people are the same things that sicken and kill others – liver disease, congestive heart failure, substance abuse. But the system isn’t equipped to handle the problems.

“Their needs are actually straightforward, they’re easy to describe,” he declared. “They’re known quantities. But the way that our systems respond, or don’t respond, to that creates the complexity. It’s the systems that are complex.”

Morbidity, mortality rates ‘go off a cliff’

A 2017 study in The Lancet compared morbidity and mortality in high-income countries, grouping people by their “level of deprivation.” The morbidity and mortality ticked higher with each deprivation level, but skyrocketed – nearly 10 times higher – for the group that included those experiencing homelessness or imprisonment, sex workers, and those with substance use disorders. As Dr. Perri put it, the rates “go off a cliff.”

Studies by the Boston Healthcare for the Homeless program have tracked mortality, and from 1988 to 1993 the average age at death was 47, so, “if you died while homeless, you probably died young.” Moreover, from their first contact to receive care through the program, to their death, only 25 months had elapsed.

“If there’s going to be an effective health care intervention, an acute one at least, you’ve got to get cracking,” Dr. Perri said.

Age at death has improved somewhat over time but drug overdose has become a much more common cause, Dr. Perri noted.

“There is utilitarian value in learning from people experiencing homelessness,” he said.

The same program looked at a high-risk cohort of 199 – those who went unsheltered for more than 6 months,were age 60 or older, or had certain serious health conditions, such as cirrhosis, substance abuse, and AIDS. A third of these people died within 5 years.

“There aren’t any other common diseases that I’m aware of that have statistics like that,” he said.

These people had an average of 31 emergency department visits a year and accounted for 871 hospitalizations. The estimated cost per-person, per-year was $22,000, while the average annual rent for a one-bedroom in Boston was $10,000.

“We’re hemorrhaging utilization around this population,” Dr. Perri said. “Maybe it makes sense to invest in something else other than acute health care. It’s not really yielding very much return on investment.”

Street medicine could be the answer

Housing First, a program to provide housing without the need to meet preconditions such as sobriety or passing background checks, has had a nonsignificant effect on mortality, substance use disorders, and mental health but has improved self-reported health status and quality of life. Analyses of the program suggest that better interventions are needed, Dr. Perri said.

Street medicine could be an answer, he said. Teams of medical staff go to where the people are, and the concept is intended as a continuous, cost-effective, flexible approach to care. Lehigh Valley Street Medicine in Pennsylvania has reported a reduction in emergency department visits and hospitalizations, Dr. Perri said. The programs are still too new to gauge the effect on actual health outcomes, but they hold the promise of being able to do so, he continued.

Curiosity about those experiencing homeless is a key first step in improving care, he said. The HOUSED BEDS tool, developed in Los Angeles, can help guide clinicians through their interactions with patients who do not have homes.

Dr. Perri said it is “enlightening” when you “express interest, genuine curiosity, about other people’s experiences.”

Catherine Kiley, MD, a retired internal medicine physician who volunteers as a preceptor for medical students in Cincinnati, said there is a void when it comes to teaching students about those experiencing homelessness.

“I don’t think there’s much of this type of discussion that they’re exposed to as part of medical education,” Dr. Kiley said. “Their experiences over time, as with most of medicine, will inform them.”

But the findings shared in the session show “how great the need is to speak out, speak up, about patients as people, and what they have to teach us.”

Dr. Perri disclosed no relevant financial relationships.

CHICAGO – Patrick Perri, MD, said during a talk that he frequently thinks about a group of people who were homeless and lived in a park about a hundred yards from the medical center in Boston where he did his training.

On a return visit about 10 years later, Dr. Perri went to the park and inquired about the men.

“I came to the horrible realization that all of these people were dead. All of them in 10 years,” he continued, speaking to an audience at the annual meeting of the American College of Physicians.

