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9/11 first responders show mutations linked to blood cancers
. These results add to concerns about the long-term health effects of that exposure and further underscore a need for screening of those exposed.
“These data demonstrate that environmental exposure to the WTC disaster site is associated with a higher burden of clonal hematopoiesis, exceeding that expected in normal aging, and establish a rationale for mutational testing of the larger WTC-exposed population,” report the authors in the study, published March 7 in Nature Medicine.
The findings come from a study of blood samples from WTC first responders, including 429 firefighters and 52 emergency medical service workers, collected between December 2013 and October 2015.
For comparisons, the authors collected blood samples from 255 firefighters from in and around Nashville, Tenn., none of whom had been exposed to the 9/11 disaster.
Genetic analysis of the samples showed that 10% of those in the WTC-exposed cohort (n = 48) had unique somatic mutations considered to likely be pathogenic, and six of those individuals carried one or more of the mutations.
After a multivariate adjustment controlling for age, sex and race/ethnicity, those among the WTC-exposed first responders had a significantly increased odds of clonal hematopoiesis versus nonexposed workers (odds ratio [OR] = 3.14; P = .0006).
The higher risk was further observed in a comparison limited only to the WTC-exposed firefighters versus nonexposed firefighters (OR = 2.93; P = .0014) after the multivariate adjustment. The greater association between WTC exposure and clonal hematopoiesis remained after the researchers controlled for smoking as well as other risk factors among the WTC-exposed group overall (OR = 3.05; P = .0015) and the firefighters-only comparison (OR = 2.78; P = .004).
A history of smoking was not significantly associated with an increased risk of clonal hematopoiesis in either model.
As a risk factor for hematologic malignancy, cardiovascular events, and mortality, “clonal hematopoiesis is a concerning acquired risk not only for diseases that are already associated with WTC exposure but also as the population ages, this may exacerbate their risk profile,” Dr. Anna Nolan, coauthor of the study, and professor of medicine and environmental medicine in the division of pulmonary and critical care, New York University, said in an interview.
The most common gene mutations observed in the WTC-exposed group were those associated with myeloid malignancies, such as chronic myeloid leukemia; however, blood counts in the exposed group showed no association between exposure and mutations linked to cytopenias.
A further analysis on mice, investigating how WTC particulate matter uniquely affects DNA, surprisingly showed that just one exposure to the material was associated with clonal hematopoietic changes.
“Exposure to particulates, even at a single time point, can yield clonal mutations that may be risk for multisystem end-organ changes,” Dr. Nolan said.
While the serious health effects of WTC exposure on humans, have been extensively documented, including a study published in February showing increases in skin, prostate and thyroid cancers, clonal hematopoiesis suggests further heightened risks as the exposed population grows older, Dr. Nolan noted.
“[Clonal hematopoiesis] is a concerning acquired risk not only for diseases that are already associated with WTC exposure, but also, as the population ages, this may exacerbate their risk profile,” she said.
Due to the risk, “clinicians should be aware that WTC-exposed first responders have had a significant exposure and that they are at risk for developing several conditions.”
Commenting on this study, William K. Oh, MD, whose team at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, has reported in a previous study on the increased risk of prostate cancer among WTC first responders, noted that more time may be necessary to better understand the full effects of the increases in clonal hematopoiesis.
“Though these findings are of concern, there were still no differences in the cohorts in actual hematologic cancers or even cytopenias, suggesting that more time and additional DNA damaging events were needed to transform the clonal hematopoiesis findings to clinically relevant diseases,” Dr. Oh, clinical professor of medicine, said in an interview.
Nevertheless, “if a patient is found on testing to have clonal hematopoiesis, they should be screened more closely for blood disorders and cardiovascular issues than they might otherwise be, though this remains an area of active investigation,” Dr. Oh said.
Dr. Nolan had no disclosures to report. Dr. Oh is the chief medical science officer at Sema4, a genomic testing and data company.
. These results add to concerns about the long-term health effects of that exposure and further underscore a need for screening of those exposed.
“These data demonstrate that environmental exposure to the WTC disaster site is associated with a higher burden of clonal hematopoiesis, exceeding that expected in normal aging, and establish a rationale for mutational testing of the larger WTC-exposed population,” report the authors in the study, published March 7 in Nature Medicine.
The findings come from a study of blood samples from WTC first responders, including 429 firefighters and 52 emergency medical service workers, collected between December 2013 and October 2015.
For comparisons, the authors collected blood samples from 255 firefighters from in and around Nashville, Tenn., none of whom had been exposed to the 9/11 disaster.
Genetic analysis of the samples showed that 10% of those in the WTC-exposed cohort (n = 48) had unique somatic mutations considered to likely be pathogenic, and six of those individuals carried one or more of the mutations.
After a multivariate adjustment controlling for age, sex and race/ethnicity, those among the WTC-exposed first responders had a significantly increased odds of clonal hematopoiesis versus nonexposed workers (odds ratio [OR] = 3.14; P = .0006).
The higher risk was further observed in a comparison limited only to the WTC-exposed firefighters versus nonexposed firefighters (OR = 2.93; P = .0014) after the multivariate adjustment. The greater association between WTC exposure and clonal hematopoiesis remained after the researchers controlled for smoking as well as other risk factors among the WTC-exposed group overall (OR = 3.05; P = .0015) and the firefighters-only comparison (OR = 2.78; P = .004).
A history of smoking was not significantly associated with an increased risk of clonal hematopoiesis in either model.
As a risk factor for hematologic malignancy, cardiovascular events, and mortality, “clonal hematopoiesis is a concerning acquired risk not only for diseases that are already associated with WTC exposure but also as the population ages, this may exacerbate their risk profile,” Dr. Anna Nolan, coauthor of the study, and professor of medicine and environmental medicine in the division of pulmonary and critical care, New York University, said in an interview.
The most common gene mutations observed in the WTC-exposed group were those associated with myeloid malignancies, such as chronic myeloid leukemia; however, blood counts in the exposed group showed no association between exposure and mutations linked to cytopenias.
A further analysis on mice, investigating how WTC particulate matter uniquely affects DNA, surprisingly showed that just one exposure to the material was associated with clonal hematopoietic changes.
“Exposure to particulates, even at a single time point, can yield clonal mutations that may be risk for multisystem end-organ changes,” Dr. Nolan said.
While the serious health effects of WTC exposure on humans, have been extensively documented, including a study published in February showing increases in skin, prostate and thyroid cancers, clonal hematopoiesis suggests further heightened risks as the exposed population grows older, Dr. Nolan noted.
“[Clonal hematopoiesis] is a concerning acquired risk not only for diseases that are already associated with WTC exposure, but also, as the population ages, this may exacerbate their risk profile,” she said.
Due to the risk, “clinicians should be aware that WTC-exposed first responders have had a significant exposure and that they are at risk for developing several conditions.”
Commenting on this study, William K. Oh, MD, whose team at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, has reported in a previous study on the increased risk of prostate cancer among WTC first responders, noted that more time may be necessary to better understand the full effects of the increases in clonal hematopoiesis.
“Though these findings are of concern, there were still no differences in the cohorts in actual hematologic cancers or even cytopenias, suggesting that more time and additional DNA damaging events were needed to transform the clonal hematopoiesis findings to clinically relevant diseases,” Dr. Oh, clinical professor of medicine, said in an interview.
Nevertheless, “if a patient is found on testing to have clonal hematopoiesis, they should be screened more closely for blood disorders and cardiovascular issues than they might otherwise be, though this remains an area of active investigation,” Dr. Oh said.
Dr. Nolan had no disclosures to report. Dr. Oh is the chief medical science officer at Sema4, a genomic testing and data company.
. These results add to concerns about the long-term health effects of that exposure and further underscore a need for screening of those exposed.
“These data demonstrate that environmental exposure to the WTC disaster site is associated with a higher burden of clonal hematopoiesis, exceeding that expected in normal aging, and establish a rationale for mutational testing of the larger WTC-exposed population,” report the authors in the study, published March 7 in Nature Medicine.
The findings come from a study of blood samples from WTC first responders, including 429 firefighters and 52 emergency medical service workers, collected between December 2013 and October 2015.
For comparisons, the authors collected blood samples from 255 firefighters from in and around Nashville, Tenn., none of whom had been exposed to the 9/11 disaster.
Genetic analysis of the samples showed that 10% of those in the WTC-exposed cohort (n = 48) had unique somatic mutations considered to likely be pathogenic, and six of those individuals carried one or more of the mutations.
After a multivariate adjustment controlling for age, sex and race/ethnicity, those among the WTC-exposed first responders had a significantly increased odds of clonal hematopoiesis versus nonexposed workers (odds ratio [OR] = 3.14; P = .0006).
The higher risk was further observed in a comparison limited only to the WTC-exposed firefighters versus nonexposed firefighters (OR = 2.93; P = .0014) after the multivariate adjustment. The greater association between WTC exposure and clonal hematopoiesis remained after the researchers controlled for smoking as well as other risk factors among the WTC-exposed group overall (OR = 3.05; P = .0015) and the firefighters-only comparison (OR = 2.78; P = .004).
A history of smoking was not significantly associated with an increased risk of clonal hematopoiesis in either model.
As a risk factor for hematologic malignancy, cardiovascular events, and mortality, “clonal hematopoiesis is a concerning acquired risk not only for diseases that are already associated with WTC exposure but also as the population ages, this may exacerbate their risk profile,” Dr. Anna Nolan, coauthor of the study, and professor of medicine and environmental medicine in the division of pulmonary and critical care, New York University, said in an interview.
The most common gene mutations observed in the WTC-exposed group were those associated with myeloid malignancies, such as chronic myeloid leukemia; however, blood counts in the exposed group showed no association between exposure and mutations linked to cytopenias.
A further analysis on mice, investigating how WTC particulate matter uniquely affects DNA, surprisingly showed that just one exposure to the material was associated with clonal hematopoietic changes.
“Exposure to particulates, even at a single time point, can yield clonal mutations that may be risk for multisystem end-organ changes,” Dr. Nolan said.
While the serious health effects of WTC exposure on humans, have been extensively documented, including a study published in February showing increases in skin, prostate and thyroid cancers, clonal hematopoiesis suggests further heightened risks as the exposed population grows older, Dr. Nolan noted.
“[Clonal hematopoiesis] is a concerning acquired risk not only for diseases that are already associated with WTC exposure, but also, as the population ages, this may exacerbate their risk profile,” she said.
Due to the risk, “clinicians should be aware that WTC-exposed first responders have had a significant exposure and that they are at risk for developing several conditions.”
Commenting on this study, William K. Oh, MD, whose team at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, has reported in a previous study on the increased risk of prostate cancer among WTC first responders, noted that more time may be necessary to better understand the full effects of the increases in clonal hematopoiesis.
“Though these findings are of concern, there were still no differences in the cohorts in actual hematologic cancers or even cytopenias, suggesting that more time and additional DNA damaging events were needed to transform the clonal hematopoiesis findings to clinically relevant diseases,” Dr. Oh, clinical professor of medicine, said in an interview.
Nevertheless, “if a patient is found on testing to have clonal hematopoiesis, they should be screened more closely for blood disorders and cardiovascular issues than they might otherwise be, though this remains an area of active investigation,” Dr. Oh said.
Dr. Nolan had no disclosures to report. Dr. Oh is the chief medical science officer at Sema4, a genomic testing and data company.
FROM NATURE MEDICINE
Evidence mounts for paramagnetic rim lesions in diagnosing MS
WEST PALM BEACH, FLA. – , new research suggests.
Results from two studies add to the mounting evidence underscoring the importance of the imaging features, researchers noted. “Our data suggest that the presence and number of iron rim lesions hold a prognostic value for long-term disability in MS, especially the presence of four or more rim lesions,” said Amjad I. AlTokhis, School of Medicine, University of Nottingham, United Kingdom, and Division of Clinical Neuroscience, Nottingham University Hospitals NHS Trust, who was the lead author of both studies.
Importantly, the effect of the rim lesions on disability was greater than that of established prognostic biomarkers of T2 white matter lesion count and volume, she noted.
“This could support the use of iron rim lesions as an imaging biomarker for disease severity and worse prognosis,” said Dr. AlTokhis. “These findings also support that iron rim lesions might be clinically useful not only diagnostically but also for disease progression and predicting future disability in MS,” she added.
The findings were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022.
Sign of aggressive disease?
Dozens of studies have linked rim lesions, which are also known as iron rim lesions because of their composition of iron-laden macrophages/microglia, to more severe disease course in MS, as well as to having potential as an important imaging biomarker for diagnosis. However, studies have often been limited to smaller longitudinal cohorts.
In the first study, Dr. AlTokhis and colleagues enrolled 91 patients with MS (56 women) between 2008 and 2013 for whom 7 Tesla (7T) MRI was available with SWI-filtered phase sequencing.
At baseline, among 42 patients with clinically isolated syndrome, 50% had one or more of the rim lesions. The corresponding rates were 38% among 34 patients with relapsing-remitting MS, 38% among 18 patients with primary-progressive MS, and as high as 71% among 17 patients with secondary-progressive MS (P < .05 vs. primary progressive MS and clinically isolated syndrome).
At a median follow-up of 9 years, 18 of the patients with clinically isolated syndrome and relapsing-remitting MS progressed to secondary progressive MS; and among them, 56% had at least one rim lesion.
Of 24 who did not progress to secondary progressive MS, only 33% had at least one rim lesion.
The median baseline level of disease severity in the entire cohort, as measured by Age-Related Multiple Sclerosis Score (ARMSS), was 5.4. However, the median score among patients with rim lesions was higher, compared with those without the lesions (ARMSS, 6.7 vs. 5.0).
After the median 9-year follow-up, disease severity remained higher among those with versus those without the lesions (ARMSS, 7.3 vs. 6.3).
Patients with rim lesions had more white matter lesions overall; and a further analysis surprisingly showed that the number of rim lesions was indeed associated with long-term disability (P = .005).
“Detecting four or more iron rim lesions could be a sign of more aggressive disease and disability – thus, possibly useful in earlier treatment and a potential target for therapies,” Dr. AlTokhis said.
“Also, for clinical practicality, [the number of] iron rim lesions had the most direct effect on disability compared to white matter lesion count and volume, supporting its role as an independent prognostic imaging biomarker,” she added.
Dr. AlTokhis noted that “detecting and counting rim lesions is much easier than assessing all white matter lesions, adding to the clinical utility of this sign.”
Diagnostic value
The second study, presented at the meeting by coinvestigator Brian Renner, MD, Department of Neurology at Cedars Sinai, Los Angeles, reported on the significance of the rim lesions in MS diagnosis. It included 95 patients who had presented for new evaluation on suspicion of MS at 10 centers in the North American Imaging in MS Cooperative (NAIMS).
Of these participants, 44 (46%) were positively diagnosed according to McDonald 2017 criteria (MC2017) for MS, while 37 (39%) were given an alternative diagnosis to MS. Fourteen were considered at risk for MS with diagnoses of clinically isolating syndrome or radiologically isolating syndrome.
Overall, among the 44 with an MS diagnosis, 34 had one or more rim lesions; among the 51 who did not meet an MS diagnosis, only six had one or more of the rim lesions. One or more rim lesions were further observed in three patients with radiologically isolating syndrome and one patient with clinically isolating syndrome.
Among those with one or more of the rim lesions, a diagnosis of MS with MC2017 MS criteria was identified with a high sensitivity of 80%, high specificity of 88%, accuracy of 84%, and an AUC of 81%.
“We’ve shown that paramagnetic rim lesions are highly specific for MS, and the sensitivity of rim lesions for MS is higher than previously reported, despite similar techniques in rating, processing, and evaluation – which was likely related to the nature of the cohort,” Dr. Renner said.
Promising data
During the NAIMS symposium, Christopher C. Hemond, MD, assistant professor or neurology at the University of Massachusetts Medical School, Worcester, noted to meeting attendees that the rim lesions were seen across the entire course of the MS disease spectrum, spanning from radiologically isolating syndrome to secondary progressive MS.
“We know paramagnetic rim lesions are visible at all disease stages. They are uniquely larger and more destructive than their rimless peers and are associated with stronger disease severity,” said Dr. Hemond, who was not involved with the research.
“There is promising data at this point suggesting that [the rim lesions] may represent a biomarker predictive of future disability accumulation,” he added.
Dr. Hemond noted that, unlike in Dr. Renner’s study, the bulk of previous studies have indicated that rim lesions “are associated with a high specificity but only modest sensitivity, in the mid-50% range, for the diagnosis of MS in comparison to some conditions that mimic MS.”
Commenting on the findings, Dr. Hemond noted the results from Dr. Renner’s ongoing study “are critical in building confidence in the translational use of this biomarker to assist in ruling in a diagnosis of MS,” while Dr. AlTokis’ study “adds to and is consistent with the growing literature of pathological associations of paramagnetic rim lesions in MS.”
Dr. Hemond added that the NAIMS cooperative plans to publish guidance in the area in the coming months.
“Although paramagnetic rim lesions have strong pathological associations in MS, it remains unclear if the presence of these lesions should change MS clinical management at the present time,” he said.
During the NAIMS session, Francesca Bagnato, MD, PhD, Vanderbilt University Medical Center, Nashville, Tenn., noted the growing importance of the role of rim lesions in clinical research. “It is clear that these paramagnetic rim lesions are going to be the new biomarker for the next generation of clinical trials,” she said.
Dr. Renner’s study received funding from the Race to Erase MS Foundation. Dr. AlTokhis, Dr. Renner, and Dr. Hemond have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
WEST PALM BEACH, FLA. – , new research suggests.
Results from two studies add to the mounting evidence underscoring the importance of the imaging features, researchers noted. “Our data suggest that the presence and number of iron rim lesions hold a prognostic value for long-term disability in MS, especially the presence of four or more rim lesions,” said Amjad I. AlTokhis, School of Medicine, University of Nottingham, United Kingdom, and Division of Clinical Neuroscience, Nottingham University Hospitals NHS Trust, who was the lead author of both studies.
Importantly, the effect of the rim lesions on disability was greater than that of established prognostic biomarkers of T2 white matter lesion count and volume, she noted.
“This could support the use of iron rim lesions as an imaging biomarker for disease severity and worse prognosis,” said Dr. AlTokhis. “These findings also support that iron rim lesions might be clinically useful not only diagnostically but also for disease progression and predicting future disability in MS,” she added.
The findings were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022.
Sign of aggressive disease?
Dozens of studies have linked rim lesions, which are also known as iron rim lesions because of their composition of iron-laden macrophages/microglia, to more severe disease course in MS, as well as to having potential as an important imaging biomarker for diagnosis. However, studies have often been limited to smaller longitudinal cohorts.
In the first study, Dr. AlTokhis and colleagues enrolled 91 patients with MS (56 women) between 2008 and 2013 for whom 7 Tesla (7T) MRI was available with SWI-filtered phase sequencing.
At baseline, among 42 patients with clinically isolated syndrome, 50% had one or more of the rim lesions. The corresponding rates were 38% among 34 patients with relapsing-remitting MS, 38% among 18 patients with primary-progressive MS, and as high as 71% among 17 patients with secondary-progressive MS (P < .05 vs. primary progressive MS and clinically isolated syndrome).
At a median follow-up of 9 years, 18 of the patients with clinically isolated syndrome and relapsing-remitting MS progressed to secondary progressive MS; and among them, 56% had at least one rim lesion.
Of 24 who did not progress to secondary progressive MS, only 33% had at least one rim lesion.
