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Outcomes with CDK4/6 Inhibitors Vary in BC
Lead investigator Claudio Vernieri, MD, PhD, presented these findings of the PALMARES-2 study at the annual meeting of the American Society of Clinical Oncology.
“Along with different safety profiles, drug-drug interactions, and costs of the three available CDK4/6 inhibitor molecules, our efficacy data may help clinicians and patients in choosing the most appropriate CDK4/6 inhibitor in specific clinical contexts,” Dr. Vernieri, who is from the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, said during the meeting.
CDK4/6 inhibitors combined with ET, are the standard of care as first line treatment for this population, noted Dr. Vernieri. However, their efficacy has never been directly compared in a large clinical trial.
“Since these compounds have different pharmacokinetics, pharmacodynamics, safety profiles, costs, and drug-drug interactions, identifying which of the three CDK4/6 inhibitors may be more effective in specific clinical contexts is a highly clinically relevant issue,” he said. “Real-world data represent a key source to perform direct comparisons.”
The PALMARES-2 study was a retrospective, multicenter, population-based study, in 18 Italian cancer centers. Its two main objectives were to compare the real-world PFS of abemaciclib versus ribociclib versus palbociclib, in combination with ET, in the whole study cohort, as well as in various subgroups including patients with endocrine-resistant disease, luminal B-like disease, or in premenopausal women.
A total of 1,850 patients (median age, 63 years) were enrolled between January 1, 2016 and September 1, 2023, with 750 (40.6%) receiving palbociclib, and 676 (36.5%) and 424 (22.9%) receiving ribociclib and abemaciclib, respectively.
Baseline imbalance
Importantly, there were significant imbalances in baseline characteristics of the patients, with those receiving abemaciclib being more likely to have endocrine-resistant disease, low progesterone receptor expression, and liver metastasis, and less likely to have de novo metastatic disease, compared with other patients, said Dr. Vernieri.
The analysis showed that across the entire cohort, the median real-world PFS and overall survival (OS) were 34.7 months and 66.6 months, respectively, by a January 1, 2024, data cutoff date. “I believe that the overall survival data are still immature to make a definitive conclusion,” he commented, noting that at enrollment only about half of patients had undergone disease progression, and at the close of the study only about 25% had died.
After adjusting for clinically relevant patient- and tumor-related covariates, “we found that both abemaciclib and ribociclib were more effective than palbociclib, whereas we did not find statistically significant differences between abemaciclib and ribociclib,” he reported.
Specifically, the adjusted hazard ratio (aHR) for PFS was 0.71 for abemaciclib versus palbociclib (95% CI, 0.56-0.90; P = .005), 0.81 for ribociclib versus palbociclib (95% CI, 0.65-0.99; P = .048), and 0.91 for abemaciclib versus ribociclib (95% CI, 0.70-1.19; P = .505).
“Regarding subgroup analysis, we found that abemaciclib and ribociclib were more effective than palbociclib in patients with endocrine-resistant or luminal B-like disease, as well as in premenopausal women. Abemaciclib was superior to palbociclib in patients with poorer ECOG [Eastern Cooperative Oncology Group] performance status and to both palbociclib and ribociclib in patients with de novo metastatic disease. Both ribociclib and abemaciclib showed a trend toward higher efficacy in patients with liver metastases. However, this difference only reached statistical significance in patients treated with ribociclib. And finally, the three CDK4/6 inhibitors were similarly effective in patients who were older or at bone-only disease,” he concluded.
Justifying adjustment
Speaking during the audience question period Giuseppe Del Priore, MD, from Morehouse School of Medicine in Atlanta, Georgia, said he preferred unadjusted results when examining real-world data, “because that’s the benefit,” and he questioned why the researchers had adjusted their numbers.
Dr. Vernieri explained that the adjustments were made to account for the important imbalances in the baseline characteristics of the patients.