Thomas R. Collins/MDedge News

People experiencing homelessness don’t have to have such a grim health outlook, said Dr. Perri, who is medical director of the Center for Inclusion Health at the Allegheny Health Network in Pittsburgh.

During his talk, filled with jarring statistics on the health plight of those who struggle to stay sheltered, Dr. Perri said that many of the things that sicken and kill these people are the same things that sicken and kill others – liver disease, congestive heart failure, substance abuse. But the system isn’t equipped to handle the problems.

“Their needs are actually straightforward, they’re easy to describe,” he declared. “They’re known quantities. But the way that our systems respond, or don’t respond, to that creates the complexity. It’s the systems that are complex.”

Morbidity, mortality rates ‘go off a cliff’

A 2017 study in The Lancet compared morbidity and mortality in high-income countries, grouping people by their “level of deprivation.” The morbidity and mortality ticked higher with each deprivation level, but skyrocketed – nearly 10 times higher – for the group that included those experiencing homelessness or imprisonment, sex workers, and those with substance use disorders. As Dr. Perri put it, the rates “go off a cliff.”

Studies by the Boston Healthcare for the Homeless program have tracked mortality, and from 1988 to 1993 the average age at death was 47, so, “if you died while homeless, you probably died young.” Moreover, from their first contact to receive care through the program, to their death, only 25 months had elapsed.

“If there’s going to be an effective health care intervention, an acute one at least, you’ve got to get cracking,” Dr. Perri said.

Age at death has improved somewhat over time but drug overdose has become a much more common cause, Dr. Perri noted.

“There is utilitarian value in learning from people experiencing homelessness,” he said.

The same program looked at a high-risk cohort of 199 – those who went unsheltered for more than 6 months,were age 60 or older, or had certain serious health conditions, such as cirrhosis, substance abuse, and AIDS. A third of these people died within 5 years.

“There aren’t any other common diseases that I’m aware of that have statistics like that,” he said.

These people had an average of 31 emergency department visits a year and accounted for 871 hospitalizations. The estimated cost per-person, per-year was $22,000, while the average annual rent for a one-bedroom in Boston was $10,000.

“We’re hemorrhaging utilization around this population,” Dr. Perri said. “Maybe it makes sense to invest in something else other than acute health care. It’s not really yielding very much return on investment.”

Street medicine could be the answer

Housing First, a program to provide housing without the need to meet preconditions such as sobriety or passing background checks, has had a nonsignificant effect on mortality, substance use disorders, and mental health but has improved self-reported health status and quality of life. Analyses of the program suggest that better interventions are needed, Dr. Perri said.

Street medicine could be an answer, he said. Teams of medical staff go to where the people are, and the concept is intended as a continuous, cost-effective, flexible approach to care. Lehigh Valley Street Medicine in Pennsylvania has reported a reduction in emergency department visits and hospitalizations, Dr. Perri said. The programs are still too new to gauge the effect on actual health outcomes, but they hold the promise of being able to do so, he continued.

Curiosity about those experiencing homeless is a key first step in improving care, he said. The HOUSED BEDS tool, developed in Los Angeles, can help guide clinicians through their interactions with patients who do not have homes.

Dr. Perri said it is “enlightening” when you “express interest, genuine curiosity, about other people’s experiences.”

Catherine Kiley, MD, a retired internal medicine physician who volunteers as a preceptor for medical students in Cincinnati, said there is a void when it comes to teaching students about those experiencing homelessness.

“I don’t think there’s much of this type of discussion that they’re exposed to as part of medical education,” Dr. Kiley said. “Their experiences over time, as with most of medicine, will inform them.”

But the findings shared in the session show “how great the need is to speak out, speak up, about patients as people, and what they have to teach us.”

Dr. Perri disclosed no relevant financial relationships.