The median baseline level of disease severity in the entire cohort, as measured by Age-Related Multiple Sclerosis Score (ARMSS), was 5.4. However, the median score among patients with rim lesions was higher, compared with those without the lesions (ARMSS, 6.7 vs. 5.0).
After the median 9-year follow-up, disease severity remained higher among those with versus those without the lesions (ARMSS, 7.3 vs. 6.3).
Patients with rim lesions had more white matter lesions overall; and a further analysis surprisingly showed that the number of rim lesions was indeed associated with long-term disability (P = .005).
“Detecting four or more iron rim lesions could be a sign of more aggressive disease and disability – thus, possibly useful in earlier treatment and a potential target for therapies,” Dr. AlTokhis said.
“Also, for clinical practicality, [the number of] iron rim lesions had the most direct effect on disability compared to white matter lesion count and volume, supporting its role as an independent prognostic imaging biomarker,” she added.
Dr. AlTokhis noted that “detecting and counting rim lesions is much easier than assessing all white matter lesions, adding to the clinical utility of this sign.”
Diagnostic value
The second study, presented at the meeting by coinvestigator Brian Renner, MD, Department of Neurology at Cedars Sinai, Los Angeles, reported on the significance of the rim lesions in MS diagnosis. It included 95 patients who had presented for new evaluation on suspicion of MS at 10 centers in the North American Imaging in MS Cooperative (NAIMS).
Of these participants, 44 (46%) were positively diagnosed according to McDonald 2017 criteria (MC2017) for MS, while 37 (39%) were given an alternative diagnosis to MS. Fourteen were considered at risk for MS with diagnoses of clinically isolating syndrome or radiologically isolating syndrome.
Overall, among the 44 with an MS diagnosis, 34 had one or more rim lesions; among the 51 who did not meet an MS diagnosis, only six had one or more of the rim lesions. One or more rim lesions were further observed in three patients with radiologically isolating syndrome and one patient with clinically isolating syndrome.
Among those with one or more of the rim lesions, a diagnosis of MS with MC2017 MS criteria was identified with a high sensitivity of 80%, high specificity of 88%, accuracy of 84%, and an AUC of 81%.
“We’ve shown that paramagnetic rim lesions are highly specific for MS, and the sensitivity of rim lesions for MS is higher than previously reported, despite similar techniques in rating, processing, and evaluation – which was likely related to the nature of the cohort,” Dr. Renner said.
Promising data
During the NAIMS symposium, Christopher C. Hemond, MD, assistant professor or neurology at the University of Massachusetts Medical School, Worcester, noted to meeting attendees that the rim lesions were seen across the entire course of the MS disease spectrum, spanning from radiologically isolating syndrome to secondary progressive MS.
“We know paramagnetic rim lesions are visible at all disease stages. They are uniquely larger and more destructive than their rimless peers and are associated with stronger disease severity,” said Dr. Hemond, who was not involved with the research.
“There is promising data at this point suggesting that [the rim lesions] may represent a biomarker predictive of future disability accumulation,” he added.
Dr. Hemond noted that, unlike in Dr. Renner’s study, the bulk of previous studies have indicated that rim lesions “are associated with a high specificity but only modest sensitivity, in the mid-50% range, for the diagnosis of MS in comparison to some conditions that mimic MS.”
Commenting on the findings, Dr. Hemond noted the results from Dr. Renner’s ongoing study “are critical in building confidence in the translational use of this biomarker to assist in ruling in a diagnosis of MS,” while Dr. AlTokis’ study “adds to and is consistent with the growing literature of pathological associations of paramagnetic rim lesions in MS.”
Dr. Hemond added that the NAIMS cooperative plans to publish guidance in the area in the coming months.
“Although paramagnetic rim lesions have strong pathological associations in MS, it remains unclear if the presence of these lesions should change MS clinical management at the present time,” he said.
During the NAIMS session, Francesca Bagnato, MD, PhD, Vanderbilt University Medical Center, Nashville, Tenn., noted the growing importance of the role of rim lesions in clinical research. “It is clear that these paramagnetic rim lesions are going to be the new biomarker for the next generation of clinical trials,” she said.
Dr. Renner’s study received funding from the Race to Erase MS Foundation. Dr. AlTokhis, Dr. Renner, and Dr. Hemond have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
WEST PALM BEACH, FLA. – , new research suggests.
Results from two studies add to the mounting evidence underscoring the importance of the imaging features, researchers noted. “Our data suggest that the presence and number of iron rim lesions hold a prognostic value for long-term disability in MS, especially the presence of four or more rim lesions,” said Amjad I. AlTokhis, School of Medicine, University of Nottingham, United Kingdom, and Division of Clinical Neuroscience, Nottingham University Hospitals NHS Trust, who was the lead author of both studies.
Importantly, the effect of the rim lesions on disability was greater than that of established prognostic biomarkers of T2 white matter lesion count and volume, she noted.
“This could support the use of iron rim lesions as an imaging biomarker for disease severity and worse prognosis,” said Dr. AlTokhis. “These findings also support that iron rim lesions might be clinically useful not only diagnostically but also for disease progression and predicting future disability in MS,” she added.
The findings were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022.
Sign of aggressive disease?
Dozens of studies have linked rim lesions, which are also known as iron rim lesions because of their composition of iron-laden macrophages/microglia, to more severe disease course in MS, as well as to having potential as an important imaging biomarker for diagnosis. However, studies have often been limited to smaller longitudinal cohorts.
In the first study, Dr. AlTokhis and colleagues enrolled 91 patients with MS (56 women) between 2008 and 2013 for whom 7 Tesla (7T) MRI was available with SWI-filtered phase sequencing.
At baseline, among 42 patients with clinically isolated syndrome, 50% had one or more of the rim lesions. The corresponding rates were 38% among 34 patients with relapsing-remitting MS, 38% among 18 patients with primary-progressive MS, and as high as 71% among 17 patients with secondary-progressive MS (P < .05 vs. primary progressive MS and clinically isolated syndrome).
At a median follow-up of 9 years, 18 of the patients with clinically isolated syndrome and relapsing-remitting MS progressed to secondary progressive MS; and among them, 56% had at least one rim lesion.
Of 24 who did not progress to secondary progressive MS, only 33% had at least one rim lesion.
The median baseline level of disease severity in the entire cohort, as measured by Age-Related Multiple Sclerosis Score (ARMSS), was 5.4. However, the median score among patients with rim lesions was higher, compared with those without the lesions (ARMSS, 6.7 vs. 5.0).
After the median 9-year follow-up, disease severity remained higher among those with versus those without the lesions (ARMSS, 7.3 vs. 6.3).
Patients with rim lesions had more white matter lesions overall; and a further analysis surprisingly showed that the number of rim lesions was indeed associated with long-term disability (P = .005).
“Detecting four or more iron rim lesions could be a sign of more aggressive disease and disability – thus, possibly useful in earlier treatment and a potential target for therapies,” Dr. AlTokhis said.
“Also, for clinical practicality, [the number of] iron rim lesions had the most direct effect on disability compared to white matter lesion count and volume, supporting its role as an independent prognostic imaging biomarker,” she added.
Dr. AlTokhis noted that “detecting and counting rim lesions is much easier than assessing all white matter lesions, adding to the clinical utility of this sign.”
Diagnostic value
The second study, presented at the meeting by coinvestigator Brian Renner, MD, Department of Neurology at Cedars Sinai, Los Angeles, reported on the significance of the rim lesions in MS diagnosis. It included 95 patients who had presented for new evaluation on suspicion of MS at 10 centers in the North American Imaging in MS Cooperative (NAIMS).
Of these participants, 44 (46%) were positively diagnosed according to McDonald 2017 criteria (MC2017) for MS, while 37 (39%) were given an alternative diagnosis to MS. Fourteen were considered at risk for MS with diagnoses of clinically isolating syndrome or radiologically isolating syndrome.
Overall, among the 44 with an MS diagnosis, 34 had one or more rim lesions; among the 51 who did not meet an MS diagnosis, only six had one or more of the rim lesions. One or more rim lesions were further observed in three patients with radiologically isolating syndrome and one patient with clinically isolating syndrome.
Among those with one or more of the rim lesions, a diagnosis of MS with MC2017 MS criteria was identified with a high sensitivity of 80%, high specificity of 88%, accuracy of 84%, and an AUC of 81%.
“We’ve shown that paramagnetic rim lesions are highly specific for MS, and the sensitivity of rim lesions for MS is higher than previously reported, despite similar techniques in rating, processing, and evaluation – which was likely related to the nature of the cohort,” Dr. Renner said.
Promising data
During the NAIMS symposium, Christopher C. Hemond, MD, assistant professor or neurology at the University of Massachusetts Medical School, Worcester, noted to meeting attendees that the rim lesions were seen across the entire course of the MS disease spectrum, spanning from radiologically isolating syndrome to secondary progressive MS.
“We know paramagnetic rim lesions are visible at all disease stages. They are uniquely larger and more destructive than their rimless peers and are associated with stronger disease severity,” said Dr. Hemond, who was not involved with the research.
“There is promising data at this point suggesting that [the rim lesions] may represent a biomarker predictive of future disability accumulation,” he added.
Dr. Hemond noted that, unlike in Dr. Renner’s study, the bulk of previous studies have indicated that rim lesions “are associated with a high specificity but only modest sensitivity, in the mid-50% range, for the diagnosis of MS in comparison to some conditions that mimic MS.”
Commenting on the findings, Dr. Hemond noted the results from Dr. Renner’s ongoing study “are critical in building confidence in the translational use of this biomarker to assist in ruling in a diagnosis of MS,” while Dr. AlTokis’ study “adds to and is consistent with the growing literature of pathological associations of paramagnetic rim lesions in MS.”
Dr. Hemond added that the NAIMS cooperative plans to publish guidance in the area in the coming months.
“Although paramagnetic rim lesions have strong pathological associations in MS, it remains unclear if the presence of these lesions should change MS clinical management at the present time,” he said.
During the NAIMS session, Francesca Bagnato, MD, PhD, Vanderbilt University Medical Center, Nashville, Tenn., noted the growing importance of the role of rim lesions in clinical research. “It is clear that these paramagnetic rim lesions are going to be the new biomarker for the next generation of clinical trials,” she said.
Dr. Renner’s study received funding from the Race to Erase MS Foundation. Dr. AlTokhis, Dr. Renner, and Dr. Hemond have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
REPORTING FROM ACTRIMS FORUM 2022
Spinal cord atrophy predicts ‘silent progression’ in MS
WEST PALM BEACH, FLA. – , new research shows. Study results suggest that this is a potentially important biomarker for disease progression that may otherwise go unrecognized by clinicians and patients, investigators noted.
“We found that cervical cord atrophy at the C1 level, as obtained from routine brain MRI, is the strongest indicator of silent progression and secondary progressive MS conversion,” said lead author Antje Bischof, MD, department of neurology and Institute of Translational Neurology, University Hospital, Munster, Germany.
“Silent progression and secondary progressive MS conversion are each predominantly related to spinal cord atrophy,” she added.
Dr. Bischof presented the findings at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Relatively new concept
Secondary progressive MS (SPMS) generally occurs when relapsing-remitting MS (RRMS) progresses, with relapses ceasing and a more steady accumulation of disability occurring.
However, a relapse-free “silent progression” of MS, described in previous research as occurring in as many as one-third or more of patients with relapsing MS, emerges at a much earlier stage prior to secondary progression. This potentially involves widespread neurodegeneration in early disease stages.
“Because the concept of silent progression is relatively new and directly challenges the long-accepted two-stage hypothesis, many clinicians have yet to actively identify silent progression in clinical practice,” said coinvestigator Bruce A. C. Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco).
To investigate the underlying structural or pathophysiologic changes that are linked to silent progression, the researchers focused on spinal cord measures, which are known to strongly correlate with disability.
They evaluated 360 patients with RRMS and 47 with SPMS and compared outcomes with 80 participants who acted as the study controls. The groups were matched for age, sex, disease duration, and treatments over a 12-year observation period using data from the UCSF MS Center.
To examine spinal cord changes in areas that could affect MS, the investigators used a novel orientation of MRI brain scans to capture the upper cervical cord area.
Among the patients with RRMS, 54 converted to SPMS over 12 years; 159 had silent progression during the period. Silent progression was defined as the onset of irreversible worsening of scores on the Expanded Disability Status Scale (EDSS). Silent progression was confirmed over 12 months and occurred independently of relapses.
‘Strongest predictor’
The analysis showed spinal cord atrophy at the C1 vertebral level to be the strongest predictor of silent progression, with each 1% increase in spinal cord atrophy associated with a 69% shorter time to silent clinical progression (P < .0001).
Those who converted from RRMS to SPMS showed spinal atrophy rates of –2.19% per year, versus –0.88% per year among those who did not convert (P < .001).
“C1A atrophy rates in patients with silent progression were faster even when combining RRMS and SPMS patients,” Dr. Bischof said.
Of note, the patients who silently progressed showed a lower EDSS score at baseline, she added.
Next to spinal atrophy, ventricular enlargement was the second strongest MRI metric associated with silent progression over the 12 years. Each 1% increase in lateral ventricle size was associated with a 16% reduced time to silent clinical progression (P = .007).
“These findings extend the prognostic value of spinal cord atrophy not only for the conversion to SPMS but also silent progression,” Dr. Bischof said. “Furthermore, we show that the enlargement of the lateral ventricles is the second strongest indicator of impending silent progression and the strongest of all brain measures,” she said.
Standard of care?
While the unique MRI techniques used in the study may not be easily obtained in standard practice, Dr. Cree noted that efforts are underway to facilitate the process. “Development of a fully automated software package to obtain those measurements for both clinical trials and in some [clinical settings] is underway,” he said.
Dr. Cree noted that once those technologies are available, the assessment of spinal cord atrophy could become standard in MS care. “I predict that when upper cervical cord measurements can be readily measured, assessment for decrease in the upper cervical cord area will be an essential component of routine care of relapsing MS patients,” he said.
“Because decreases in upper cervical cord areas herald disability worsening, there may well be a window of opportunity to use highly effective treatments to arrest or even reverse this process before irreversible disability accumulates,” Dr. Cree added.
Treatment implications
Commenting on the findings, ACTRIMS program cochair Anne Cross, MD, professor of neurology and the Manny and Rosalyn Rosenthal–Dr John Trotter MS Chair in Neuroimmunology, Washington University, St. Louis, noted that the study is important for two key reasons.
“We lack a good prognostic marker of future progression, but this could have very important implications for the choice of treatment of patients, particularly if the findings are applicable not only at the group level, as in the study, but also at the level of the individual patient,” said Dr. Cross, who was not involved with the research.
Secondly, the results suggest benefits in the selection of patients for clinical trials of agents that might stop progression. “Choosing patients who would deliver the most impact in studies of potential new treatments for progressive MS” is important, Dr. Cross said.
“We don’t want to dilute our trial patient populations with patients who might not be destined to progress in the ensuing years,” she added.
Also commenting on the findings, Benjamin Segal, MD, director of the University of Michigan’s Multiple Sclerosis Center and the Holtom-Garrett Program in Neuroimmunology, Ann Arbor, agreed that the study offers valuable insights. “These findings are striking in that they underscore the fact that even patients with relapsing-remitting MS undergo functional decline in between overt clinical exacerbations, although the decline is more subtle than that experienced by people with progressive forms of MS,” Dr. Segal said.
He noted that the strong correlation between silent progression and spinal cord atrophy, more so than with brain measures, “is not so surprising, since clinical decline was measured using the EDSS scale – which emphasizes ambulation over other functions,” such as cognition.
“It would be interesting to correlate silent progression with serum neurofilament light chain levels, at baseline as well as change over time,” Dr. Segal added.
Dr. Bischof and Dr. Segal have reported no relevant financial relationships. Dr. Cree has received personal compensation for consulting from Biogen, EMD Serono, and Novartis.
A version of this article first appeared on Medscape.com.
WEST PALM BEACH, FLA. – , new research shows. Study results suggest that this is a potentially important biomarker for disease progression that may otherwise go unrecognized by clinicians and patients, investigators noted.
“We found that cervical cord atrophy at the C1 level, as obtained from routine brain MRI, is the strongest indicator of silent progression and secondary progressive MS conversion,” said lead author Antje Bischof, MD, department of neurology and Institute of Translational Neurology, University Hospital, Munster, Germany.
“Silent progression and secondary progressive MS conversion are each predominantly related to spinal cord atrophy,” she added.
Dr. Bischof presented the findings at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Relatively new concept
Secondary progressive MS (SPMS) generally occurs when relapsing-remitting MS (RRMS) progresses, with relapses ceasing and a more steady accumulation of disability occurring.
However, a relapse-free “silent progression” of MS, described in previous research as occurring in as many as one-third or more of patients with relapsing MS, emerges at a much earlier stage prior to secondary progression. This potentially involves widespread neurodegeneration in early disease stages.
“Because the concept of silent progression is relatively new and directly challenges the long-accepted two-stage hypothesis, many clinicians have yet to actively identify silent progression in clinical practice,” said coinvestigator Bruce A. C. Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco).
To investigate the underlying structural or pathophysiologic changes that are linked to silent progression, the researchers focused on spinal cord measures, which are known to strongly correlate with disability.
They evaluated 360 patients with RRMS and 47 with SPMS and compared outcomes with 80 participants who acted as the study controls. The groups were matched for age, sex, disease duration, and treatments over a 12-year observation period using data from the UCSF MS Center.
To examine spinal cord changes in areas that could affect MS, the investigators used a novel orientation of MRI brain scans to capture the upper cervical cord area.
Among the patients with RRMS, 54 converted to SPMS over 12 years; 159 had silent progression during the period. Silent progression was defined as the onset of irreversible worsening of scores on the Expanded Disability Status Scale (EDSS). Silent progression was confirmed over 12 months and occurred independently of relapses.
‘Strongest predictor’
The analysis showed spinal cord atrophy at the C1 vertebral level to be the strongest predictor of silent progression, with each 1% increase in spinal cord atrophy associated with a 69% shorter time to silent clinical progression (P < .0001).
Those who converted from RRMS to SPMS showed spinal atrophy rates of –2.19% per year, versus –0.88% per year among those who did not convert (P < .001).
“C1A atrophy rates in patients with silent progression were faster even when combining RRMS and SPMS patients,” Dr. Bischof said.
Of note, the patients who silently progressed showed a lower EDSS score at baseline, she added.
Next to spinal atrophy, ventricular enlargement was the second strongest MRI metric associated with silent progression over the 12 years. Each 1% increase in lateral ventricle size was associated with a 16% reduced time to silent clinical progression (P = .007).
“These findings extend the prognostic value of spinal cord atrophy not only for the conversion to SPMS but also silent progression,” Dr. Bischof said. “Furthermore, we show that the enlargement of the lateral ventricles is the second strongest indicator of impending silent progression and the strongest of all brain measures,” she said.
Standard of care?
While the unique MRI techniques used in the study may not be easily obtained in standard practice, Dr. Cree noted that efforts are underway to facilitate the process. “Development of a fully automated software package to obtain those measurements for both clinical trials and in some [clinical settings] is underway,” he said.
Dr. Cree noted that once those technologies are available, the assessment of spinal cord atrophy could become standard in MS care. “I predict that when upper cervical cord measurements can be readily measured, assessment for decrease in the upper cervical cord area will be an essential component of routine care of relapsing MS patients,” he said.