Portaccio and colleagues explored this issue and concluded that disease progression independent of relapse activity (PIRA) was a major contributor of confirmed disability accrual (CDA) in early relapse after the onset of MS, with age being a major determinant in the way that CDA occurs. In a retrospective cohort analysis of 5169 patients with either clinically isolated syndrome or early relapsing-remitting MS who were assessed within 1 year of onset and followed-up for ≥ 5 years, PIRA accounted for 27.6% of disability-worsening events, whereas relapse-associated worsening accounted for 17.8% of events, with relapse-associated worsening being more frequent in younger (hazard ratio [HR] 0.87) and PIRA in older (HR 1.19; both P < .001) patients. Recognition of disease relapse or progression is not always simple in a complex disease, but failure to recognize these issues can result in long-term accumulation of economically important disability. Multiple other issues related to effective disease management also require effective juggling in routine care. Adherence to treatment, timing of DMT change, and interval between discontinuing a DMT and starting a different one continue to be critical concerns as well. Malpas and associates explored this issue and noted that the importance of adherence impact on disease control also relates to treatment interruption and timing of duration between stopping one DMT and starting another agent. The annualized relapse rate (ARR) and the rate of severe relapses was explored in a cohort of 685 people with MS and did not increase significantly after discontinuation of fingolimod in this population, but delaying the commencement of immunotherapy increased the risk for relapse. The ARR was not significantly different during and after fingolimod cessation (mean difference −0.06; 95% CI −0.14 to 0.01), with no severe relapses reported in the year prior to and after fingolimod cessation. However, delaying the recommencement of DMT, or if change in DMT was delayed from 2 to 4 months, vs beginning within 2 months (odds ratio 1.67; 95% CI 1.22-2.27) was associated with a higher risk for relapse. Discontinuation of DMT or treatment interruption also relates to planned or unplanned pregnancy in people with MS. In another study Portaccio and colleagues continued treatment with natalizumab until conception and then restarted treatment within 1 month after delivery. This reduced the risk for disease activity more than natalizumab cessation before conception or restarting 1 month after delivery in women with MS. No major developmental abnormalities were noted in the infants born of 72 pregnancies in 70 women with MS who were treated for at least 2 years. Specifically, relapses occurred in 29.4% of people with MS treated until conception vs 70.2% in those who discontinued prior to conception, after a mean follow-up of 6.1 years (P = .001), with timing of treatment cessation being the only predictor of relapses (HR 4.1; P = .003). No developmental abnormalities were observed in the infants.

Practical points for the treating clinician are many and continue to highlight the complexity of managing people with MS in the real world, with real issues from COVID-19 vaccination, SARS-CoV-2 infection, recognition or awareness of relapse, and the increased challenges of adherence and timing of DMT change and of DMT use relative to pregnancy. Data-driven, reliable, relevant information is critical to incorporate into routine care to enhance and optimize decision-making.