“Because decreases in upper cervical cord areas herald disability worsening, there may well be a window of opportunity to use highly effective treatments to arrest or even reverse this process before irreversible disability accumulates,” Dr. Cree added.
Treatment implications
Commenting on the findings, ACTRIMS program cochair Anne Cross, MD, professor of neurology and the Manny and Rosalyn Rosenthal–Dr John Trotter MS Chair in Neuroimmunology, Washington University, St. Louis, noted that the study is important for two key reasons.
“We lack a good prognostic marker of future progression, but this could have very important implications for the choice of treatment of patients, particularly if the findings are applicable not only at the group level, as in the study, but also at the level of the individual patient,” said Dr. Cross, who was not involved with the research.
Secondly, the results suggest benefits in the selection of patients for clinical trials of agents that might stop progression. “Choosing patients who would deliver the most impact in studies of potential new treatments for progressive MS” is important, Dr. Cross said.
“We don’t want to dilute our trial patient populations with patients who might not be destined to progress in the ensuing years,” she added.
Also commenting on the findings, Benjamin Segal, MD, director of the University of Michigan’s Multiple Sclerosis Center and the Holtom-Garrett Program in Neuroimmunology, Ann Arbor, agreed that the study offers valuable insights. “These findings are striking in that they underscore the fact that even patients with relapsing-remitting MS undergo functional decline in between overt clinical exacerbations, although the decline is more subtle than that experienced by people with progressive forms of MS,” Dr. Segal said.
He noted that the strong correlation between silent progression and spinal cord atrophy, more so than with brain measures, “is not so surprising, since clinical decline was measured using the EDSS scale – which emphasizes ambulation over other functions,” such as cognition.
“It would be interesting to correlate silent progression with serum neurofilament light chain levels, at baseline as well as change over time,” Dr. Segal added.
Dr. Bischof and Dr. Segal have reported no relevant financial relationships. Dr. Cree has received personal compensation for consulting from Biogen, EMD Serono, and Novartis.
A version of this article first appeared on Medscape.com.
WEST PALM BEACH, FLA. – , new research shows. Study results suggest that this is a potentially important biomarker for disease progression that may otherwise go unrecognized by clinicians and patients, investigators noted.
“We found that cervical cord atrophy at the C1 level, as obtained from routine brain MRI, is the strongest indicator of silent progression and secondary progressive MS conversion,” said lead author Antje Bischof, MD, department of neurology and Institute of Translational Neurology, University Hospital, Munster, Germany.
“Silent progression and secondary progressive MS conversion are each predominantly related to spinal cord atrophy,” she added.
Dr. Bischof presented the findings at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Relatively new concept
Secondary progressive MS (SPMS) generally occurs when relapsing-remitting MS (RRMS) progresses, with relapses ceasing and a more steady accumulation of disability occurring.
However, a relapse-free “silent progression” of MS, described in previous research as occurring in as many as one-third or more of patients with relapsing MS, emerges at a much earlier stage prior to secondary progression. This potentially involves widespread neurodegeneration in early disease stages.
“Because the concept of silent progression is relatively new and directly challenges the long-accepted two-stage hypothesis, many clinicians have yet to actively identify silent progression in clinical practice,” said coinvestigator Bruce A. C. Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco).
To investigate the underlying structural or pathophysiologic changes that are linked to silent progression, the researchers focused on spinal cord measures, which are known to strongly correlate with disability.
They evaluated 360 patients with RRMS and 47 with SPMS and compared outcomes with 80 participants who acted as the study controls. The groups were matched for age, sex, disease duration, and treatments over a 12-year observation period using data from the UCSF MS Center.
To examine spinal cord changes in areas that could affect MS, the investigators used a novel orientation of MRI brain scans to capture the upper cervical cord area.
Among the patients with RRMS, 54 converted to SPMS over 12 years; 159 had silent progression during the period. Silent progression was defined as the onset of irreversible worsening of scores on the Expanded Disability Status Scale (EDSS). Silent progression was confirmed over 12 months and occurred independently of relapses.
‘Strongest predictor’
The analysis showed spinal cord atrophy at the C1 vertebral level to be the strongest predictor of silent progression, with each 1% increase in spinal cord atrophy associated with a 69% shorter time to silent clinical progression (P < .0001).
Those who converted from RRMS to SPMS showed spinal atrophy rates of –2.19% per year, versus –0.88% per year among those who did not convert (P < .001).
“C1A atrophy rates in patients with silent progression were faster even when combining RRMS and SPMS patients,” Dr. Bischof said.
Of note, the patients who silently progressed showed a lower EDSS score at baseline, she added.
Next to spinal atrophy, ventricular enlargement was the second strongest MRI metric associated with silent progression over the 12 years. Each 1% increase in lateral ventricle size was associated with a 16% reduced time to silent clinical progression (P = .007).
“These findings extend the prognostic value of spinal cord atrophy not only for the conversion to SPMS but also silent progression,” Dr. Bischof said. “Furthermore, we show that the enlargement of the lateral ventricles is the second strongest indicator of impending silent progression and the strongest of all brain measures,” she said.
Standard of care?
While the unique MRI techniques used in the study may not be easily obtained in standard practice, Dr. Cree noted that efforts are underway to facilitate the process. “Development of a fully automated software package to obtain those measurements for both clinical trials and in some [clinical settings] is underway,” he said.
Dr. Cree noted that once those technologies are available, the assessment of spinal cord atrophy could become standard in MS care. “I predict that when upper cervical cord measurements can be readily measured, assessment for decrease in the upper cervical cord area will be an essential component of routine care of relapsing MS patients,” he said.
“Because decreases in upper cervical cord areas herald disability worsening, there may well be a window of opportunity to use highly effective treatments to arrest or even reverse this process before irreversible disability accumulates,” Dr. Cree added.
Treatment implications
Commenting on the findings, ACTRIMS program cochair Anne Cross, MD, professor of neurology and the Manny and Rosalyn Rosenthal–Dr John Trotter MS Chair in Neuroimmunology, Washington University, St. Louis, noted that the study is important for two key reasons.
“We lack a good prognostic marker of future progression, but this could have very important implications for the choice of treatment of patients, particularly if the findings are applicable not only at the group level, as in the study, but also at the level of the individual patient,” said Dr. Cross, who was not involved with the research.
Secondly, the results suggest benefits in the selection of patients for clinical trials of agents that might stop progression. “Choosing patients who would deliver the most impact in studies of potential new treatments for progressive MS” is important, Dr. Cross said.
“We don’t want to dilute our trial patient populations with patients who might not be destined to progress in the ensuing years,” she added.
Also commenting on the findings, Benjamin Segal, MD, director of the University of Michigan’s Multiple Sclerosis Center and the Holtom-Garrett Program in Neuroimmunology, Ann Arbor, agreed that the study offers valuable insights. “These findings are striking in that they underscore the fact that even patients with relapsing-remitting MS undergo functional decline in between overt clinical exacerbations, although the decline is more subtle than that experienced by people with progressive forms of MS,” Dr. Segal said.
He noted that the strong correlation between silent progression and spinal cord atrophy, more so than with brain measures, “is not so surprising, since clinical decline was measured using the EDSS scale – which emphasizes ambulation over other functions,” such as cognition.
“It would be interesting to correlate silent progression with serum neurofilament light chain levels, at baseline as well as change over time,” Dr. Segal added.
Dr. Bischof and Dr. Segal have reported no relevant financial relationships. Dr. Cree has received personal compensation for consulting from Biogen, EMD Serono, and Novartis.
A version of this article first appeared on Medscape.com.
REPORTING FROM ACTRIMS FORUM 2022
Global data suggest rising CLL incidence since 1990
Either way, “to our best knowledge, this study is the first study to provide a comprehensive description of the epidemiology and global burden of CLL worldwide,” the authors reported in BioMedical Engineering Online.
The findings are an evaluation of data from the 2019 Global Burden of Disease study, which includes epidemiological data on 369 diseases in 204 nations and territories around the world.
According to the analysis, the age-standardized incidence rate of CLL rose globally over the last 3 decades, from 0.76 per 100,000 persons in 1990 to 1.34 per 100,000 in 2019, for an estimated annual percentage change of 1.86%.
While increases were observed across all economic levels, the highest increases were observed in regions with the highest social determinant index. Notably, the fastest rise was observed in middle-income regions.
“What cannot be ignored is the rapid growth of the disease burden in middle [social determinant index] regions, which potentially indicated an underestimated incidence and mortality in underdeveloped countries,” write the authors, led by senior author Huafeng Wang, MD, of the department of hematology, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
The highest annual age-standardized incidence rates in 2019 occurred in western Europe, high-income areas of North America and central Europe, while the fastest increase in the incidence of CLL occurred in east Asia, central Europe, and Andean Latin America, according to the study.
Mortality rates
The age-standardized death rate from CLL also increased globally, from 0.40 per 100,000 persons in 1990 to 0.58 per 100,000 in 2019, for an estimated annual percentage change of 1.17.
The increases in death rates were observed across all income regions over the study period, with the highest age-standardized death rate in 2019, consistent with incidence rates, occurring in the highest-income regions, specifically in central Europe, western Europe, and high-income North America.
The geographic trends were similar in terms of disability-adjusted life-years, which increased globally from 9.20 per 100,000 persons in 1990 to 12.26 per 100,000 in 2019, for an estimated annual percentage change of 0.92%.
The authors noted that the geographic variation of CLL is consistent with research suggesting that White ancestry is a risk factor for this leukemia. And while the incidence of CLL is generally low in the 22 nations of the Arab League, the burden of disease is high in Israel.
Age and gender
The study shows that, during the past 30 years in general, CLL was more common among males, with some regional differences. For instance, in contrast to global trends, females in low-income regions accounted for the majority of incidence and mortality.
The majority of CLL cases occurred in people over the age of 50, which is consistent with known patterns of CLL occurring in older patients. Of note, the majority of cases between the ages of 50 and 69 were in low-income regions, while more than half of the incidence cases in higher-income regions were among those over the age of 70.
Risk factors
Key risk factors that may to be linked to CLL-related mortality and disability include high body mass index, occupational exposure to benzene and formaldehyde, and smoking, which was the strongest risk factor, the authors reported.
Obesity has previously been linked with an increased risk of lymphohematopoietic cancers in general and with poorer responses to treatment and reduced progression-free survival in CLL, in particular.
While the database otherwise provided only limited insights into potential CLL risk factors, “among the factors [the database] provided, the risk of benzene and formaldehyde exposure should be paid attention to,” Dr. Wang said in an interview.
“Different from other risk factors, emerging evidence has clearly pointed out the close relationship between benzene and formaldehyde exposure and hematological malignancies,” he explained. “With globalization, a large number of factories moved to less developed regions. The problem of occupational toxic exposure needs to be addressed.”
In general, the trends in the current study are consistent with previous research showing that, while there was a significant global decrease in leukemia incidence between 1990 and 2017, the incidence rates of CLL as well as acute myeloid leukemia (AML) significantly increased in most countries during that period.
“The age-standardized incidence rate of AML has steadily increased over the past 30 years, but not as rapidly as CLL,” Dr. Wang said.
He added that an encouraging sign is the “significant decline” in the age-standardized rate of chronic myeloid leukemia seen with the advent of tyrosine kinase inhibitors (TKIs).
“Perhaps for CLL, the emergence of epoch-making therapies like TKIs will also contribute to the reduction of disease burden [with that disease],” he said.
Surveillance bias?
The authors note a key caveat that the lower rates observed in low-income regions could be related to underreporting and lower screening of cancers in those regions. However, commenting on the study, Robert Peter Gale, MD, PhD, suggested that, conversely, the trends may represent a surveillance bias, reflecting an increased detection of CLL.
In fact, “it is most unlikely the incidence of CLL is really increasing,” Dr. Gale, visiting professor of hematology at the Hematology Research Centre, department of immunology and inflammation, Imperial College London, said in an interview.
“More than one-half of people with CLL have no signs or symptoms, and the diagnosis is made when they have a blood test done for unrelated reasons,” such as in the process of qualifying for life or medical insurance or for a new job, he explained. “The more testing you do, the more cases you will detect.”
Dr. Gale pointed out that research his team has conducted in China also showed an increasing incidence of CLL. However, “on closer study, we found about two-thirds of cases were incidental, namely cases detected under circumstances [such as blood testing for a job].”
Shen-Miao Yang, MD, first author of that study, agreed and noted that improved treatment with drugs such as Bruton kinase inhibitors also can have the effect of increasing incidence – by extending lives.
“More patients are diagnosed, [and] receive the new agent, and their longer survival contributes to the increased burden of CLL,” Dr. Yang of People’s Hospital of Peking University, Peking University Institute of Hematology, Beijing, said in an interview.
Furthermore, “advanced techniques such as flow cytometry and fluorescence in situ hybridization are routinely used for the diagnosis and prognosis of CLL patients – that also increases the CLL burden.”
Dr. Yang had no disclosures to report. Dr. Gale disclosed that he is a consultant to BeiGene, Fusion Pharma, La Jolla NanoMedical, MingSight Pharmaceuticals, CStone Pharmaceuticals, NexImmune, and Prolacta Bioscience; an adviser to Antengene Biotech; medical director of FFF Enterprises; a partner of AZCA; member of the board of directors of the Russian Foundation for Cancer Research Support; and on the scientific advisory board of StemRad.
Either way, “to our best knowledge, this study is the first study to provide a comprehensive description of the epidemiology and global burden of CLL worldwide,” the authors reported in BioMedical Engineering Online.
The findings are an evaluation of data from the 2019 Global Burden of Disease study, which includes epidemiological data on 369 diseases in 204 nations and territories around the world.
According to the analysis, the age-standardized incidence rate of CLL rose globally over the last 3 decades, from 0.76 per 100,000 persons in 1990 to 1.34 per 100,000 in 2019, for an estimated annual percentage change of 1.86%.
While increases were observed across all economic levels, the highest increases were observed in regions with the highest social determinant index. Notably, the fastest rise was observed in middle-income regions.
“What cannot be ignored is the rapid growth of the disease burden in middle [social determinant index] regions, which potentially indicated an underestimated incidence and mortality in underdeveloped countries,” write the authors, led by senior author Huafeng Wang, MD, of the department of hematology, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
The highest annual age-standardized incidence rates in 2019 occurred in western Europe, high-income areas of North America and central Europe, while the fastest increase in the incidence of CLL occurred in east Asia, central Europe, and Andean Latin America, according to the study.
Mortality rates
The age-standardized death rate from CLL also increased globally, from 0.40 per 100,000 persons in 1990 to 0.58 per 100,000 in 2019, for an estimated annual percentage change of 1.17.
The increases in death rates were observed across all income regions over the study period, with the highest age-standardized death rate in 2019, consistent with incidence rates, occurring in the highest-income regions, specifically in central Europe, western Europe, and high-income North America.
The geographic trends were similar in terms of disability-adjusted life-years, which increased globally from 9.20 per 100,000 persons in 1990 to 12.26 per 100,000 in 2019, for an estimated annual percentage change of 0.92%.
The authors noted that the geographic variation of CLL is consistent with research suggesting that White ancestry is a risk factor for this leukemia. And while the incidence of CLL is generally low in the 22 nations of the Arab League, the burden of disease is high in Israel.
Age and gender
The study shows that, during the past 30 years in general, CLL was more common among males, with some regional differences. For instance, in contrast to global trends, females in low-income regions accounted for the majority of incidence and mortality.
The majority of CLL cases occurred in people over the age of 50, which is consistent with known patterns of CLL occurring in older patients. Of note, the majority of cases between the ages of 50 and 69 were in low-income regions, while more than half of the incidence cases in higher-income regions were among those over the age of 70.
Risk factors
Key risk factors that may to be linked to CLL-related mortality and disability include high body mass index, occupational exposure to benzene and formaldehyde, and smoking, which was the strongest risk factor, the authors reported.
Obesity has previously been linked with an increased risk of lymphohematopoietic cancers in general and with poorer responses to treatment and reduced progression-free survival in CLL, in particular.
While the database otherwise provided only limited insights into potential CLL risk factors, “among the factors [the database] provided, the risk of benzene and formaldehyde exposure should be paid attention to,” Dr. Wang said in an interview.
“Different from other risk factors, emerging evidence has clearly pointed out the close relationship between benzene and formaldehyde exposure and hematological malignancies,” he explained. “With globalization, a large number of factories moved to less developed regions. The problem of occupational toxic exposure needs to be addressed.”
In general, the trends in the current study are consistent with previous research showing that, while there was a significant global decrease in leukemia incidence between 1990 and 2017, the incidence rates of CLL as well as acute myeloid leukemia (AML) significantly increased in most countries during that period.
“The age-standardized incidence rate of AML has steadily increased over the past 30 years, but not as rapidly as CLL,” Dr. Wang said.
He added that an encouraging sign is the “significant decline” in the age-standardized rate of chronic myeloid leukemia seen with the advent of tyrosine kinase inhibitors (TKIs).
“Perhaps for CLL, the emergence of epoch-making therapies like TKIs will also contribute to the reduction of disease burden [with that disease],” he said.
Surveillance bias?
The authors note a key caveat that the lower rates observed in low-income regions could be related to underreporting and lower screening of cancers in those regions. However, commenting on the study, Robert Peter Gale, MD, PhD, suggested that, conversely, the trends may represent a surveillance bias, reflecting an increased detection of CLL.
In fact, “it is most unlikely the incidence of CLL is really increasing,” Dr. Gale, visiting professor of hematology at the Hematology Research Centre, department of immunology and inflammation, Imperial College London, said in an interview.
“More than one-half of people with CLL have no signs or symptoms, and the diagnosis is made when they have a blood test done for unrelated reasons,” such as in the process of qualifying for life or medical insurance or for a new job, he explained. “The more testing you do, the more cases you will detect.”
Dr. Gale pointed out that research his team has conducted in China also showed an increasing incidence of CLL. However, “on closer study, we found about two-thirds of cases were incidental, namely cases detected under circumstances [such as blood testing for a job].”
Shen-Miao Yang, MD, first author of that study, agreed and noted that improved treatment with drugs such as Bruton kinase inhibitors also can have the effect of increasing incidence – by extending lives.
“More patients are diagnosed, [and] receive the new agent, and their longer survival contributes to the increased burden of CLL,” Dr. Yang of People’s Hospital of Peking University, Peking University Institute of Hematology, Beijing, said in an interview.
Furthermore, “advanced techniques such as flow cytometry and fluorescence in situ hybridization are routinely used for the diagnosis and prognosis of CLL patients – that also increases the CLL burden.”
Dr. Yang had no disclosures to report. Dr. Gale disclosed that he is a consultant to BeiGene, Fusion Pharma, La Jolla NanoMedical, MingSight Pharmaceuticals, CStone Pharmaceuticals, NexImmune, and Prolacta Bioscience; an adviser to Antengene Biotech; medical director of FFF Enterprises; a partner of AZCA; member of the board of directors of the Russian Foundation for Cancer Research Support; and on the scientific advisory board of StemRad.
Either way, “to our best knowledge, this study is the first study to provide a comprehensive description of the epidemiology and global burden of CLL worldwide,” the authors reported in BioMedical Engineering Online.
The findings are an evaluation of data from the 2019 Global Burden of Disease study, which includes epidemiological data on 369 diseases in 204 nations and territories around the world.
According to the analysis, the age-standardized incidence rate of CLL rose globally over the last 3 decades, from 0.76 per 100,000 persons in 1990 to 1.34 per 100,000 in 2019, for an estimated annual percentage change of 1.86%.
While increases were observed across all economic levels, the highest increases were observed in regions with the highest social determinant index. Notably, the fastest rise was observed in middle-income regions.
“What cannot be ignored is the rapid growth of the disease burden in middle [social determinant index] regions, which potentially indicated an underestimated incidence and mortality in underdeveloped countries,” write the authors, led by senior author Huafeng Wang, MD, of the department of hematology, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
The highest annual age-standardized incidence rates in 2019 occurred in western Europe, high-income areas of North America and central Europe, while the fastest increase in the incidence of CLL occurred in east Asia, central Europe, and Andean Latin America, according to the study.
Mortality rates
The age-standardized death rate from CLL also increased globally, from 0.40 per 100,000 persons in 1990 to 0.58 per 100,000 in 2019, for an estimated annual percentage change of 1.17.
The increases in death rates were observed across all income regions over the study period, with the highest age-standardized death rate in 2019, consistent with incidence rates, occurring in the highest-income regions, specifically in central Europe, western Europe, and high-income North America.
The geographic trends were similar in terms of disability-adjusted life-years, which increased globally from 9.20 per 100,000 persons in 1990 to 12.26 per 100,000 in 2019, for an estimated annual percentage change of 0.92%.
The authors noted that the geographic variation of CLL is consistent with research suggesting that White ancestry is a risk factor for this leukemia. And while the incidence of CLL is generally low in the 22 nations of the Arab League, the burden of disease is high in Israel.
Age and gender
The study shows that, during the past 30 years in general, CLL was more common among males, with some regional differences. For instance, in contrast to global trends, females in low-income regions accounted for the majority of incidence and mortality.
The majority of CLL cases occurred in people over the age of 50, which is consistent with known patterns of CLL occurring in older patients. Of note, the majority of cases between the ages of 50 and 69 were in low-income regions, while more than half of the incidence cases in higher-income regions were among those over the age of 70.
Risk factors
Key risk factors that may to be linked to CLL-related mortality and disability include high body mass index, occupational exposure to benzene and formaldehyde, and smoking, which was the strongest risk factor, the authors reported.
Obesity has previously been linked with an increased risk of lymphohematopoietic cancers in general and with poorer responses to treatment and reduced progression-free survival in CLL, in particular.
While the database otherwise provided only limited insights into potential CLL risk factors, “among the factors [the database] provided, the risk of benzene and formaldehyde exposure should be paid attention to,” Dr. Wang said in an interview.
“Different from other risk factors, emerging evidence has clearly pointed out the close relationship between benzene and formaldehyde exposure and hematological malignancies,” he explained. “With globalization, a large number of factories moved to less developed regions. The problem of occupational toxic exposure needs to be addressed.”
In general, the trends in the current study are consistent with previous research showing that, while there was a significant global decrease in leukemia incidence between 1990 and 2017, the incidence rates of CLL as well as acute myeloid leukemia (AML) significantly increased in most countries during that period.
“The age-standardized incidence rate of AML has steadily increased over the past 30 years, but not as rapidly as CLL,” Dr. Wang said.
He added that an encouraging sign is the “significant decline” in the age-standardized rate of chronic myeloid leukemia seen with the advent of tyrosine kinase inhibitors (TKIs).
“Perhaps for CLL, the emergence of epoch-making therapies like TKIs will also contribute to the reduction of disease burden [with that disease],” he said.
Surveillance bias?
The authors note a key caveat that the lower rates observed in low-income regions could be related to underreporting and lower screening of cancers in those regions. However, commenting on the study, Robert Peter Gale, MD, PhD, suggested that, conversely, the trends may represent a surveillance bias, reflecting an increased detection of CLL.
In fact, “it is most unlikely the incidence of CLL is really increasing,” Dr. Gale, visiting professor of hematology at the Hematology Research Centre, department of immunology and inflammation, Imperial College London, said in an interview.
“More than one-half of people with CLL have no signs or symptoms, and the diagnosis is made when they have a blood test done for unrelated reasons,” such as in the process of qualifying for life or medical insurance or for a new job, he explained. “The more testing you do, the more cases you will detect.”
Dr. Gale pointed out that research his team has conducted in China also showed an increasing incidence of CLL. However, “on closer study, we found about two-thirds of cases were incidental, namely cases detected under circumstances [such as blood testing for a job].”
Shen-Miao Yang, MD, first author of that study, agreed and noted that improved treatment with drugs such as Bruton kinase inhibitors also can have the effect of increasing incidence – by extending lives.
“More patients are diagnosed, [and] receive the new agent, and their longer survival contributes to the increased burden of CLL,” Dr. Yang of People’s Hospital of Peking University, Peking University Institute of Hematology, Beijing, said in an interview.
Furthermore, “advanced techniques such as flow cytometry and fluorescence in situ hybridization are routinely used for the diagnosis and prognosis of CLL patients – that also increases the CLL burden.”
Dr. Yang had no disclosures to report. Dr. Gale disclosed that he is a consultant to BeiGene, Fusion Pharma, La Jolla NanoMedical, MingSight Pharmaceuticals, CStone Pharmaceuticals, NexImmune, and Prolacta Bioscience; an adviser to Antengene Biotech; medical director of FFF Enterprises; a partner of AZCA; member of the board of directors of the Russian Foundation for Cancer Research Support; and on the scientific advisory board of StemRad.
FROM BIOMEDICAL ENGINEERING ONLINE
Radiofrequency ablation an option for thyroid microcarcinoma
(PTC) when measures beyond active surveillance are warranted, results from a new review show.
“The results in the current study suggest that RFA could function as a useful alternative treatment strategy in which patients are treated minimally invasively with curative intentions,” reported the authors of the meta-analysis published online in JAMA Otolaryngology – Head and Neck Surgery.
Commenting on the research, Joanna Klubo-Gwiezdzinska, MD, PhD, said the work offers useful evidence on the potential role for RFA in low-risk micro-PTC – with some notable caveats.
“I agree that RFA might be a good option for patients unwilling or unable to accept active surveillance and for patients who are at high surgical risk because of comorbid conditions,” she told this news organization.
However, “RFA for patients with an evidence of nodule growth requires more data to be analyzed and a longer follow-up period in lieu of the fact that 21% of nodules subjected to RFA did not disappear, based on the data the authors provide,” noted Dr. Klubo-Gwiezdzinska, who is acting chief of thyroid tumors and functional thyroid disorders at the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, in Bethesda, Md.
When active surveillance isn’t enough
Microcarcinoma PTC, defined as measuring 10 mm or less, is highly common, making up approximately half of papillary thyroid cancers diagnosed in some countries, and the outcomes of those cancers are excellent, with disease-specific survival of more than 99% after 10 years.
Guidelines in the United States and Europe typically recommend surgery (lobectomy) as a standard treatment for thyroid cancer, however, with many of the low-risk microcarcinomas remaining indolent and never progressing to the point of requiring treatment over a person’s lifetime, some also recommend considering active surveillance, or watchful waiting, for those lower-risk cancers.
In situations such as evidence of tumor growth during active surveillance, some countries, particularly Asian countries, also suggest considering thermal ablation techniques, including RFA, as an alternative to surgery, with key benefits including lower costs and potentially a lower risk of complications, compared with surgical lobectomy.
Otherwise, RFA is more typically reserved for benign nodules, recurrent PTC, or inoperable disease.
New meta-analysis
To investigate reported outcomes with RFA specifically in the treatment of microcarcinoma PTC, the authors, led by Sam P.J. van Dijk, BSc, of University Medical Center Rotterdam (the Netherlands), identified 15 studies published after 2016 involving 1,770 adult patients and 1,822 tumors who received RFA for the treatment of low-risk PTC microcarcinomas, defined as measuring 10 mm or less.
The studies were conducted in China and South Korea, where RFA is more commonly used in low-risk microcarcinoma PTC.
Patients were 77.9% women and a mean age of 45.4 years. The analysis excluded patients with pre-ablation lymph node or distant metastases, recurrence of disease, or extrathyroidal extension.
Of the 1,822 tumors treated with RFA, 49 required an additional RFA treatment and 1 tumor had two additional treatments.
With a mean follow-up of 33 months (range, 6-131 months), the primary outcome of the pooled rate of complete disappearance of microcarcinoma PTC on ultrasonography was 79%.
The overall rate of tumor progression was 1.5% (26 patients), and local residual microcarcinoma PTC occurred in 0.4% (7 tumors).
New microcarcinoma PTC occurred in 0.9% (15) of patients; 0.2% (4) developed lymph node metastases during follow-up, and no distant metastases were observed.
Minor complications occurred in 45 patients, and there were three major complications, including two voice changes that lasted more than 2 months and one cardiac arrhythmia.
“This study suggests that radiofrequency ablation is a safe and efficient method to treat selected low-risk papillary microcarcinoma of the thyroid,” the researchers said.
Questions surrounding the 20% of patients who still had residual nodules
While the analysis did not include direct comparisons between RFA and lobectomy, Dr. Klubo-Gwiezdzinska noted that, in general, “RFA appears to be associated with a lower complication rate compared with surgery, but also lower efficacy, with 21% of patients with residual nodules.”
The results raise the question of whether “all of the residual lesions are associated with persistent disease, and, if so, do they warrant further intervention?” she added.
To that point, the authors noted that only seven (0.4%) of the 21% of patients with persistent nodules showed residual microcarcinoma PTC cells after RFA, a fact that underscores that “the assessment of tumor response in patients with mPTC after RFA is complicated,” they wrote.
A key concern with assessing responses in RFA is that fine needle aspiration has been shown to have reduced diagnostic accuracy following treatment due to insufficient cellularity in the ablation area, the authors noted.
They add that core needle biopsy is believed to have higher accuracy.
While commenting that the analysis used the “best standards,” Dr. Klubo-Gwiezdzinska noted the caveat that it provides “low- to moderate-quality evidence as it included either case series or retrospective cohort studies, characterized by an inherent bias associated with these study designs.”
And as the authors also acknowledge, possible overlap in the included cohorts “could mean that sample sizes might be smaller than reported,” Dr. Klubo-Gwiezdzinska commented.
To further evaluate the pros and cons of RFA, the authors suggested that “future studies may focus on improving complete disappearance rates of the tumor volume, possibly with more advanced or longer RFA procedures.”
RFA an option for some patients
In the meantime, senior author Tessa M. van Ginhoven, MD, PhD, of the department of surgical oncology and gastrointestinal surgery, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, suggests that, in addition to cases of local tumor growth, possible uses of RFA for micro-PTC could include situations of patient anxiety due to active surveillance.
“If active surveillance is appropriate for your population, but the patient is anxious and prefers lobectomy, one could envision RFA as a possible adjunct to active surveillance,” she told this news organization.
The authors and Dr. Klubo-Gwiezdzinska reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
(PTC) when measures beyond active surveillance are warranted, results from a new review show.
“The results in the current study suggest that RFA could function as a useful alternative treatment strategy in which patients are treated minimally invasively with curative intentions,” reported the authors of the meta-analysis published online in JAMA Otolaryngology – Head and Neck Surgery.
Commenting on the research, Joanna Klubo-Gwiezdzinska, MD, PhD, said the work offers useful evidence on the potential role for RFA in low-risk micro-PTC – with some notable caveats.
“I agree that RFA might be a good option for patients unwilling or unable to accept active surveillance and for patients who are at high surgical risk because of comorbid conditions,” she told this news organization.
However, “RFA for patients with an evidence of nodule growth requires more data to be analyzed and a longer follow-up period in lieu of the fact that 21% of nodules subjected to RFA did not disappear, based on the data the authors provide,” noted Dr. Klubo-Gwiezdzinska, who is acting chief of thyroid tumors and functional thyroid disorders at the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, in Bethesda, Md.
When active surveillance isn’t enough
Microcarcinoma PTC, defined as measuring 10 mm or less, is highly common, making up approximately half of papillary thyroid cancers diagnosed in some countries, and the outcomes of those cancers are excellent, with disease-specific survival of more than 99% after 10 years.
Guidelines in the United States and Europe typically recommend surgery (lobectomy) as a standard treatment for thyroid cancer, however, with many of the low-risk microcarcinomas remaining indolent and never progressing to the point of requiring treatment over a person’s lifetime, some also recommend considering active surveillance, or watchful waiting, for those lower-risk cancers.
In situations such as evidence of tumor growth during active surveillance, some countries, particularly Asian countries, also suggest considering thermal ablation techniques, including RFA, as an alternative to surgery, with key benefits including lower costs and potentially a lower risk of complications, compared with surgical lobectomy.
Otherwise, RFA is more typically reserved for benign nodules, recurrent PTC, or inoperable disease.
New meta-analysis
To investigate reported outcomes with RFA specifically in the treatment of microcarcinoma PTC, the authors, led by Sam P.J. van Dijk, BSc, of University Medical Center Rotterdam (the Netherlands), identified 15 studies published after 2016 involving 1,770 adult patients and 1,822 tumors who received RFA for the treatment of low-risk PTC microcarcinomas, defined as measuring 10 mm or less.
The studies were conducted in China and South Korea, where RFA is more commonly used in low-risk microcarcinoma PTC.
Patients were 77.9% women and a mean age of 45.4 years. The analysis excluded patients with pre-ablation lymph node or distant metastases, recurrence of disease, or extrathyroidal extension.
Of the 1,822 tumors treated with RFA, 49 required an additional RFA treatment and 1 tumor had two additional treatments.
With a mean follow-up of 33 months (range, 6-131 months), the primary outcome of the pooled rate of complete disappearance of microcarcinoma PTC on ultrasonography was 79%.
The overall rate of tumor progression was 1.5% (26 patients), and local residual microcarcinoma PTC occurred in 0.4% (7 tumors).
New microcarcinoma PTC occurred in 0.9% (15) of patients; 0.2% (4) developed lymph node metastases during follow-up, and no distant metastases were observed.
Minor complications occurred in 45 patients, and there were three major complications, including two voice changes that lasted more than 2 months and one cardiac arrhythmia.
“This study suggests that radiofrequency ablation is a safe and efficient method to treat selected low-risk papillary microcarcinoma of the thyroid,” the researchers said.
Questions surrounding the 20% of patients who still had residual nodules
While the analysis did not include direct comparisons between RFA and lobectomy, Dr. Klubo-Gwiezdzinska noted that, in general, “RFA appears to be associated with a lower complication rate compared with surgery, but also lower efficacy, with 21% of patients with residual nodules.”
The results raise the question of whether “all of the residual lesions are associated with persistent disease, and, if so, do they warrant further intervention?” she added.
To that point, the authors noted that only seven (0.4%) of the 21% of patients with persistent nodules showed residual microcarcinoma PTC cells after RFA, a fact that underscores that “the assessment of tumor response in patients with mPTC after RFA is complicated,” they wrote.
A key concern with assessing responses in RFA is that fine needle aspiration has been shown to have reduced diagnostic accuracy following treatment due to insufficient cellularity in the ablation area, the authors noted.
They add that core needle biopsy is believed to have higher accuracy.
While commenting that the analysis used the “best standards,” Dr. Klubo-Gwiezdzinska noted the caveat that it provides “low- to moderate-quality evidence as it included either case series or retrospective cohort studies, characterized by an inherent bias associated with these study designs.”
And as the authors also acknowledge, possible overlap in the included cohorts “could mean that sample sizes might be smaller than reported,” Dr. Klubo-Gwiezdzinska commented.
To further evaluate the pros and cons of RFA, the authors suggested that “future studies may focus on improving complete disappearance rates of the tumor volume, possibly with more advanced or longer RFA procedures.”
RFA an option for some patients
In the meantime, senior author Tessa M. van Ginhoven, MD, PhD, of the department of surgical oncology and gastrointestinal surgery, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, suggests that, in addition to cases of local tumor growth, possible uses of RFA for micro-PTC could include situations of patient anxiety due to active surveillance.
“If active surveillance is appropriate for your population, but the patient is anxious and prefers lobectomy, one could envision RFA as a possible adjunct to active surveillance,” she told this news organization.
The authors and Dr. Klubo-Gwiezdzinska reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
(PTC) when measures beyond active surveillance are warranted, results from a new review show.
“The results in the current study suggest that RFA could function as a useful alternative treatment strategy in which patients are treated minimally invasively with curative intentions,” reported the authors of the meta-analysis published online in JAMA Otolaryngology – Head and Neck Surgery.
Commenting on the research, Joanna Klubo-Gwiezdzinska, MD, PhD, said the work offers useful evidence on the potential role for RFA in low-risk micro-PTC – with some notable caveats.
“I agree that RFA might be a good option for patients unwilling or unable to accept active surveillance and for patients who are at high surgical risk because of comorbid conditions,” she told this news organization.
However, “RFA for patients with an evidence of nodule growth requires more data to be analyzed and a longer follow-up period in lieu of the fact that 21% of nodules subjected to RFA did not disappear, based on the data the authors provide,” noted Dr. Klubo-Gwiezdzinska, who is acting chief of thyroid tumors and functional thyroid disorders at the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, in Bethesda, Md.
When active surveillance isn’t enough
Microcarcinoma PTC, defined as measuring 10 mm or less, is highly common, making up approximately half of papillary thyroid cancers diagnosed in some countries, and the outcomes of those cancers are excellent, with disease-specific survival of more than 99% after 10 years.
Guidelines in the United States and Europe typically recommend surgery (lobectomy) as a standard treatment for thyroid cancer, however, with many of the low-risk microcarcinomas remaining indolent and never progressing to the point of requiring treatment over a person’s lifetime, some also recommend considering active surveillance, or watchful waiting, for those lower-risk cancers.
In situations such as evidence of tumor growth during active surveillance, some countries, particularly Asian countries, also suggest considering thermal ablation techniques, including RFA, as an alternative to surgery, with key benefits including lower costs and potentially a lower risk of complications, compared with surgical lobectomy.
Otherwise, RFA is more typically reserved for benign nodules, recurrent PTC, or inoperable disease.
New meta-analysis
To investigate reported outcomes with RFA specifically in the treatment of microcarcinoma PTC, the authors, led by Sam P.J. van Dijk, BSc, of University Medical Center Rotterdam (the Netherlands), identified 15 studies published after 2016 involving 1,770 adult patients and 1,822 tumors who received RFA for the treatment of low-risk PTC microcarcinomas, defined as measuring 10 mm or less.
The studies were conducted in China and South Korea, where RFA is more commonly used in low-risk microcarcinoma PTC.
Patients were 77.9% women and a mean age of 45.4 years. The analysis excluded patients with pre-ablation lymph node or distant metastases, recurrence of disease, or extrathyroidal extension.
Of the 1,822 tumors treated with RFA, 49 required an additional RFA treatment and 1 tumor had two additional treatments.
With a mean follow-up of 33 months (range, 6-131 months), the primary outcome of the pooled rate of complete disappearance of microcarcinoma PTC on ultrasonography was 79%.
The overall rate of tumor progression was 1.5% (26 patients), and local residual microcarcinoma PTC occurred in 0.4% (7 tumors).
New microcarcinoma PTC occurred in 0.9% (15) of patients; 0.2% (4) developed lymph node metastases during follow-up, and no distant metastases were observed.
Minor complications occurred in 45 patients, and there were three major complications, including two voice changes that lasted more than 2 months and one cardiac arrhythmia.
“This study suggests that radiofrequency ablation is a safe and efficient method to treat selected low-risk papillary microcarcinoma of the thyroid,” the researchers said.