Portaccio and colleagues explored this issue and concluded that disease progression independent of relapse activity (PIRA) was a major contributor of confirmed disability accrual (CDA) in early relapse after the onset of MS, with age being a major determinant in the way that CDA occurs. In a retrospective cohort analysis of 5169 patients with either clinically isolated syndrome or early relapsing-remitting MS who were assessed within 1 year of onset and followed-up for ≥ 5 years, PIRA accounted for 27.6% of disability-worsening events, whereas relapse-associated worsening accounted for 17.8% of events, with relapse-associated worsening being more frequent in younger (hazard ratio [HR] 0.87) and PIRA in older (HR 1.19; both P < .001) patients. Recognition of disease relapse or progression is not always simple in a complex disease, but failure to recognize these issues can result in long-term accumulation of economically important disability. Multiple other issues related to effective disease management also require effective juggling in routine care. Adherence to treatment, timing of DMT change, and interval between discontinuing a DMT and starting a different one continue to be critical concerns as well. Malpas and associates explored this issue and noted that the importance of adherence impact on disease control also relates to treatment interruption and timing of duration between stopping one DMT and starting another agent. The annualized relapse rate (ARR) and the rate of severe relapses was explored in a cohort of 685 people with MS and did not increase significantly after discontinuation of fingolimod in this population, but delaying the commencement of immunotherapy increased the risk for relapse. The ARR was not significantly different during and after fingolimod cessation (mean difference −0.06; 95% CI −0.14 to 0.01), with no severe relapses reported in the year prior to and after fingolimod cessation. However, delaying the recommencement of DMT, or if change in DMT was delayed from 2 to 4 months, vs beginning within 2 months (odds ratio 1.67; 95% CI 1.22-2.27) was associated with a higher risk for relapse. Discontinuation of DMT or treatment interruption also relates to planned or unplanned pregnancy in people with MS. In another study Portaccio and colleagues continued treatment with natalizumab until conception and then restarted treatment within 1 month after delivery. This reduced the risk for disease activity more than natalizumab cessation before conception or restarting 1 month after delivery in women with MS. No major developmental abnormalities were noted in the infants born of 72 pregnancies in 70 women with MS who were treated for at least 2 years. Specifically, relapses occurred in 29.4% of people with MS treated until conception vs 70.2% in those who discontinued prior to conception, after a mean follow-up of 6.1 years (P = .001), with timing of treatment cessation being the only predictor of relapses (HR 4.1; P = .003). No developmental abnormalities were observed in the infants.

Practical points for the treating clinician are many and continue to highlight the complexity of managing people with MS in the real world, with real issues from COVID-19 vaccination, SARS-CoV-2 infection, recognition or awareness of relapse, and the increased challenges of adherence and timing of DMT change and of DMT use relative to pregnancy. Data-driven, reliable, relevant information is critical to incorporate into routine care to enhance and optimize decision-making.

Portaccio and colleagues explored this issue and concluded that disease progression independent of relapse activity (PIRA) was a major contributor of confirmed disability accrual (CDA) in early relapse after the onset of MS, with age being a major determinant in the way that CDA occurs. In a retrospective cohort analysis of 5169 patients with either clinically isolated syndrome or early relapsing-remitting MS who were assessed within 1 year of onset and followed-up for ≥ 5 years, PIRA accounted for 27.6% of disability-worsening events, whereas relapse-associated worsening accounted for 17.8% of events, with relapse-associated worsening being more frequent in younger (hazard ratio [HR] 0.87) and PIRA in older (HR 1.19; both P < .001) patients. Recognition of disease relapse or progression is not always simple in a complex disease, but failure to recognize these issues can result in long-term accumulation of economically important disability. Multiple other issues related to effective disease management also require effective juggling in routine care. Adherence to treatment, timing of DMT change, and interval between discontinuing a DMT and starting a different one continue to be critical concerns as well. Malpas and associates explored this issue and noted that the importance of adherence impact on disease control also relates to treatment interruption and timing of duration between stopping one DMT and starting another agent. The annualized relapse rate (ARR) and the rate of severe relapses was explored in a cohort of 685 people with MS and did not increase significantly after discontinuation of fingolimod in this population, but delaying the commencement of immunotherapy increased the risk for relapse. The ARR was not significantly different during and after fingolimod cessation (mean difference −0.06; 95% CI −0.14 to 0.01), with no severe relapses reported in the year prior to and after fingolimod cessation. However, delaying the recommencement of DMT, or if change in DMT was delayed from 2 to 4 months, vs beginning within 2 months (odds ratio 1.67; 95% CI 1.22-2.27) was associated with a higher risk for relapse. Discontinuation of DMT or treatment interruption also relates to planned or unplanned pregnancy in people with MS. In another study Portaccio and colleagues continued treatment with natalizumab until conception and then restarted treatment within 1 month after delivery. This reduced the risk for disease activity more than natalizumab cessation before conception or restarting 1 month after delivery in women with MS. No major developmental abnormalities were noted in the infants born of 72 pregnancies in 70 women with MS who were treated for at least 2 years. Specifically, relapses occurred in 29.4% of people with MS treated until conception vs 70.2% in those who discontinued prior to conception, after a mean follow-up of 6.1 years (P = .001), with timing of treatment cessation being the only predictor of relapses (HR 4.1; P = .003). No developmental abnormalities were observed in the infants.