Questions surrounding the 20% of patients who still had residual nodules
While the analysis did not include direct comparisons between RFA and lobectomy, Dr. Klubo-Gwiezdzinska noted that, in general, “RFA appears to be associated with a lower complication rate compared with surgery, but also lower efficacy, with 21% of patients with residual nodules.”
The results raise the question of whether “all of the residual lesions are associated with persistent disease, and, if so, do they warrant further intervention?” she added.
To that point, the authors noted that only seven (0.4%) of the 21% of patients with persistent nodules showed residual microcarcinoma PTC cells after RFA, a fact that underscores that “the assessment of tumor response in patients with mPTC after RFA is complicated,” they wrote.
A key concern with assessing responses in RFA is that fine needle aspiration has been shown to have reduced diagnostic accuracy following treatment due to insufficient cellularity in the ablation area, the authors noted.
They add that core needle biopsy is believed to have higher accuracy.
While commenting that the analysis used the “best standards,” Dr. Klubo-Gwiezdzinska noted the caveat that it provides “low- to moderate-quality evidence as it included either case series or retrospective cohort studies, characterized by an inherent bias associated with these study designs.”
And as the authors also acknowledge, possible overlap in the included cohorts “could mean that sample sizes might be smaller than reported,” Dr. Klubo-Gwiezdzinska commented.
To further evaluate the pros and cons of RFA, the authors suggested that “future studies may focus on improving complete disappearance rates of the tumor volume, possibly with more advanced or longer RFA procedures.”
RFA an option for some patients
In the meantime, senior author Tessa M. van Ginhoven, MD, PhD, of the department of surgical oncology and gastrointestinal surgery, Erasmus MC Cancer Institute, University Medical Centre Rotterdam, suggests that, in addition to cases of local tumor growth, possible uses of RFA for micro-PTC could include situations of patient anxiety due to active surveillance.
“If active surveillance is appropriate for your population, but the patient is anxious and prefers lobectomy, one could envision RFA as a possible adjunct to active surveillance,” she told this news organization.
The authors and Dr. Klubo-Gwiezdzinska reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
IBD or something else? Key characteristics offer clues
Immune-mediated inflammatory diseases (IMIDs) of the gastrointestinal (GI) tract, with features that often mimic each other, commonly present clinical challenges. But key characteristics can help distinguish the most common – inflammatory bowel disease (IBD) – from other IMIDs, allowing for proper diagnosis and treatment, according to a new review.
“Although these disorders share a common pathophysiology, the defects can occur anywhere in the complex network of cytokines, inflammatory mediators, and innate and adaptive systems, leading to unregulated inflammation,” the authors of the review reported in JGH Open.
“Precise knowledge about them will help determine the possible targeted therapy. Thus, it is essential to distinguish these disorders from IBD,” underscored the authors, who were affiliated with the department of gastroenterology at All India Institute of Medical Sciences, New Delhi, India.
IBD, with its two major phenotypes of Crohn’s disease and ulcerative colitis, represents the most common IMIDs of the GI tract.
However, alternative diagnoses with overlapping features that can often be confused with IBD are plentiful, including celiac disease, GI vasculitis, eosinophilic gastroenteritis, some monogenic disorders, sarcoidosis, immune checkpoint inhibitor-induced colitis (ICI colitis), and microscopic colitis, explained the authors.
They recommended that, when evaluating patients with the common features that the disorders share, “one should think with an open mind and look for other possibilities, especially in patients not responding to conventional therapies.”
Monogenic disorders that mimic IBD
To determine monogenic disorders that mimic IBD, a key starting point can be the utilization of next-generation sequencing methods, which have become more available and less costly, the authors explained.
Most monogenic IBD variants present in the first decade of life and can be classified into different groups based on the pathways involved, they noted. These include disorders of epithelial barrier integrity, immune dysregulation, immunodeficiency, autoinflammatory disorders, and innate immune defects, including phagocyte killing.
Though monogenic IBD phenotypes are rare, measures to identify them are important, and can include taking peripheral blood counts, immunoglobulin profiles, and lymphocyte assays to identify common immunodeficiency disorders such as CVID and lymphocyte disorders.
While treatment can be difficult, “targeting the underlying defective immune pathway might be beneficial,” the authors noted, adding that some monogenic disorders, such as mutations of IL-10, can be effectively cured by hematopoietic stem cell transplantation (HSCT), while IL-1b receptor antagonists may be helpful in those with excesses in IL-1b.
Celiac disease
Celiac disease, previously believed to be a childhood disease, can occur at any age and, unlike IBD, has known environmental and genetic causes, with genetically predisposed individuals experiencing symptoms triggered by the ingestion of gluten proteins.
The disease can be diagnosed by the presence of serological markers including IgA tTG, anti-endomysial antibody, and anti-deamidated gliadin peptide antibodies, the authors noted.
In addition, they may have evidence of villous atrophy of the duodenal epithelium “with the exception in children, where more than 10 times elevation of IgA tTG is sufficient to make a diagnosis.”
Management includes avoidance of gluten-containing food products and nutritional supplementation of deficient nutrients and vitamins, and fewer than 5% of patients do not respond if they adhere to a gluten-free diet.
Other considerations besides IBD
Additional non-IBD phenotype disorders mimicking IBD to consider include the following:
Vasculitis-related enteropathy, characterized by inflammation of blood vessels and with clinical manifestations varying from abdominal pain and diarrhea to acute intestinal perforation. Symptoms can vary according to the type of vasculitis, ranging from mild abdominal pain and diarrhea to acute intestinal perforation.
Eosinophilic gastroenteritis, a rare eosinophil-mediated inflammatory disorder that can be difficult to diagnose and mimics IBD and other GI disorders.
“Mucosal disease is the most common clinical presentation, occurring in approximately 50% of cases and presents with abdominal pain, malabsorption, and protein-losing enteropathy,” the authors explained. “Whereas muscular disease presents as intestinal obstruction and serosal disease presents with eosinophilic ascites and pleural effusion.”
Microscopic colitis, an inflammatory disease of the large intestine, is often missed or confused with diarrhea-predominant irritable bowel syndrome (IBS), and the symptoms can result in severe impairment in the quality of life.
Unlike some other disorders, its incidence tends to increase with age, with a peak incidence in the sixth and seventh decades of life, the authors noted.
Immune checkpoint inhibitor–induced colitis, a major immune-mediated adverse event associated with checkpoint inhibitor drugs. Immune-mediated colitis (IMC) has clinical, radiological, and histopathological manifestations that mimic those of IBD, and may require urgent therapy depending on the grade of severity.
Major risk factors include the dose, type of agent, use of NSAIDs, preexisting IBD, as well as the type of tumor, the authors wrote.
“Management is more or less similar to that of IBD, and it depends on the severity of IMC,” they added.
Gastrointestinal sarcoidosis occurs in fewer than 1% of cases of sarcoidosis, a systemic granulomatous disease of unknown etiology, characterized by the formation of nonnecrotizing granulomas.
Diagnosis can be made by demonstrating nonnecrotizing granulomas on histopathology, with pulmonary and thoracic involvement suggesting sarcoidosis, and corticosteroid treatment.
Key indicators that it’s not IBD
Overall, key red flags that should raise suspicion of non-IBD disorder should include the presence of atypical features such as very young age of onset, being refractory to biologics, and involvement of other organ systems, the authors noted.
“Immunoglobulin assays, lymphocyte profiling, and neutrophilic functional assays should be carried out in patients with suspected underlying immunodeficiency disorder,” they added. “Whole-exome/genome sequencing and targeted gene analysis should be reserved for cases with a strong suspicion of monogenic disorders with IBD-like phenotype.”
Joseph A. Murray, MD, professor of medicine at the Mayo Clinic in Rochester, Minn., noted in an interview that the review offers some important insights.
“This is a very good review for people who are seeing patients and considering whether they have inflammatory bowel disease, and is comprehensive in the area of monogenic causes of inflammation,” he said.
In addition to the disorders described in the review, Dr. Murray noted that “other types of diseases that I often see include drug-induced enteropathy, tropical sprue [a chronic diarrheal disease], autoimmune enteropathy, and lymphoproliferative diseases.”
Other drug-induced enteropathies include those associated with angiotensin receptor blockers and azathioprine enteritis, he noted.
Dr. Murray and colleagues previously reported on further nonceliac enteropathies in a separate review, titled “Not All That Flattens Villi Is Celiac Disease: A Review of Enteropathies” in the Mayo Clinic Proceedings.
Further commenting, Tauseef Ali, MD, executive medical director, Saints Digestive Health Institute, SSM Health, Oklahoma City, noted that “the publication is one of the first and most comprehensive reviews summarizing the gastrointestinal tract’s different immune-mediated inflammatory diseases.
“The review gives us an excellent glimpse of the complex interplay of shared genetic and immune pathways involved in many inflammatory bowel conditions,” he added, noting that it also provides “an excellent platform for developing future clinical research methodologies and designs.”
The review authors had no disclosures to report. Dr. Murray has received grant support from the NIH, Alvine Pharmaceuticals and Alba Therapeutics, and receives ongoing support from Oberkotter Foundation and Broad Medical Research Program at CCFA. He serves on the advisory board of Celimmune and ImmunoGenx, was a consultant to BioLineRx, GlaxoSmithKline, Genentech and Glenmark Pharmaceuticals, and currently serves as a consultant to ImmunosanT, Institute for Protein Design (PvP Biologics), Takeda Pharmaceuticals, Innovate Biopharmaceuticals, and Intrexon. Dr. Ali has received honoraria for speaking, teaching, and consultation from AbbVie, Janssen, Pfizer, RedHill Biopharma, and Takeda.
Immune-mediated inflammatory diseases (IMIDs) of the gastrointestinal (GI) tract, with features that often mimic each other, commonly present clinical challenges. But key characteristics can help distinguish the most common – inflammatory bowel disease (IBD) – from other IMIDs, allowing for proper diagnosis and treatment, according to a new review.
“Although these disorders share a common pathophysiology, the defects can occur anywhere in the complex network of cytokines, inflammatory mediators, and innate and adaptive systems, leading to unregulated inflammation,” the authors of the review reported in JGH Open.
“Precise knowledge about them will help determine the possible targeted therapy. Thus, it is essential to distinguish these disorders from IBD,” underscored the authors, who were affiliated with the department of gastroenterology at All India Institute of Medical Sciences, New Delhi, India.
IBD, with its two major phenotypes of Crohn’s disease and ulcerative colitis, represents the most common IMIDs of the GI tract.
However, alternative diagnoses with overlapping features that can often be confused with IBD are plentiful, including celiac disease, GI vasculitis, eosinophilic gastroenteritis, some monogenic disorders, sarcoidosis, immune checkpoint inhibitor-induced colitis (ICI colitis), and microscopic colitis, explained the authors.
They recommended that, when evaluating patients with the common features that the disorders share, “one should think with an open mind and look for other possibilities, especially in patients not responding to conventional therapies.”
Monogenic disorders that mimic IBD
To determine monogenic disorders that mimic IBD, a key starting point can be the utilization of next-generation sequencing methods, which have become more available and less costly, the authors explained.
Most monogenic IBD variants present in the first decade of life and can be classified into different groups based on the pathways involved, they noted. These include disorders of epithelial barrier integrity, immune dysregulation, immunodeficiency, autoinflammatory disorders, and innate immune defects, including phagocyte killing.
Though monogenic IBD phenotypes are rare, measures to identify them are important, and can include taking peripheral blood counts, immunoglobulin profiles, and lymphocyte assays to identify common immunodeficiency disorders such as CVID and lymphocyte disorders.
While treatment can be difficult, “targeting the underlying defective immune pathway might be beneficial,” the authors noted, adding that some monogenic disorders, such as mutations of IL-10, can be effectively cured by hematopoietic stem cell transplantation (HSCT), while IL-1b receptor antagonists may be helpful in those with excesses in IL-1b.
Celiac disease
Celiac disease, previously believed to be a childhood disease, can occur at any age and, unlike IBD, has known environmental and genetic causes, with genetically predisposed individuals experiencing symptoms triggered by the ingestion of gluten proteins.
The disease can be diagnosed by the presence of serological markers including IgA tTG, anti-endomysial antibody, and anti-deamidated gliadin peptide antibodies, the authors noted.
In addition, they may have evidence of villous atrophy of the duodenal epithelium “with the exception in children, where more than 10 times elevation of IgA tTG is sufficient to make a diagnosis.”
Management includes avoidance of gluten-containing food products and nutritional supplementation of deficient nutrients and vitamins, and fewer than 5% of patients do not respond if they adhere to a gluten-free diet.
Other considerations besides IBD
Additional non-IBD phenotype disorders mimicking IBD to consider include the following:
Vasculitis-related enteropathy, characterized by inflammation of blood vessels and with clinical manifestations varying from abdominal pain and diarrhea to acute intestinal perforation. Symptoms can vary according to the type of vasculitis, ranging from mild abdominal pain and diarrhea to acute intestinal perforation.
Eosinophilic gastroenteritis, a rare eosinophil-mediated inflammatory disorder that can be difficult to diagnose and mimics IBD and other GI disorders.
“Mucosal disease is the most common clinical presentation, occurring in approximately 50% of cases and presents with abdominal pain, malabsorption, and protein-losing enteropathy,” the authors explained. “Whereas muscular disease presents as intestinal obstruction and serosal disease presents with eosinophilic ascites and pleural effusion.”
Microscopic colitis, an inflammatory disease of the large intestine, is often missed or confused with diarrhea-predominant irritable bowel syndrome (IBS), and the symptoms can result in severe impairment in the quality of life.
Unlike some other disorders, its incidence tends to increase with age, with a peak incidence in the sixth and seventh decades of life, the authors noted.
Immune checkpoint inhibitor–induced colitis, a major immune-mediated adverse event associated with checkpoint inhibitor drugs. Immune-mediated colitis (IMC) has clinical, radiological, and histopathological manifestations that mimic those of IBD, and may require urgent therapy depending on the grade of severity.
Major risk factors include the dose, type of agent, use of NSAIDs, preexisting IBD, as well as the type of tumor, the authors wrote.
“Management is more or less similar to that of IBD, and it depends on the severity of IMC,” they added.
Gastrointestinal sarcoidosis occurs in fewer than 1% of cases of sarcoidosis, a systemic granulomatous disease of unknown etiology, characterized by the formation of nonnecrotizing granulomas.
Diagnosis can be made by demonstrating nonnecrotizing granulomas on histopathology, with pulmonary and thoracic involvement suggesting sarcoidosis, and corticosteroid treatment.
Key indicators that it’s not IBD
Overall, key red flags that should raise suspicion of non-IBD disorder should include the presence of atypical features such as very young age of onset, being refractory to biologics, and involvement of other organ systems, the authors noted.
“Immunoglobulin assays, lymphocyte profiling, and neutrophilic functional assays should be carried out in patients with suspected underlying immunodeficiency disorder,” they added. “Whole-exome/genome sequencing and targeted gene analysis should be reserved for cases with a strong suspicion of monogenic disorders with IBD-like phenotype.”
Joseph A. Murray, MD, professor of medicine at the Mayo Clinic in Rochester, Minn., noted in an interview that the review offers some important insights.
“This is a very good review for people who are seeing patients and considering whether they have inflammatory bowel disease, and is comprehensive in the area of monogenic causes of inflammation,” he said.
In addition to the disorders described in the review, Dr. Murray noted that “other types of diseases that I often see include drug-induced enteropathy, tropical sprue [a chronic diarrheal disease], autoimmune enteropathy, and lymphoproliferative diseases.”
Other drug-induced enteropathies include those associated with angiotensin receptor blockers and azathioprine enteritis, he noted.
Dr. Murray and colleagues previously reported on further nonceliac enteropathies in a separate review, titled “Not All That Flattens Villi Is Celiac Disease: A Review of Enteropathies” in the Mayo Clinic Proceedings.
Further commenting, Tauseef Ali, MD, executive medical director, Saints Digestive Health Institute, SSM Health, Oklahoma City, noted that “the publication is one of the first and most comprehensive reviews summarizing the gastrointestinal tract’s different immune-mediated inflammatory diseases.
“The review gives us an excellent glimpse of the complex interplay of shared genetic and immune pathways involved in many inflammatory bowel conditions,” he added, noting that it also provides “an excellent platform for developing future clinical research methodologies and designs.”
The review authors had no disclosures to report. Dr. Murray has received grant support from the NIH, Alvine Pharmaceuticals and Alba Therapeutics, and receives ongoing support from Oberkotter Foundation and Broad Medical Research Program at CCFA. He serves on the advisory board of Celimmune and ImmunoGenx, was a consultant to BioLineRx, GlaxoSmithKline, Genentech and Glenmark Pharmaceuticals, and currently serves as a consultant to ImmunosanT, Institute for Protein Design (PvP Biologics), Takeda Pharmaceuticals, Innovate Biopharmaceuticals, and Intrexon. Dr. Ali has received honoraria for speaking, teaching, and consultation from AbbVie, Janssen, Pfizer, RedHill Biopharma, and Takeda.
Immune-mediated inflammatory diseases (IMIDs) of the gastrointestinal (GI) tract, with features that often mimic each other, commonly present clinical challenges. But key characteristics can help distinguish the most common – inflammatory bowel disease (IBD) – from other IMIDs, allowing for proper diagnosis and treatment, according to a new review.
“Although these disorders share a common pathophysiology, the defects can occur anywhere in the complex network of cytokines, inflammatory mediators, and innate and adaptive systems, leading to unregulated inflammation,” the authors of the review reported in JGH Open.
“Precise knowledge about them will help determine the possible targeted therapy. Thus, it is essential to distinguish these disorders from IBD,” underscored the authors, who were affiliated with the department of gastroenterology at All India Institute of Medical Sciences, New Delhi, India.
IBD, with its two major phenotypes of Crohn’s disease and ulcerative colitis, represents the most common IMIDs of the GI tract.
However, alternative diagnoses with overlapping features that can often be confused with IBD are plentiful, including celiac disease, GI vasculitis, eosinophilic gastroenteritis, some monogenic disorders, sarcoidosis, immune checkpoint inhibitor-induced colitis (ICI colitis), and microscopic colitis, explained the authors.
They recommended that, when evaluating patients with the common features that the disorders share, “one should think with an open mind and look for other possibilities, especially in patients not responding to conventional therapies.”
Monogenic disorders that mimic IBD
To determine monogenic disorders that mimic IBD, a key starting point can be the utilization of next-generation sequencing methods, which have become more available and less costly, the authors explained.
Most monogenic IBD variants present in the first decade of life and can be classified into different groups based on the pathways involved, they noted. These include disorders of epithelial barrier integrity, immune dysregulation, immunodeficiency, autoinflammatory disorders, and innate immune defects, including phagocyte killing.
Though monogenic IBD phenotypes are rare, measures to identify them are important, and can include taking peripheral blood counts, immunoglobulin profiles, and lymphocyte assays to identify common immunodeficiency disorders such as CVID and lymphocyte disorders.
While treatment can be difficult, “targeting the underlying defective immune pathway might be beneficial,” the authors noted, adding that some monogenic disorders, such as mutations of IL-10, can be effectively cured by hematopoietic stem cell transplantation (HSCT), while IL-1b receptor antagonists may be helpful in those with excesses in IL-1b.
Celiac disease
Celiac disease, previously believed to be a childhood disease, can occur at any age and, unlike IBD, has known environmental and genetic causes, with genetically predisposed individuals experiencing symptoms triggered by the ingestion of gluten proteins.
The disease can be diagnosed by the presence of serological markers including IgA tTG, anti-endomysial antibody, and anti-deamidated gliadin peptide antibodies, the authors noted.
In addition, they may have evidence of villous atrophy of the duodenal epithelium “with the exception in children, where more than 10 times elevation of IgA tTG is sufficient to make a diagnosis.”
Management includes avoidance of gluten-containing food products and nutritional supplementation of deficient nutrients and vitamins, and fewer than 5% of patients do not respond if they adhere to a gluten-free diet.
Other considerations besides IBD
Additional non-IBD phenotype disorders mimicking IBD to consider include the following:
Vasculitis-related enteropathy, characterized by inflammation of blood vessels and with clinical manifestations varying from abdominal pain and diarrhea to acute intestinal perforation. Symptoms can vary according to the type of vasculitis, ranging from mild abdominal pain and diarrhea to acute intestinal perforation.
Eosinophilic gastroenteritis, a rare eosinophil-mediated inflammatory disorder that can be difficult to diagnose and mimics IBD and other GI disorders.
“Mucosal disease is the most common clinical presentation, occurring in approximately 50% of cases and presents with abdominal pain, malabsorption, and protein-losing enteropathy,” the authors explained. “Whereas muscular disease presents as intestinal obstruction and serosal disease presents with eosinophilic ascites and pleural effusion.”
Microscopic colitis, an inflammatory disease of the large intestine, is often missed or confused with diarrhea-predominant irritable bowel syndrome (IBS), and the symptoms can result in severe impairment in the quality of life.
Unlike some other disorders, its incidence tends to increase with age, with a peak incidence in the sixth and seventh decades of life, the authors noted.
Immune checkpoint inhibitor–induced colitis, a major immune-mediated adverse event associated with checkpoint inhibitor drugs. Immune-mediated colitis (IMC) has clinical, radiological, and histopathological manifestations that mimic those of IBD, and may require urgent therapy depending on the grade of severity.
Major risk factors include the dose, type of agent, use of NSAIDs, preexisting IBD, as well as the type of tumor, the authors wrote.
“Management is more or less similar to that of IBD, and it depends on the severity of IMC,” they added.
Gastrointestinal sarcoidosis occurs in fewer than 1% of cases of sarcoidosis, a systemic granulomatous disease of unknown etiology, characterized by the formation of nonnecrotizing granulomas.
Diagnosis can be made by demonstrating nonnecrotizing granulomas on histopathology, with pulmonary and thoracic involvement suggesting sarcoidosis, and corticosteroid treatment.
Key indicators that it’s not IBD
Overall, key red flags that should raise suspicion of non-IBD disorder should include the presence of atypical features such as very young age of onset, being refractory to biologics, and involvement of other organ systems, the authors noted.
“Immunoglobulin assays, lymphocyte profiling, and neutrophilic functional assays should be carried out in patients with suspected underlying immunodeficiency disorder,” they added. “Whole-exome/genome sequencing and targeted gene analysis should be reserved for cases with a strong suspicion of monogenic disorders with IBD-like phenotype.”
Joseph A. Murray, MD, professor of medicine at the Mayo Clinic in Rochester, Minn., noted in an interview that the review offers some important insights.
“This is a very good review for people who are seeing patients and considering whether they have inflammatory bowel disease, and is comprehensive in the area of monogenic causes of inflammation,” he said.
In addition to the disorders described in the review, Dr. Murray noted that “other types of diseases that I often see include drug-induced enteropathy, tropical sprue [a chronic diarrheal disease], autoimmune enteropathy, and lymphoproliferative diseases.”
Other drug-induced enteropathies include those associated with angiotensin receptor blockers and azathioprine enteritis, he noted.
Dr. Murray and colleagues previously reported on further nonceliac enteropathies in a separate review, titled “Not All That Flattens Villi Is Celiac Disease: A Review of Enteropathies” in the Mayo Clinic Proceedings.
Further commenting, Tauseef Ali, MD, executive medical director, Saints Digestive Health Institute, SSM Health, Oklahoma City, noted that “the publication is one of the first and most comprehensive reviews summarizing the gastrointestinal tract’s different immune-mediated inflammatory diseases.
“The review gives us an excellent glimpse of the complex interplay of shared genetic and immune pathways involved in many inflammatory bowel conditions,” he added, noting that it also provides “an excellent platform for developing future clinical research methodologies and designs.”
The review authors had no disclosures to report. Dr. Murray has received grant support from the NIH, Alvine Pharmaceuticals and Alba Therapeutics, and receives ongoing support from Oberkotter Foundation and Broad Medical Research Program at CCFA. He serves on the advisory board of Celimmune and ImmunoGenx, was a consultant to BioLineRx, GlaxoSmithKline, Genentech and Glenmark Pharmaceuticals, and currently serves as a consultant to ImmunosanT, Institute for Protein Design (PvP Biologics), Takeda Pharmaceuticals, Innovate Biopharmaceuticals, and Intrexon. Dr. Ali has received honoraria for speaking, teaching, and consultation from AbbVie, Janssen, Pfizer, RedHill Biopharma, and Takeda.
FROM JGH OPEN
Male alopecia agents ranked by efficacy in meta-analysis
While up to 90% of men experience AGA in their lifetime, only three therapies are currently approved for treatment of the condition by the Food and Drug Administration – topical minoxidil, oral finasteride 1 mg, and low-level light therapy.
However, with common use of off-label oral minoxidil, as well as oral dutasteride and higher doses of oral finasteride, the latter two being 5-alpha reductase inhibitors, Aditya K. Gupta, MD, PhD, of Mediprobe Research, in London, Ont., and colleagues sought to compare the data on the three agents. Their results were published in JAMA Dermatology.
They note that, while there have been recent comparisons between oral and topical minoxidil, “to our knowledge no study has determined the comparative effectiveness of these 2 [formulations] with that of local and systemic dutasteride and finasteride.”
For the meta-analysis, the authors identified 23 studies meeting their criteria, involving patients with mean ages ranging from 22.8 to 41.8 years.
For the primary endpoint of the greatest increases in total hair count at 24 weeks, the analysis showed the 0.5-mg/day dose of dutasteride topped the list, with significantly greater efficacy, compared with 1 mg/day of finasteride (mean difference, 7.1 hairs per cm2).
The 0.5-mg/d dutasteride dose also showed higher efficacy than oral minoxidil at 0.25 mg/day (mean difference, 23.7 hairs per cm2) and 5 mg/day (mean difference, 15.0 hairs per cm2) and topical minoxidil at 2% (mean difference, 8.5 hairs per cm2).
For the secondary endpoint of the greatest increase in terminal hair count at 24 weeks, the 5-mg/day dose of minoxidil had significantly greater efficacy compared with the 0.25-mg/day dose of the drug, as well as with minoxidil’s 2% and 5% topical formulations.
The minoxidil 5-mg/day dose was also significantly more effective than 1 mg/day of finasteride for terminal hair count at 24 weeks.
In longer-term outcomes at 48 weeks, the greatest increase in total hair count at 48 weeks was observed with 5 mg/day of finasteride, which was significantly more effective, compared with 2% topical minoxidil.
And the greatest increase in terminal hair count at 48 weeks was observed with 1 mg/day of oral finasteride, which was significantly more effective than 2% as well as 5% topical minoxidil.
Based on the results, the authors ranked the agents in a decreasing order of efficacy: 0.5 mg/day of oral dutasteride, 5 mg/day of oral finasteride, 5 mg/day of oral minoxidil, 1 mg/day of oral finasteride, 5% topical minoxidil, 2% topical minoxidil, and 0.25 mg/day of oral minoxidil.
Commenting on the analysis in an accompanying editorial, Kathie P. Huang, MD, of the department of dermatology, Brigham and Women’s Hospital, Boston, and Maryanne M. Senna, MD, of the department of dermatology, Massachusetts General Hospital, Boston, said the results, in general, are consistent with their experiences, noting that 2% minoxidil is typically not used in men.
They noted that, “although topical minoxidil ranked higher than the very-low-dose 0.25 mg oral minoxidil, our personal experience is that oral minoxidil at doses of 1.25 mg to 5 mg are far superior to topical minoxidil for treating AGA.”
Adverse event considerations important
Importantly, however, strong consideration needs to be given to adverse-event profiles, as well as patient comorbidities in selecting agents, the editorial authors asserted.
With 1 mg finasteride, for instance, potential adverse events include decreased libido, erectile dysfunction, decreased ejaculatory volume, reduction in sperm count, testicular pain, depression, and gynecomastia, they noted.
And while finasteride appears to be associated with a decreased risk of prostate cancer, those receiving the drug who do develop prostate cancer may be diagnosed with higher-grade prostate cancer; however, that “might be related to tissue sampling artifact,” the editorial authors said.
Less has been published on dutasteride’s adverse-event profile, and that, in itself, is a concern.
Overall, “as more direct-to-consumer companies treating male AGA emerge, it is especially important that the potential risks of these medications be made clear to patients,” they added.
Further commenting on the analysis to this news organization, Antonella Tosti, MD, the Fredric Brandt Endowed Professor of Dermatology and Cutaneous Surgery at the University of Miami, said the study offers some important insights – and caveats.
“I think this is a very interesting study, but you have to consider what works for your patients,” she said.
Dr. Tosti noted that the 5-mg dose of minoxidil is a concern in terms of side effects. “That dose is pretty high and could feasibly cause some hypertrichosis, which can be a concern to men as well as women.”
She agrees that the lack of data on side effects with dutasteride is also a concern, especially in light of some of the known side effects with other agents.
“That’s why I don’t use it very much in younger patients – because I’m afraid it could potentially affect their fertility,” Dr. Tosti said.
In general, Dr. Tosti said she finds a combination of agents provides the best results, as many clinicians use.
“I find dutasteride (0.5 mg/day) plus oral minoxidil (1-2.5 mg/day) plus topical 5% minoxidil is the best combination,” she said.
The authors and Dr. Tosti disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
While up to 90% of men experience AGA in their lifetime, only three therapies are currently approved for treatment of the condition by the Food and Drug Administration – topical minoxidil, oral finasteride 1 mg, and low-level light therapy.
However, with common use of off-label oral minoxidil, as well as oral dutasteride and higher doses of oral finasteride, the latter two being 5-alpha reductase inhibitors, Aditya K. Gupta, MD, PhD, of Mediprobe Research, in London, Ont., and colleagues sought to compare the data on the three agents. Their results were published in JAMA Dermatology.
They note that, while there have been recent comparisons between oral and topical minoxidil, “to our knowledge no study has determined the comparative effectiveness of these 2 [formulations] with that of local and systemic dutasteride and finasteride.”
For the meta-analysis, the authors identified 23 studies meeting their criteria, involving patients with mean ages ranging from 22.8 to 41.8 years.
For the primary endpoint of the greatest increases in total hair count at 24 weeks, the analysis showed the 0.5-mg/day dose of dutasteride topped the list, with significantly greater efficacy, compared with 1 mg/day of finasteride (mean difference, 7.1 hairs per cm2).
The 0.5-mg/d dutasteride dose also showed higher efficacy than oral minoxidil at 0.25 mg/day (mean difference, 23.7 hairs per cm2) and 5 mg/day (mean difference, 15.0 hairs per cm2) and topical minoxidil at 2% (mean difference, 8.5 hairs per cm2).
For the secondary endpoint of the greatest increase in terminal hair count at 24 weeks, the 5-mg/day dose of minoxidil had significantly greater efficacy compared with the 0.25-mg/day dose of the drug, as well as with minoxidil’s 2% and 5% topical formulations.
The minoxidil 5-mg/day dose was also significantly more effective than 1 mg/day of finasteride for terminal hair count at 24 weeks.
In longer-term outcomes at 48 weeks, the greatest increase in total hair count at 48 weeks was observed with 5 mg/day of finasteride, which was significantly more effective, compared with 2% topical minoxidil.
And the greatest increase in terminal hair count at 48 weeks was observed with 1 mg/day of oral finasteride, which was significantly more effective than 2% as well as 5% topical minoxidil.
Based on the results, the authors ranked the agents in a decreasing order of efficacy: 0.5 mg/day of oral dutasteride, 5 mg/day of oral finasteride, 5 mg/day of oral minoxidil, 1 mg/day of oral finasteride, 5% topical minoxidil, 2% topical minoxidil, and 0.25 mg/day of oral minoxidil.
Commenting on the analysis in an accompanying editorial, Kathie P. Huang, MD, of the department of dermatology, Brigham and Women’s Hospital, Boston, and Maryanne M. Senna, MD, of the department of dermatology, Massachusetts General Hospital, Boston, said the results, in general, are consistent with their experiences, noting that 2% minoxidil is typically not used in men.
They noted that, “although topical minoxidil ranked higher than the very-low-dose 0.25 mg oral minoxidil, our personal experience is that oral minoxidil at doses of 1.25 mg to 5 mg are far superior to topical minoxidil for treating AGA.”
Adverse event considerations important
Importantly, however, strong consideration needs to be given to adverse-event profiles, as well as patient comorbidities in selecting agents, the editorial authors asserted.
With 1 mg finasteride, for instance, potential adverse events include decreased libido, erectile dysfunction, decreased ejaculatory volume, reduction in sperm count, testicular pain, depression, and gynecomastia, they noted.
And while finasteride appears to be associated with a decreased risk of prostate cancer, those receiving the drug who do develop prostate cancer may be diagnosed with higher-grade prostate cancer; however, that “might be related to tissue sampling artifact,” the editorial authors said.
Less has been published on dutasteride’s adverse-event profile, and that, in itself, is a concern.
Overall, “as more direct-to-consumer companies treating male AGA emerge, it is especially important that the potential risks of these medications be made clear to patients,” they added.
Further commenting on the analysis to this news organization, Antonella Tosti, MD, the Fredric Brandt Endowed Professor of Dermatology and Cutaneous Surgery at the University of Miami, said the study offers some important insights – and caveats.
“I think this is a very interesting study, but you have to consider what works for your patients,” she said.
Dr. Tosti noted that the 5-mg dose of minoxidil is a concern in terms of side effects. “That dose is pretty high and could feasibly cause some hypertrichosis, which can be a concern to men as well as women.”
She agrees that the lack of data on side effects with dutasteride is also a concern, especially in light of some of the known side effects with other agents.
“That’s why I don’t use it very much in younger patients – because I’m afraid it could potentially affect their fertility,” Dr. Tosti said.
In general, Dr. Tosti said she finds a combination of agents provides the best results, as many clinicians use.
“I find dutasteride (0.5 mg/day) plus oral minoxidil (1-2.5 mg/day) plus topical 5% minoxidil is the best combination,” she said.
The authors and Dr. Tosti disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
While up to 90% of men experience AGA in their lifetime, only three therapies are currently approved for treatment of the condition by the Food and Drug Administration – topical minoxidil, oral finasteride 1 mg, and low-level light therapy.
However, with common use of off-label oral minoxidil, as well as oral dutasteride and higher doses of oral finasteride, the latter two being 5-alpha reductase inhibitors, Aditya K. Gupta, MD, PhD, of Mediprobe Research, in London, Ont., and colleagues sought to compare the data on the three agents. Their results were published in JAMA Dermatology.
They note that, while there have been recent comparisons between oral and topical minoxidil, “to our knowledge no study has determined the comparative effectiveness of these 2 [formulations] with that of local and systemic dutasteride and finasteride.”
For the meta-analysis, the authors identified 23 studies meeting their criteria, involving patients with mean ages ranging from 22.8 to 41.8 years.
For the primary endpoint of the greatest increases in total hair count at 24 weeks, the analysis showed the 0.5-mg/day dose of dutasteride topped the list, with significantly greater efficacy, compared with 1 mg/day of finasteride (mean difference, 7.1 hairs per cm2).
The 0.5-mg/d dutasteride dose also showed higher efficacy than oral minoxidil at 0.25 mg/day (mean difference, 23.7 hairs per cm2) and 5 mg/day (mean difference, 15.0 hairs per cm2) and topical minoxidil at 2% (mean difference, 8.5 hairs per cm2).
For the secondary endpoint of the greatest increase in terminal hair count at 24 weeks, the 5-mg/day dose of minoxidil had significantly greater efficacy compared with the 0.25-mg/day dose of the drug, as well as with minoxidil’s 2% and 5% topical formulations.
The minoxidil 5-mg/day dose was also significantly more effective than 1 mg/day of finasteride for terminal hair count at 24 weeks.
In longer-term outcomes at 48 weeks, the greatest increase in total hair count at 48 weeks was observed with 5 mg/day of finasteride, which was significantly more effective, compared with 2% topical minoxidil.
And the greatest increase in terminal hair count at 48 weeks was observed with 1 mg/day of oral finasteride, which was significantly more effective than 2% as well as 5% topical minoxidil.
Based on the results, the authors ranked the agents in a decreasing order of efficacy: 0.5 mg/day of oral dutasteride, 5 mg/day of oral finasteride, 5 mg/day of oral minoxidil, 1 mg/day of oral finasteride, 5% topical minoxidil, 2% topical minoxidil, and 0.25 mg/day of oral minoxidil.
Commenting on the analysis in an accompanying editorial, Kathie P. Huang, MD, of the department of dermatology, Brigham and Women’s Hospital, Boston, and Maryanne M. Senna, MD, of the department of dermatology, Massachusetts General Hospital, Boston, said the results, in general, are consistent with their experiences, noting that 2% minoxidil is typically not used in men.
They noted that, “although topical minoxidil ranked higher than the very-low-dose 0.25 mg oral minoxidil, our personal experience is that oral minoxidil at doses of 1.25 mg to 5 mg are far superior to topical minoxidil for treating AGA.”
Adverse event considerations important
Importantly, however, strong consideration needs to be given to adverse-event profiles, as well as patient comorbidities in selecting agents, the editorial authors asserted.
With 1 mg finasteride, for instance, potential adverse events include decreased libido, erectile dysfunction, decreased ejaculatory volume, reduction in sperm count, testicular pain, depression, and gynecomastia, they noted.
And while finasteride appears to be associated with a decreased risk of prostate cancer, those receiving the drug who do develop prostate cancer may be diagnosed with higher-grade prostate cancer; however, that “might be related to tissue sampling artifact,” the editorial authors said.
Less has been published on dutasteride’s adverse-event profile, and that, in itself, is a concern.
Overall, “as more direct-to-consumer companies treating male AGA emerge, it is especially important that the potential risks of these medications be made clear to patients,” they added.
Further commenting on the analysis to this news organization, Antonella Tosti, MD, the Fredric Brandt Endowed Professor of Dermatology and Cutaneous Surgery at the University of Miami, said the study offers some important insights – and caveats.
“I think this is a very interesting study, but you have to consider what works for your patients,” she said.
Dr. Tosti noted that the 5-mg dose of minoxidil is a concern in terms of side effects. “That dose is pretty high and could feasibly cause some hypertrichosis, which can be a concern to men as well as women.”
She agrees that the lack of data on side effects with dutasteride is also a concern, especially in light of some of the known side effects with other agents.
“That’s why I don’t use it very much in younger patients – because I’m afraid it could potentially affect their fertility,” Dr. Tosti said.
In general, Dr. Tosti said she finds a combination of agents provides the best results, as many clinicians use.
“I find dutasteride (0.5 mg/day) plus oral minoxidil (1-2.5 mg/day) plus topical 5% minoxidil is the best combination,” she said.