Practical points for the treating clinician are many and continue to highlight the complexity of managing people with MS in the real world, with real issues from COVID-19 vaccination, SARS-CoV-2 infection, recognition or awareness of relapse, and the increased challenges of adherence and timing of DMT change and of DMT use relative to pregnancy. Data-driven, reliable, relevant information is critical to incorporate into routine care to enhance and optimize decision-making.

A meta-analysis including over 5000 patients with metastatic hormone receptor–positive (HR+) and HER2- breast cancer showed a significant overall survival (OS) benefit with the addition of cyclin-dependent kinase (CDK) 4/6 inhibitors to endocrine therapy (hazard ratio 1.33; P < .001), albeit with higher rates of toxicities, including neutropenia, leukopenia, and diarrhea.³The MONALEESA-2 study randomly assigned 668 postmenopausal women with metastatic HR+/HER2- breast cancer, treatment-naive in the advanced setting, to either ribociclib or placebo plus letrozole. Updated results with a median follow-up of 6.6 years demonstrated a significant OS benefit with ribociclib + letrozole compared with placebo + letrozole (median OS 63.9 months vs 51.4 months; hazard ratio 0.76; P = .008) (Hortobagyi and colleagues). An OS > 5 years with ribociclib plus endocrine therapy is certainly impressive, and efficacy as well as respective toxicities of the various CDK 4/6 inhibitors are factors taken into consideration when choosing the appropriate therapy for an individual patient.

The optimization of adjuvant endocrine therapy (ET) for HR+ early breast cancer, including use of ovarian suppression and extended adjuvant therapy, has improved outcomes for these women. However, there is a high-risk subset for whom the risk for distant recurrence persists. The phase 3 monarchE trial, which included 5637 patients with high-risk early breast cancer (≥ 4 positive nodes, or 1-3 nodes and either tumor size ≥ 5 cm, histologic grade 3, or central Ki-67 ≥ 20%), demonstrated benefits in invasive disease-free and distant-relapse-free survival with the addition of abemaciclib for 2 years to ET. A safety analysis of the monarchE study among patients who had received at least one dose of the study drug (n = 5591) demonstrated an overall manageable side-effect profile, with the majority of these toxicities addressed via dose holds/reductions or supportive medications (Rugo and colleagues). Abemaciclib + ET led to higher incidence of grade ≥ 3 adverse events vs ET alone (49.7% vs 16.3%), with neutropenia being the most frequent (grade 3 = 19.6%) although without significant clinical implications. Diarrhea was common (83.5%), although the majority was low grade (grade 1/2 = 75.7%), with grade 2/3 events characterized by early onset and short duration. Discontinuation of abemaciclib occurred in 18.5%, with two thirds due to grade 1/2 events and in over half without dose reduction.⁴ These findings show an acceptable safety profile with abemaciclib in the curative setting and highlight the importance of education, recognition, and early management of side effects to maintain patients on treatment.