The authors and Dr. Tosti disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA DERMATOLOGY
C. difficile: New vancomycin-resistant strains raise concerns
Samples from patients in the United States and Kenya show an increasing emergence of previously undetected vancomycin-resistant strains of Clostridioides difficile, sparking concern as recurrences in the treatment of C. difficile infection (CDI) continue to rise.
“Our results may help explain a decreasing effectiveness of antibiotic-based therapy in C. difficile infection, since a significant proportion of patients harboring strains with reduced susceptibility to vancomycin may not respond to treatment,” reported the authors in research published recently in Clinical Infectious Diseases.
The spread of the resistant strains “has serious public health implications, underscoring an urgent need for a comprehensive analysis of the circulating strains to help inform clinical decisions,” they added.
Commenting on the findings, Cornelius J. Clancy, MD, professor of medicine at the University of Pittsburgh, and chief of infectious diseases at the Veterans Affairs Pittsburgh Healthcare System, echoed the concern.
“The casual belief has been that [C. difficile] strains at most centers can be assumed to be vancomycin susceptible,” he told this news organization. “This study shows that this assumption can no longer be taken as a given.”
Dr. Clancy, who was not involved with this research, noted that “based on this study, there might be need for the Infectious Diseases Society of America and other organizations to offer guidance on generating good, quality surveillance data for C. difficile resistance.”
With C. difficile showing the ability to resist multiple antibiotics, drugs in the armamentarium to treat the infection have declined in recent years, and recurrences with the infection are reported in up to 25% of cases.
Oral vancomycin is recommended as the antibiotic of choice by the IDSA and the Society for Healthcare Epidemiology of America for severe as well as nonsevere cases of CDI, and although there are reports of nine vancomycin-resistant gene clusters, most involve Enterococcus.
To take a closer look at the prevalence of vancomycin-resistant C. difficile strains, first author Charles Darkoh, PhD, with the Center for Infectious Diseases at the University of Texas Health Science Center, Houston, and colleagues analyzed stool samples from patients with CDI, including 438 patients in Houston, taken between 2012 and 2017, and 98 in Nairobi, Kenya, taken in 2017.
They found that, among samples from patients in Houston, over the time period, 26% showed vancomycin nonsusceptible C. difficile isolates and 29% had isolates that were metronidazole resistant.
And among samples from the Nairobi patients, 67% harbored vancomycin-resistant isolates and 85% had isolates resistant to metronidazole.
Of note, the proportion of samples containing vancomycin-resistant C. difficile in the Houston patients showed a marked increase over time, from «complete absence» in 2012 to approximately 35% in 2017, the authors reported.
“These nonsusceptibility rates significantly exceeded prior reports from other studies conducted in the United States and Europe from 2011 to 2014, suggesting a lower percentage of resistance to both metronidazole and vancomycin,” the authors wrote.
Further experiments on mouse models infected with one of the vancomycin-resistant isolates showed that treatment with vancomycin failed to eradicate the infection, and 5-day survival was significantly lower after vancomycin treatment in those mice (25%) versus those infected with strains known to be vancomycin sensitive (50%).
Unrecognized genetic strains
Whole-genome sequencing of 10 of the resistant isolates showed no matches with gene clusters that have been previously recognized as being vancomycin resistant, suggesting the emergence of new clusters.
“Together, these results suggest unknown genetic elements associated with vancomycin nonsusceptibility in isolates circulating in the patient population,” the authors wrote.
Dr. Darkoh told this news organization that the research team is currently working to further investigate the patterns and mechanisms.
“We are currently working on a follow-up study for the next 5 years to find out how widespread this is,” he said. “We want to make sure it’s not necessarily just occurring in the settings we studied, and we also need to establish the mechanism of resistance.”
Further commenting on the results, Dr. Clancy noted that “the extent of resistance caught many in the field a bit off guard, as they are higher than previously reported.”
“The data are also concerning because most centers do not routinely test C. difficile for drug susceptibility.”
Dr. Clancy noted that “another immediately pressing need is to understand mechanisms of resistance. It was quite striking that vancomycin-resistant strains in this study did not carry vanA genes, pointing to previously unrecognized mechanisms of resistance.”
“As is often the case, antibiotic overuse was likely a factor in the resistances, with overtesting often leading to overtreatment of C. difficile,” Dr. Clancy said. “The situation may have been compounded by failure to appreciate how entrenched C. difficile resistance may be at certain hospitals, since widespread susceptibility testing is generally not routinely performed.”
As alternative treatments, Dr. Clancy pointed to the recent IDSA update, which included a stronger endorsement of fidaxomicin.
“Of course, there is also the need to assure that data on resistance to agents like fidaxomicin are generated going forward,” he noted.
The study was supported by was supported by National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Texas Medical Center Digestive Diseases Center, and the University of Texas Health Science Center. Dr. Darkoh has disclosed no relevant financial relationships. One coauthor received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics. Dr. Clancy disclosed advisory board, consulting and/or research relationships with Merck, Qpex Biopharma, Shionogi, Astellas, Cidara, Scynexis, and Needham & Associates.
Help your patients understand their C. difficile diagnosis by sharing patient education from the AGA GI Patient Center: www.gastro.org/Cdiff.
A version of this article first appeared on Medscape.com.
Samples from patients in the United States and Kenya show an increasing emergence of previously undetected vancomycin-resistant strains of Clostridioides difficile, sparking concern as recurrences in the treatment of C. difficile infection (CDI) continue to rise.
“Our results may help explain a decreasing effectiveness of antibiotic-based therapy in C. difficile infection, since a significant proportion of patients harboring strains with reduced susceptibility to vancomycin may not respond to treatment,” reported the authors in research published recently in Clinical Infectious Diseases.
The spread of the resistant strains “has serious public health implications, underscoring an urgent need for a comprehensive analysis of the circulating strains to help inform clinical decisions,” they added.
Commenting on the findings, Cornelius J. Clancy, MD, professor of medicine at the University of Pittsburgh, and chief of infectious diseases at the Veterans Affairs Pittsburgh Healthcare System, echoed the concern.
“The casual belief has been that [C. difficile] strains at most centers can be assumed to be vancomycin susceptible,” he told this news organization. “This study shows that this assumption can no longer be taken as a given.”
Dr. Clancy, who was not involved with this research, noted that “based on this study, there might be need for the Infectious Diseases Society of America and other organizations to offer guidance on generating good, quality surveillance data for C. difficile resistance.”
With C. difficile showing the ability to resist multiple antibiotics, drugs in the armamentarium to treat the infection have declined in recent years, and recurrences with the infection are reported in up to 25% of cases.
Oral vancomycin is recommended as the antibiotic of choice by the IDSA and the Society for Healthcare Epidemiology of America for severe as well as nonsevere cases of CDI, and although there are reports of nine vancomycin-resistant gene clusters, most involve Enterococcus.
To take a closer look at the prevalence of vancomycin-resistant C. difficile strains, first author Charles Darkoh, PhD, with the Center for Infectious Diseases at the University of Texas Health Science Center, Houston, and colleagues analyzed stool samples from patients with CDI, including 438 patients in Houston, taken between 2012 and 2017, and 98 in Nairobi, Kenya, taken in 2017.
They found that, among samples from patients in Houston, over the time period, 26% showed vancomycin nonsusceptible C. difficile isolates and 29% had isolates that were metronidazole resistant.
And among samples from the Nairobi patients, 67% harbored vancomycin-resistant isolates and 85% had isolates resistant to metronidazole.
Of note, the proportion of samples containing vancomycin-resistant C. difficile in the Houston patients showed a marked increase over time, from «complete absence» in 2012 to approximately 35% in 2017, the authors reported.
“These nonsusceptibility rates significantly exceeded prior reports from other studies conducted in the United States and Europe from 2011 to 2014, suggesting a lower percentage of resistance to both metronidazole and vancomycin,” the authors wrote.
Further experiments on mouse models infected with one of the vancomycin-resistant isolates showed that treatment with vancomycin failed to eradicate the infection, and 5-day survival was significantly lower after vancomycin treatment in those mice (25%) versus those infected with strains known to be vancomycin sensitive (50%).
Unrecognized genetic strains
Whole-genome sequencing of 10 of the resistant isolates showed no matches with gene clusters that have been previously recognized as being vancomycin resistant, suggesting the emergence of new clusters.
“Together, these results suggest unknown genetic elements associated with vancomycin nonsusceptibility in isolates circulating in the patient population,” the authors wrote.
Dr. Darkoh told this news organization that the research team is currently working to further investigate the patterns and mechanisms.
“We are currently working on a follow-up study for the next 5 years to find out how widespread this is,” he said. “We want to make sure it’s not necessarily just occurring in the settings we studied, and we also need to establish the mechanism of resistance.”
Further commenting on the results, Dr. Clancy noted that “the extent of resistance caught many in the field a bit off guard, as they are higher than previously reported.”
“The data are also concerning because most centers do not routinely test C. difficile for drug susceptibility.”
Dr. Clancy noted that “another immediately pressing need is to understand mechanisms of resistance. It was quite striking that vancomycin-resistant strains in this study did not carry vanA genes, pointing to previously unrecognized mechanisms of resistance.”
“As is often the case, antibiotic overuse was likely a factor in the resistances, with overtesting often leading to overtreatment of C. difficile,” Dr. Clancy said. “The situation may have been compounded by failure to appreciate how entrenched C. difficile resistance may be at certain hospitals, since widespread susceptibility testing is generally not routinely performed.”
As alternative treatments, Dr. Clancy pointed to the recent IDSA update, which included a stronger endorsement of fidaxomicin.
“Of course, there is also the need to assure that data on resistance to agents like fidaxomicin are generated going forward,” he noted.
The study was supported by was supported by National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Texas Medical Center Digestive Diseases Center, and the University of Texas Health Science Center. Dr. Darkoh has disclosed no relevant financial relationships. One coauthor received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics. Dr. Clancy disclosed advisory board, consulting and/or research relationships with Merck, Qpex Biopharma, Shionogi, Astellas, Cidara, Scynexis, and Needham & Associates.
Help your patients understand their C. difficile diagnosis by sharing patient education from the AGA GI Patient Center: www.gastro.org/Cdiff.
A version of this article first appeared on Medscape.com.
Samples from patients in the United States and Kenya show an increasing emergence of previously undetected vancomycin-resistant strains of Clostridioides difficile, sparking concern as recurrences in the treatment of C. difficile infection (CDI) continue to rise.
“Our results may help explain a decreasing effectiveness of antibiotic-based therapy in C. difficile infection, since a significant proportion of patients harboring strains with reduced susceptibility to vancomycin may not respond to treatment,” reported the authors in research published recently in Clinical Infectious Diseases.
The spread of the resistant strains “has serious public health implications, underscoring an urgent need for a comprehensive analysis of the circulating strains to help inform clinical decisions,” they added.
Commenting on the findings, Cornelius J. Clancy, MD, professor of medicine at the University of Pittsburgh, and chief of infectious diseases at the Veterans Affairs Pittsburgh Healthcare System, echoed the concern.
“The casual belief has been that [C. difficile] strains at most centers can be assumed to be vancomycin susceptible,” he told this news organization. “This study shows that this assumption can no longer be taken as a given.”
Dr. Clancy, who was not involved with this research, noted that “based on this study, there might be need for the Infectious Diseases Society of America and other organizations to offer guidance on generating good, quality surveillance data for C. difficile resistance.”
With C. difficile showing the ability to resist multiple antibiotics, drugs in the armamentarium to treat the infection have declined in recent years, and recurrences with the infection are reported in up to 25% of cases.
Oral vancomycin is recommended as the antibiotic of choice by the IDSA and the Society for Healthcare Epidemiology of America for severe as well as nonsevere cases of CDI, and although there are reports of nine vancomycin-resistant gene clusters, most involve Enterococcus.
To take a closer look at the prevalence of vancomycin-resistant C. difficile strains, first author Charles Darkoh, PhD, with the Center for Infectious Diseases at the University of Texas Health Science Center, Houston, and colleagues analyzed stool samples from patients with CDI, including 438 patients in Houston, taken between 2012 and 2017, and 98 in Nairobi, Kenya, taken in 2017.
They found that, among samples from patients in Houston, over the time period, 26% showed vancomycin nonsusceptible C. difficile isolates and 29% had isolates that were metronidazole resistant.
And among samples from the Nairobi patients, 67% harbored vancomycin-resistant isolates and 85% had isolates resistant to metronidazole.
Of note, the proportion of samples containing vancomycin-resistant C. difficile in the Houston patients showed a marked increase over time, from «complete absence» in 2012 to approximately 35% in 2017, the authors reported.
“These nonsusceptibility rates significantly exceeded prior reports from other studies conducted in the United States and Europe from 2011 to 2014, suggesting a lower percentage of resistance to both metronidazole and vancomycin,” the authors wrote.
Further experiments on mouse models infected with one of the vancomycin-resistant isolates showed that treatment with vancomycin failed to eradicate the infection, and 5-day survival was significantly lower after vancomycin treatment in those mice (25%) versus those infected with strains known to be vancomycin sensitive (50%).
Unrecognized genetic strains
Whole-genome sequencing of 10 of the resistant isolates showed no matches with gene clusters that have been previously recognized as being vancomycin resistant, suggesting the emergence of new clusters.
“Together, these results suggest unknown genetic elements associated with vancomycin nonsusceptibility in isolates circulating in the patient population,” the authors wrote.
Dr. Darkoh told this news organization that the research team is currently working to further investigate the patterns and mechanisms.
“We are currently working on a follow-up study for the next 5 years to find out how widespread this is,” he said. “We want to make sure it’s not necessarily just occurring in the settings we studied, and we also need to establish the mechanism of resistance.”
Further commenting on the results, Dr. Clancy noted that “the extent of resistance caught many in the field a bit off guard, as they are higher than previously reported.”
“The data are also concerning because most centers do not routinely test C. difficile for drug susceptibility.”
Dr. Clancy noted that “another immediately pressing need is to understand mechanisms of resistance. It was quite striking that vancomycin-resistant strains in this study did not carry vanA genes, pointing to previously unrecognized mechanisms of resistance.”
“As is often the case, antibiotic overuse was likely a factor in the resistances, with overtesting often leading to overtreatment of C. difficile,” Dr. Clancy said. “The situation may have been compounded by failure to appreciate how entrenched C. difficile resistance may be at certain hospitals, since widespread susceptibility testing is generally not routinely performed.”
As alternative treatments, Dr. Clancy pointed to the recent IDSA update, which included a stronger endorsement of fidaxomicin.
“Of course, there is also the need to assure that data on resistance to agents like fidaxomicin are generated going forward,” he noted.
The study was supported by was supported by National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Texas Medical Center Digestive Diseases Center, and the University of Texas Health Science Center. Dr. Darkoh has disclosed no relevant financial relationships. One coauthor received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics. Dr. Clancy disclosed advisory board, consulting and/or research relationships with Merck, Qpex Biopharma, Shionogi, Astellas, Cidara, Scynexis, and Needham & Associates.
Help your patients understand their C. difficile diagnosis by sharing patient education from the AGA GI Patient Center: www.gastro.org/Cdiff.
A version of this article first appeared on Medscape.com.
FROM CLINICAL INFECTIOUS DISEASES
Stopping venetoclax treatment early reduces CLL survival outcomes
“There’s not a lot of awareness about the fact that you’re probably better off not permanently discontinuing treatment,” Anthony R. Mato, first author of the research published in Haematologica, said in an interview.
“Instead, attempting dose reductions with later resumption to complete the planned schedule for treatment probably could improve outcomes,” said Dr. Mato, who is director of the CLL Program at Memorial Sloan Kettering Cancer Center in New York.
Venetoclax, a potent B-cell lymphoma-2 (BCL2) inhibitor, provides a novel, chemotherapy-free treatment option for first-line and r/r CLL. While its safety profile is manageable, treatment interruptions are very common, and premature discontinuations are reported in about a third of patients, often because of adverse events.
Lacking data on the effects of those interruptions on survival outcomes, Dr. Mato and colleagues conducted a post hoc analysis of the phase 3 MURANO trial. In this open-label study, treatment with six cycles of venetoclax in combination with rituximab followed by venetoclax once daily for a total of 2 years showed superior progression-free survival, compared with six cycles of bendamustine plus rituximab in patients with r/r CLL (P < .0001).
The current analysis involved 194 intention-to-treat patients from the trial’s venetoclax arm, among whom 140 (72%) completed 2 years of therapy, and 54 (28%) prematurely discontinued treatment. The most common reasons for discontinuation were adverse events (53.7%) and disease progression (22.2%).
Among those with early discontinuation for any reason except disease progression, the rate of progression-free survival was significantly inferior, compared with those who completed the treatment (hazard ratio, 5.98; P < .0001), as was the rate or discontinuation caused specifically by adverse events, which most commonly involved neutropenia or thrombocytopenia (HR, 5.82; P < .0001).
Those who discontinued had a mean duration of venetoclax therapy of 11.3 months, compared with 24.4 months for all patients. For each additional month of venetoclax therapy, there was a significantly lower risk of a progression-free survival event (P = .0263) and of an overall survival event (P < .0001).
The treatment interruption rate was much higher, at 69% (134), involving neutropenia in 43% (84) of instances and requiring dose reductions in 23% (45) of cases.
However, in contrast to permanent discontinuations, the temporary interruptions and dose reductions had no significant effect on progression-free or overall survival, regardless of the duration.
“Improved progression-free and overall survival were associated with greater cumulative venetoclax treatment exposure,” the authors wrote.
“The results of these analyses highlight the importance of appropriately managing treatment modifications to ensure optimal outcomes for patients receiving targeted treatment for CLL,” they said.
Key measures including “better supportive care, use of growth factors, and more aggressive strategies for dose reduction could potentially help to improve or decrease the number of patients discontinuing due to an adverse event,” Dr. Mato added.“We can’t say definitively because this is not a randomized study – it’s a retrospective analysis from a randomized study – but those measures likely could have a positive impact on patient outcomes.”
The study received support from Genentech and AbbVie. Dr. Mato reported consulting or other relationships with AbbVie, AstraZeneca, Celgene, DTRM, Genentech, Janssen, Loxo, PCYC, Sunesis, and TG Therapeutics.
“There’s not a lot of awareness about the fact that you’re probably better off not permanently discontinuing treatment,” Anthony R. Mato, first author of the research published in Haematologica, said in an interview.
“Instead, attempting dose reductions with later resumption to complete the planned schedule for treatment probably could improve outcomes,” said Dr. Mato, who is director of the CLL Program at Memorial Sloan Kettering Cancer Center in New York.
Venetoclax, a potent B-cell lymphoma-2 (BCL2) inhibitor, provides a novel, chemotherapy-free treatment option for first-line and r/r CLL. While its safety profile is manageable, treatment interruptions are very common, and premature discontinuations are reported in about a third of patients, often because of adverse events.
Lacking data on the effects of those interruptions on survival outcomes, Dr. Mato and colleagues conducted a post hoc analysis of the phase 3 MURANO trial. In this open-label study, treatment with six cycles of venetoclax in combination with rituximab followed by venetoclax once daily for a total of 2 years showed superior progression-free survival, compared with six cycles of bendamustine plus rituximab in patients with r/r CLL (P < .0001).
The current analysis involved 194 intention-to-treat patients from the trial’s venetoclax arm, among whom 140 (72%) completed 2 years of therapy, and 54 (28%) prematurely discontinued treatment. The most common reasons for discontinuation were adverse events (53.7%) and disease progression (22.2%).