The heterogeneity of tumor biology within the HR+ breast cancer subtype indicates the need to refine treatment regimens for an individual patient. Genomic assays (70-gene signature and 21-gene recurrence score) have helped tailor adjuvant systemic therapy and in many cases have identified women for whom chemotherapy can be omitted. CDK 4/6 inhibitors have shown impressive activity in the metastatic/advanced setting, although results from trials in the adjuvant setting have produced mixed results. The phase 2 NEOPAL trial evaluated the combination of letrozole + palbociclib vs chemotherapy (sequential anthracycline-taxane) among 106 postmenopausal women with high-risk, HR+/HER2- early breast cancer (luminal B or luminal A with nodal involvement). At a median follow-up of 40.4 months, 3-year PFS (hazard ratio 1.01; P = .98) and invasive disease-free survival (hazard ratio 0.83; P = .71) were similar in the letrozole + palbociclib and chemotherapy arms (Delaloge and colleagues). The phase 2 CORALLEEN trial,⁵  which investigated neoadjuvant letrozole + ribociclib vs chemotherapy in HR+/HER2- luminal B early breast cancer, demonstrated similar percentages of patients achieving downstaging via molecular assessment at the time of surgery. The neoadjuvant space represents a valuable setting to further study CDK 4/6 inhibitors as well as other novel therapies; endpoints including pathologic complete response and residual cancer burden correlating with long-term outcomes can provide a more rapid means to identify effective therapies. Translational biomarkers can be gathered and adjuvant strategies can be tailored based on response.

Additional References

1. Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382:610-621. Doi:  10.1056/NEJMoa1914510 Source
2. Hurvitz S, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan (T-DXd; DS-8201a) versus trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): Subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021;General Session, GS3-01. Source
3. Li J, Huo X, Zhao F, et al. Association of cyclin-dependent kinases 4 and 6 inhibitors with survival in patients with hormone receptor-positive metastatic breast cancer: A systematic review and meta-analysis. JAMA Netw Open. 2020;3:e2020312. Doi: 10.1001/jamanetworkopen.2020.20312 Source
4. Harbeck N, Rastogi P, Martin M, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: Updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32:1571-1581. Doi: 10.1016/j.annonc.2021.09.015 Source
5. Prat A, Saura C, Pascual T, et al. Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2- negative, luminal B breast cancer (CORALLEEN): An open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2020;21:33-43. Doi: 10.1016/S1470-2045(19)30786-7 Source

A meta-analysis including over 5000 patients with metastatic hormone receptor–positive (HR+) and HER2- breast cancer showed a significant overall survival (OS) benefit with the addition of cyclin-dependent kinase (CDK) 4/6 inhibitors to endocrine therapy (hazard ratio 1.33; P < .001), albeit with higher rates of toxicities, including neutropenia, leukopenia, and diarrhea.³The MONALEESA-2 study randomly assigned 668 postmenopausal women with metastatic HR+/HER2- breast cancer, treatment-naive in the advanced setting, to either ribociclib or placebo plus letrozole. Updated results with a median follow-up of 6.6 years demonstrated a significant OS benefit with ribociclib + letrozole compared with placebo + letrozole (median OS 63.9 months vs 51.4 months; hazard ratio 0.76; P = .008) (Hortobagyi and colleagues). An OS > 5 years with ribociclib plus endocrine therapy is certainly impressive, and efficacy as well as respective toxicities of the various CDK 4/6 inhibitors are factors taken into consideration when choosing the appropriate therapy for an individual patient.

The optimization of adjuvant endocrine therapy (ET) for HR+ early breast cancer, including use of ovarian suppression and extended adjuvant therapy, has improved outcomes for these women. However, there is a high-risk subset for whom the risk for distant recurrence persists. The phase 3 monarchE trial, which included 5637 patients with high-risk early breast cancer (≥ 4 positive nodes, or 1-3 nodes and either tumor size ≥ 5 cm, histologic grade 3, or central Ki-67 ≥ 20%), demonstrated benefits in invasive disease-free and distant-relapse-free survival with the addition of abemaciclib for 2 years to ET. A safety analysis of the monarchE study among patients who had received at least one dose of the study drug (n = 5591) demonstrated an overall manageable side-effect profile, with the majority of these toxicities addressed via dose holds/reductions or supportive medications (Rugo and colleagues). Abemaciclib + ET led to higher incidence of grade ≥ 3 adverse events vs ET alone (49.7% vs 16.3%), with neutropenia being the most frequent (grade 3 = 19.6%) although without significant clinical implications. Diarrhea was common (83.5%), although the majority was low grade (grade 1/2 = 75.7%), with grade 2/3 events characterized by early onset and short duration. Discontinuation of abemaciclib occurred in 18.5%, with two thirds due to grade 1/2 events and in over half without dose reduction.⁴ These findings show an acceptable safety profile with abemaciclib in the curative setting and highlight the importance of education, recognition, and early management of side effects to maintain patients on treatment.