Among those with early discontinuation for any reason except disease progression, the rate of progression-free survival was significantly inferior, compared with those who completed the treatment (hazard ratio, 5.98; P < .0001), as was the rate or discontinuation caused specifically by adverse events, which most commonly involved neutropenia or thrombocytopenia (HR, 5.82; P < .0001).
Those who discontinued had a mean duration of venetoclax therapy of 11.3 months, compared with 24.4 months for all patients. For each additional month of venetoclax therapy, there was a significantly lower risk of a progression-free survival event (P = .0263) and of an overall survival event (P < .0001).
The treatment interruption rate was much higher, at 69% (134), involving neutropenia in 43% (84) of instances and requiring dose reductions in 23% (45) of cases.
However, in contrast to permanent discontinuations, the temporary interruptions and dose reductions had no significant effect on progression-free or overall survival, regardless of the duration.
“Improved progression-free and overall survival were associated with greater cumulative venetoclax treatment exposure,” the authors wrote.
“The results of these analyses highlight the importance of appropriately managing treatment modifications to ensure optimal outcomes for patients receiving targeted treatment for CLL,” they said.
Key measures including “better supportive care, use of growth factors, and more aggressive strategies for dose reduction could potentially help to improve or decrease the number of patients discontinuing due to an adverse event,” Dr. Mato added.“We can’t say definitively because this is not a randomized study – it’s a retrospective analysis from a randomized study – but those measures likely could have a positive impact on patient outcomes.”
The study received support from Genentech and AbbVie. Dr. Mato reported consulting or other relationships with AbbVie, AstraZeneca, Celgene, DTRM, Genentech, Janssen, Loxo, PCYC, Sunesis, and TG Therapeutics.
“There’s not a lot of awareness about the fact that you’re probably better off not permanently discontinuing treatment,” Anthony R. Mato, first author of the research published in Haematologica, said in an interview.
“Instead, attempting dose reductions with later resumption to complete the planned schedule for treatment probably could improve outcomes,” said Dr. Mato, who is director of the CLL Program at Memorial Sloan Kettering Cancer Center in New York.
Venetoclax, a potent B-cell lymphoma-2 (BCL2) inhibitor, provides a novel, chemotherapy-free treatment option for first-line and r/r CLL. While its safety profile is manageable, treatment interruptions are very common, and premature discontinuations are reported in about a third of patients, often because of adverse events.
Lacking data on the effects of those interruptions on survival outcomes, Dr. Mato and colleagues conducted a post hoc analysis of the phase 3 MURANO trial. In this open-label study, treatment with six cycles of venetoclax in combination with rituximab followed by venetoclax once daily for a total of 2 years showed superior progression-free survival, compared with six cycles of bendamustine plus rituximab in patients with r/r CLL (P < .0001).
The current analysis involved 194 intention-to-treat patients from the trial’s venetoclax arm, among whom 140 (72%) completed 2 years of therapy, and 54 (28%) prematurely discontinued treatment. The most common reasons for discontinuation were adverse events (53.7%) and disease progression (22.2%).
Among those with early discontinuation for any reason except disease progression, the rate of progression-free survival was significantly inferior, compared with those who completed the treatment (hazard ratio, 5.98; P < .0001), as was the rate or discontinuation caused specifically by adverse events, which most commonly involved neutropenia or thrombocytopenia (HR, 5.82; P < .0001).
Those who discontinued had a mean duration of venetoclax therapy of 11.3 months, compared with 24.4 months for all patients. For each additional month of venetoclax therapy, there was a significantly lower risk of a progression-free survival event (P = .0263) and of an overall survival event (P < .0001).
The treatment interruption rate was much higher, at 69% (134), involving neutropenia in 43% (84) of instances and requiring dose reductions in 23% (45) of cases.
However, in contrast to permanent discontinuations, the temporary interruptions and dose reductions had no significant effect on progression-free or overall survival, regardless of the duration.
“Improved progression-free and overall survival were associated with greater cumulative venetoclax treatment exposure,” the authors wrote.
“The results of these analyses highlight the importance of appropriately managing treatment modifications to ensure optimal outcomes for patients receiving targeted treatment for CLL,” they said.
Key measures including “better supportive care, use of growth factors, and more aggressive strategies for dose reduction could potentially help to improve or decrease the number of patients discontinuing due to an adverse event,” Dr. Mato added.“We can’t say definitively because this is not a randomized study – it’s a retrospective analysis from a randomized study – but those measures likely could have a positive impact on patient outcomes.”
The study received support from Genentech and AbbVie. Dr. Mato reported consulting or other relationships with AbbVie, AstraZeneca, Celgene, DTRM, Genentech, Janssen, Loxo, PCYC, Sunesis, and TG Therapeutics.
C. difficile: New vancomycin-resistant strains raise concerns
Samples from patients in the United States and Kenya show an increasing emergence of previously undetected vancomycin-resistant strains of Clostridioides difficile, sparking concern as recurrences in the treatment of C. difficile infection (CDI) continue to rise.
“Our results may help explain a decreasing effectiveness of antibiotic-based therapy in C. difficile infection, since a significant proportion of patients harboring strains with reduced susceptibility to vancomycin may not respond to treatment,” reported the authors in research published recently in Clinical Infectious Diseases.
The spread of the resistant strains “has serious public health implications, underscoring an urgent need for a comprehensive analysis of the circulating strains to help inform clinical decisions,” they added.
Commenting on the findings, Cornelius J. Clancy, MD, professor of medicine at the University of Pittsburgh, and chief of infectious diseases at the Veterans Affairs Pittsburgh Healthcare System, echoed the concern.
“The casual belief has been that [C. difficile] strains at most centers can be assumed to be vancomycin susceptible,” he told this news organization. “This study shows that this assumption can no longer be taken as a given.”
Dr. Clancy, who was not involved with this research, noted that “based on this study, there might be need for the Infectious Diseases Society of America and other organizations to offer guidance on generating good, quality surveillance data for C. difficile resistance.”
With C. difficile showing the ability to resist multiple antibiotics, drugs in the armamentarium to treat the infection have declined in recent years, and recurrences with the infection are reported in up to 25% of cases.
Oral vancomycin is recommended as the antibiotic of choice by the IDSA and the Society for Healthcare Epidemiology of America for severe as well as nonsevere cases of CDI, and although there are reports of nine vancomycin-resistant gene clusters, most involve Enterococcus.
To take a closer look at the prevalence of vancomycin-resistant C. difficile strains, first author Charles Darkoh, PhD, with the Center for Infectious Diseases at the University of Texas Health Science Center, Houston, and colleagues analyzed stool samples from patients with CDI, including 438 patients in Houston, taken between 2012 and 2017, and 98 in Nairobi, Kenya, taken in 2017.
They found that, among samples from patients in Houston, over the time period, 26% showed vancomycin nonsusceptible C. difficile isolates and 29% had isolates that were metronidazole resistant.
And among samples from the Nairobi patients, 67% harbored vancomycin-resistant isolates and 85% had isolates resistant to metronidazole.
Of note, the proportion of samples containing vancomycin-resistant C. difficile in the Houston patients showed a marked increase over time, from «complete absence» in 2012 to approximately 35% in 2017, the authors reported.
“These nonsusceptibility rates significantly exceeded prior reports from other studies conducted in the United States and Europe from 2011 to 2014, suggesting a lower percentage of resistance to both metronidazole and vancomycin,” the authors wrote.
Further experiments on mouse models infected with one of the vancomycin-resistant isolates showed that treatment with vancomycin failed to eradicate the infection, and 5-day survival was significantly lower after vancomycin treatment in those mice (25%) versus those infected with strains known to be vancomycin sensitive (50%).
Unrecognized genetic strains
Whole-genome sequencing of 10 of the resistant isolates showed no matches with gene clusters that have been previously recognized as being vancomycin resistant, suggesting the emergence of new clusters.
“Together, these results suggest unknown genetic elements associated with vancomycin nonsusceptibility in isolates circulating in the patient population,” the authors wrote.
Dr. Darkoh told this news organization that the research team is currently working to further investigate the patterns and mechanisms.
“We are currently working on a follow-up study for the next 5 years to find out how widespread this is,” he said. “We want to make sure it’s not necessarily just occurring in the settings we studied, and we also need to establish the mechanism of resistance.”
Further commenting on the results, Dr. Clancy noted that “the extent of resistance caught many in the field a bit off guard, as they are higher than previously reported.”
“The data are also concerning because most centers do not routinely test C. difficile for drug susceptibility.”
Dr. Clancy noted that “another immediately pressing need is to understand mechanisms of resistance. It was quite striking that vancomycin-resistant strains in this study did not carry vanA genes, pointing to previously unrecognized mechanisms of resistance.”
“As is often the case, antibiotic overuse was likely a factor in the resistances, with overtesting often leading to overtreatment of C. difficile,” Dr. Clancy said. “The situation may have been compounded by failure to appreciate how entrenched C. difficile resistance may be at certain hospitals, since widespread susceptibility testing is generally not routinely performed.”
As alternative treatments, Dr. Clancy pointed to the recent IDSA update, which included a stronger endorsement of fidaxomicin.
“Of course, there is also the need to assure that data on resistance to agents like fidaxomicin are generated going forward,” he noted.
The study was supported by was supported by National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Texas Medical Center Digestive Diseases Center, and the University of Texas Health Science Center. Dr. Darkoh has disclosed no relevant financial relationships. One coauthor received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics. Dr. Clancy disclosed advisory board, consulting and/or research relationships with Merck, Qpex Biopharma, Shionogi, Astellas, Cidara, Scynexis, and Needham & Associates.
A version of this article first appeared on Medscape.com.
Samples from patients in the United States and Kenya show an increasing emergence of previously undetected vancomycin-resistant strains of Clostridioides difficile, sparking concern as recurrences in the treatment of C. difficile infection (CDI) continue to rise.
“Our results may help explain a decreasing effectiveness of antibiotic-based therapy in C. difficile infection, since a significant proportion of patients harboring strains with reduced susceptibility to vancomycin may not respond to treatment,” reported the authors in research published recently in Clinical Infectious Diseases.
The spread of the resistant strains “has serious public health implications, underscoring an urgent need for a comprehensive analysis of the circulating strains to help inform clinical decisions,” they added.
Commenting on the findings, Cornelius J. Clancy, MD, professor of medicine at the University of Pittsburgh, and chief of infectious diseases at the Veterans Affairs Pittsburgh Healthcare System, echoed the concern.
“The casual belief has been that [C. difficile] strains at most centers can be assumed to be vancomycin susceptible,” he told this news organization. “This study shows that this assumption can no longer be taken as a given.”
Dr. Clancy, who was not involved with this research, noted that “based on this study, there might be need for the Infectious Diseases Society of America and other organizations to offer guidance on generating good, quality surveillance data for C. difficile resistance.”
With C. difficile showing the ability to resist multiple antibiotics, drugs in the armamentarium to treat the infection have declined in recent years, and recurrences with the infection are reported in up to 25% of cases.
Oral vancomycin is recommended as the antibiotic of choice by the IDSA and the Society for Healthcare Epidemiology of America for severe as well as nonsevere cases of CDI, and although there are reports of nine vancomycin-resistant gene clusters, most involve Enterococcus.
To take a closer look at the prevalence of vancomycin-resistant C. difficile strains, first author Charles Darkoh, PhD, with the Center for Infectious Diseases at the University of Texas Health Science Center, Houston, and colleagues analyzed stool samples from patients with CDI, including 438 patients in Houston, taken between 2012 and 2017, and 98 in Nairobi, Kenya, taken in 2017.
They found that, among samples from patients in Houston, over the time period, 26% showed vancomycin nonsusceptible C. difficile isolates and 29% had isolates that were metronidazole resistant.
And among samples from the Nairobi patients, 67% harbored vancomycin-resistant isolates and 85% had isolates resistant to metronidazole.
Of note, the proportion of samples containing vancomycin-resistant C. difficile in the Houston patients showed a marked increase over time, from «complete absence» in 2012 to approximately 35% in 2017, the authors reported.
“These nonsusceptibility rates significantly exceeded prior reports from other studies conducted in the United States and Europe from 2011 to 2014, suggesting a lower percentage of resistance to both metronidazole and vancomycin,” the authors wrote.
Further experiments on mouse models infected with one of the vancomycin-resistant isolates showed that treatment with vancomycin failed to eradicate the infection, and 5-day survival was significantly lower after vancomycin treatment in those mice (25%) versus those infected with strains known to be vancomycin sensitive (50%).
Unrecognized genetic strains
Whole-genome sequencing of 10 of the resistant isolates showed no matches with gene clusters that have been previously recognized as being vancomycin resistant, suggesting the emergence of new clusters.
“Together, these results suggest unknown genetic elements associated with vancomycin nonsusceptibility in isolates circulating in the patient population,” the authors wrote.
Dr. Darkoh told this news organization that the research team is currently working to further investigate the patterns and mechanisms.
“We are currently working on a follow-up study for the next 5 years to find out how widespread this is,” he said. “We want to make sure it’s not necessarily just occurring in the settings we studied, and we also need to establish the mechanism of resistance.”
Further commenting on the results, Dr. Clancy noted that “the extent of resistance caught many in the field a bit off guard, as they are higher than previously reported.”
“The data are also concerning because most centers do not routinely test C. difficile for drug susceptibility.”
Dr. Clancy noted that “another immediately pressing need is to understand mechanisms of resistance. It was quite striking that vancomycin-resistant strains in this study did not carry vanA genes, pointing to previously unrecognized mechanisms of resistance.”
“As is often the case, antibiotic overuse was likely a factor in the resistances, with overtesting often leading to overtreatment of C. difficile,” Dr. Clancy said. “The situation may have been compounded by failure to appreciate how entrenched C. difficile resistance may be at certain hospitals, since widespread susceptibility testing is generally not routinely performed.”
As alternative treatments, Dr. Clancy pointed to the recent IDSA update, which included a stronger endorsement of fidaxomicin.
“Of course, there is also the need to assure that data on resistance to agents like fidaxomicin are generated going forward,” he noted.
The study was supported by was supported by National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Texas Medical Center Digestive Diseases Center, and the University of Texas Health Science Center. Dr. Darkoh has disclosed no relevant financial relationships. One coauthor received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics. Dr. Clancy disclosed advisory board, consulting and/or research relationships with Merck, Qpex Biopharma, Shionogi, Astellas, Cidara, Scynexis, and Needham & Associates.
A version of this article first appeared on Medscape.com.
Samples from patients in the United States and Kenya show an increasing emergence of previously undetected vancomycin-resistant strains of Clostridioides difficile, sparking concern as recurrences in the treatment of C. difficile infection (CDI) continue to rise.
“Our results may help explain a decreasing effectiveness of antibiotic-based therapy in C. difficile infection, since a significant proportion of patients harboring strains with reduced susceptibility to vancomycin may not respond to treatment,” reported the authors in research published recently in Clinical Infectious Diseases.
The spread of the resistant strains “has serious public health implications, underscoring an urgent need for a comprehensive analysis of the circulating strains to help inform clinical decisions,” they added.
Commenting on the findings, Cornelius J. Clancy, MD, professor of medicine at the University of Pittsburgh, and chief of infectious diseases at the Veterans Affairs Pittsburgh Healthcare System, echoed the concern.
“The casual belief has been that [C. difficile] strains at most centers can be assumed to be vancomycin susceptible,” he told this news organization. “This study shows that this assumption can no longer be taken as a given.”
Dr. Clancy, who was not involved with this research, noted that “based on this study, there might be need for the Infectious Diseases Society of America and other organizations to offer guidance on generating good, quality surveillance data for C. difficile resistance.”
With C. difficile showing the ability to resist multiple antibiotics, drugs in the armamentarium to treat the infection have declined in recent years, and recurrences with the infection are reported in up to 25% of cases.
Oral vancomycin is recommended as the antibiotic of choice by the IDSA and the Society for Healthcare Epidemiology of America for severe as well as nonsevere cases of CDI, and although there are reports of nine vancomycin-resistant gene clusters, most involve Enterococcus.
To take a closer look at the prevalence of vancomycin-resistant C. difficile strains, first author Charles Darkoh, PhD, with the Center for Infectious Diseases at the University of Texas Health Science Center, Houston, and colleagues analyzed stool samples from patients with CDI, including 438 patients in Houston, taken between 2012 and 2017, and 98 in Nairobi, Kenya, taken in 2017.
They found that, among samples from patients in Houston, over the time period, 26% showed vancomycin nonsusceptible C. difficile isolates and 29% had isolates that were metronidazole resistant.
And among samples from the Nairobi patients, 67% harbored vancomycin-resistant isolates and 85% had isolates resistant to metronidazole.
Of note, the proportion of samples containing vancomycin-resistant C. difficile in the Houston patients showed a marked increase over time, from «complete absence» in 2012 to approximately 35% in 2017, the authors reported.
“These nonsusceptibility rates significantly exceeded prior reports from other studies conducted in the United States and Europe from 2011 to 2014, suggesting a lower percentage of resistance to both metronidazole and vancomycin,” the authors wrote.
Further experiments on mouse models infected with one of the vancomycin-resistant isolates showed that treatment with vancomycin failed to eradicate the infection, and 5-day survival was significantly lower after vancomycin treatment in those mice (25%) versus those infected with strains known to be vancomycin sensitive (50%).
Unrecognized genetic strains
Whole-genome sequencing of 10 of the resistant isolates showed no matches with gene clusters that have been previously recognized as being vancomycin resistant, suggesting the emergence of new clusters.
“Together, these results suggest unknown genetic elements associated with vancomycin nonsusceptibility in isolates circulating in the patient population,” the authors wrote.
Dr. Darkoh told this news organization that the research team is currently working to further investigate the patterns and mechanisms.
“We are currently working on a follow-up study for the next 5 years to find out how widespread this is,” he said. “We want to make sure it’s not necessarily just occurring in the settings we studied, and we also need to establish the mechanism of resistance.”
Further commenting on the results, Dr. Clancy noted that “the extent of resistance caught many in the field a bit off guard, as they are higher than previously reported.”
“The data are also concerning because most centers do not routinely test C. difficile for drug susceptibility.”
Dr. Clancy noted that “another immediately pressing need is to understand mechanisms of resistance. It was quite striking that vancomycin-resistant strains in this study did not carry vanA genes, pointing to previously unrecognized mechanisms of resistance.”
“As is often the case, antibiotic overuse was likely a factor in the resistances, with overtesting often leading to overtreatment of C. difficile,” Dr. Clancy said. “The situation may have been compounded by failure to appreciate how entrenched C. difficile resistance may be at certain hospitals, since widespread susceptibility testing is generally not routinely performed.”
As alternative treatments, Dr. Clancy pointed to the recent IDSA update, which included a stronger endorsement of fidaxomicin.
“Of course, there is also the need to assure that data on resistance to agents like fidaxomicin are generated going forward,” he noted.
The study was supported by was supported by National Institutes of Health, the National Institute of Allergy and Infectious Diseases, the Texas Medical Center Digestive Diseases Center, and the University of Texas Health Science Center. Dr. Darkoh has disclosed no relevant financial relationships. One coauthor received grant support from Merck, Entasis Pharmaceuticals, and MeMed Diagnostics. Dr. Clancy disclosed advisory board, consulting and/or research relationships with Merck, Qpex Biopharma, Shionogi, Astellas, Cidara, Scynexis, and Needham & Associates.
A version of this article first appeared on Medscape.com.
FROM CLINICAL INFECTIOUS DISEASES