The heterogeneity of tumor biology within the HR+ breast cancer subtype indicates the need to refine treatment regimens for an individual patient. Genomic assays (70-gene signature and 21-gene recurrence score) have helped tailor adjuvant systemic therapy and in many cases have identified women for whom chemotherapy can be omitted. CDK 4/6 inhibitors have shown impressive activity in the metastatic/advanced setting, although results from trials in the adjuvant setting have produced mixed results. The phase 2 NEOPAL trial evaluated the combination of letrozole + palbociclib vs chemotherapy (sequential anthracycline-taxane) among 106 postmenopausal women with high-risk, HR+/HER2- early breast cancer (luminal B or luminal A with nodal involvement). At a median follow-up of 40.4 months, 3-year PFS (hazard ratio 1.01; P = .98) and invasive disease-free survival (hazard ratio 0.83; P = .71) were similar in the letrozole + palbociclib and chemotherapy arms (Delaloge and colleagues). The phase 2 CORALLEEN trial,⁵  which investigated neoadjuvant letrozole + ribociclib vs chemotherapy in HR+/HER2- luminal B early breast cancer, demonstrated similar percentages of patients achieving downstaging via molecular assessment at the time of surgery. The neoadjuvant space represents a valuable setting to further study CDK 4/6 inhibitors as well as other novel therapies; endpoints including pathologic complete response and residual cancer burden correlating with long-term outcomes can provide a more rapid means to identify effective therapies. Translational biomarkers can be gathered and adjuvant strategies can be tailored based on response.

Additional References

1. Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382:610-621. Doi:  10.1056/NEJMoa1914510 Source
2. Hurvitz S, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan (T-DXd; DS-8201a) versus trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): Subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021;General Session, GS3-01. Source
3. Li J, Huo X, Zhao F, et al. Association of cyclin-dependent kinases 4 and 6 inhibitors with survival in patients with hormone receptor-positive metastatic breast cancer: A systematic review and meta-analysis. JAMA Netw Open. 2020;3:e2020312. Doi: 10.1001/jamanetworkopen.2020.20312 Source
4. Harbeck N, Rastogi P, Martin M, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: Updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32:1571-1581. Doi: 10.1016/j.annonc.2021.09.015 Source
5. Prat A, Saura C, Pascual T, et al. Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2- negative, luminal B breast cancer (CORALLEEN): An open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2020;21:33-43. Doi: 10.1016/S1470-2045(19)30786-7 Source

A meta-analysis including over 5000 patients with metastatic hormone receptor–positive (HR+) and HER2- breast cancer showed a significant overall survival (OS) benefit with the addition of cyclin-dependent kinase (CDK) 4/6 inhibitors to endocrine therapy (hazard ratio 1.33; P < .001), albeit with higher rates of toxicities, including neutropenia, leukopenia, and diarrhea.³The MONALEESA-2 study randomly assigned 668 postmenopausal women with metastatic HR+/HER2- breast cancer, treatment-naive in the advanced setting, to either ribociclib or placebo plus letrozole. Updated results with a median follow-up of 6.6 years demonstrated a significant OS benefit with ribociclib + letrozole compared with placebo + letrozole (median OS 63.9 months vs 51.4 months; hazard ratio 0.76; P = .008) (Hortobagyi and colleagues). An OS > 5 years with ribociclib plus endocrine therapy is certainly impressive, and efficacy as well as respective toxicities of the various CDK 4/6 inhibitors are factors taken into consideration when choosing the appropriate therapy for an individual patient.

The optimization of adjuvant endocrine therapy (ET) for HR+ early breast cancer, including use of ovarian suppression and extended adjuvant therapy, has improved outcomes for these women. However, there is a high-risk subset for whom the risk for distant recurrence persists. The phase 3 monarchE trial, which included 5637 patients with high-risk early breast cancer (≥ 4 positive nodes, or 1-3 nodes and either tumor size ≥ 5 cm, histologic grade 3, or central Ki-67 ≥ 20%), demonstrated benefits in invasive disease-free and distant-relapse-free survival with the addition of abemaciclib for 2 years to ET. A safety analysis of the monarchE study among patients who had received at least one dose of the study drug (n = 5591) demonstrated an overall manageable side-effect profile, with the majority of these toxicities addressed via dose holds/reductions or supportive medications (Rugo and colleagues). Abemaciclib + ET led to higher incidence of grade ≥ 3 adverse events vs ET alone (49.7% vs 16.3%), with neutropenia being the most frequent (grade 3 = 19.6%) although without significant clinical implications. Diarrhea was common (83.5%), although the majority was low grade (grade 1/2 = 75.7%), with grade 2/3 events characterized by early onset and short duration. Discontinuation of abemaciclib occurred in 18.5%, with two thirds due to grade 1/2 events and in over half without dose reduction.⁴ These findings show an acceptable safety profile with abemaciclib in the curative setting and highlight the importance of education, recognition, and early management of side effects to maintain patients on treatment.

The heterogeneity of tumor biology within the HR+ breast cancer subtype indicates the need to refine treatment regimens for an individual patient. Genomic assays (70-gene signature and 21-gene recurrence score) have helped tailor adjuvant systemic therapy and in many cases have identified women for whom chemotherapy can be omitted. CDK 4/6 inhibitors have shown impressive activity in the metastatic/advanced setting, although results from trials in the adjuvant setting have produced mixed results. The phase 2 NEOPAL trial evaluated the combination of letrozole + palbociclib vs chemotherapy (sequential anthracycline-taxane) among 106 postmenopausal women with high-risk, HR+/HER2- early breast cancer (luminal B or luminal A with nodal involvement). At a median follow-up of 40.4 months, 3-year PFS (hazard ratio 1.01; P = .98) and invasive disease-free survival (hazard ratio 0.83; P = .71) were similar in the letrozole + palbociclib and chemotherapy arms (Delaloge and colleagues). The phase 2 CORALLEEN trial,⁵  which investigated neoadjuvant letrozole + ribociclib vs chemotherapy in HR+/HER2- luminal B early breast cancer, demonstrated similar percentages of patients achieving downstaging via molecular assessment at the time of surgery. The neoadjuvant space represents a valuable setting to further study CDK 4/6 inhibitors as well as other novel therapies; endpoints including pathologic complete response and residual cancer burden correlating with long-term outcomes can provide a more rapid means to identify effective therapies. Translational biomarkers can be gathered and adjuvant strategies can be tailored based on response.

Additional References

1. Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382:610-621. Doi:  10.1056/NEJMoa1914510 Source
2. Hurvitz S, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan (T-DXd; DS-8201a) versus trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): Subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021;General Session, GS3-01. Source
3. Li J, Huo X, Zhao F, et al. Association of cyclin-dependent kinases 4 and 6 inhibitors with survival in patients with hormone receptor-positive metastatic breast cancer: A systematic review and meta-analysis. JAMA Netw Open. 2020;3:e2020312. Doi: 10.1001/jamanetworkopen.2020.20312 Source
4. Harbeck N, Rastogi P, Martin M, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: Updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32:1571-1581. Doi: 10.1016/j.annonc.2021.09.015 Source
5. Prat A, Saura C, Pascual T, et al. Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2- negative, luminal B breast cancer (CORALLEEN): An open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2020;21:33-43. Doi: 10.1016/S1470-2045(19)30786-7 Source