“When we plotted unadjusted curves, we did not find statistically significant differences between these three drugs, only a trend toward the direction that I showed you today,” he said. “However, as you saw from the tables showing the characteristics of patients, there were important imbalances in terms of important prognostic factors in the three patient cohorts. So, I think that, for this kind of data and based on this level of imbalance, adjustment is necessary.
“To reinforce our conclusions, what we did was also to perform a propensity score match–based analysis,” Dr. Vernieri continued. “I did not have the time to show the results today, but these data were fully in line with the study conclusions. And we also performed a backward selection of variables. So, we basically selected variables more likely to be associated with patient prognosis. And also those models confirm the study conclusion. So I think the conclusions are quite solid.”
Dr. Del Priore, an adjunct professor of obstetrics and gynecology with a specialty in oncology, on the other hand, said he was not convinced that any of the drugs might be better or worse in the actual population treated.
“I still maintain that unadjusted real-world data should be presented and then only a limited adjusted analysis performed using the most unbalanced variables,” he said. “To do more elaborate adjustments may falsely imply a difference in drug choice and outcomes which never should be the conclusion with observational studies. Instead, the conclusions should be that, with typical use, the following similarities in PFS and OS were observed. Then point out how drug choice and important prognostic variables might be linked, thus limiting the generalizable conclusions even further.
“I would conclude that prospective studies should balance for the variables used in the PALMARES-2 analyses, which actually may have been chosen for adjustment post hoc,” Dr. Del Priore said.
The study was funded by the Italian Association for Cancer Research, the European Research Council, the Ministero della Salute, the Scientific Directorate of Fondazione IRCCS Istituto Nazionale dei Tumori, Giuliani’s Foundation and Roche. Dr. Vernieri reported consulting or advisory roles with Daiichi Sankyo/Astra Zeneca, Novartis, and Pfizer; speakers’ bureau roles with Accademia Nazionale Di Medicina (ACCMED), Istituto Gentili, Lilly and Novartis; and research funding from Roche. Dr. Del Priore reported no conflicts of interest and disclosed that he is chief medical officer at BriaCell.
Lead investigator Claudio Vernieri, MD, PhD, presented these findings of the PALMARES-2 study at the annual meeting of the American Society of Clinical Oncology.
“Along with different safety profiles, drug-drug interactions, and costs of the three available CDK4/6 inhibitor molecules, our efficacy data may help clinicians and patients in choosing the most appropriate CDK4/6 inhibitor in specific clinical contexts,” Dr. Vernieri, who is from the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, said during the meeting.
CDK4/6 inhibitors combined with ET, are the standard of care as first line treatment for this population, noted Dr. Vernieri. However, their efficacy has never been directly compared in a large clinical trial.
“Since these compounds have different pharmacokinetics, pharmacodynamics, safety profiles, costs, and drug-drug interactions, identifying which of the three CDK4/6 inhibitors may be more effective in specific clinical contexts is a highly clinically relevant issue,” he said. “Real-world data represent a key source to perform direct comparisons.”
The PALMARES-2 study was a retrospective, multicenter, population-based study, in 18 Italian cancer centers. Its two main objectives were to compare the real-world PFS of abemaciclib versus ribociclib versus palbociclib, in combination with ET, in the whole study cohort, as well as in various subgroups including patients with endocrine-resistant disease, luminal B-like disease, or in premenopausal women.
A total of 1,850 patients (median age, 63 years) were enrolled between January 1, 2016 and September 1, 2023, with 750 (40.6%) receiving palbociclib, and 676 (36.5%) and 424 (22.9%) receiving ribociclib and abemaciclib, respectively.
Baseline imbalance
Importantly, there were significant imbalances in baseline characteristics of the patients, with those receiving abemaciclib being more likely to have endocrine-resistant disease, low progesterone receptor expression, and liver metastasis, and less likely to have de novo metastatic disease, compared with other patients, said Dr. Vernieri.
The analysis showed that across the entire cohort, the median real-world PFS and overall survival (OS) were 34.7 months and 66.6 months, respectively, by a January 1, 2024, data cutoff date. “I believe that the overall survival data are still immature to make a definitive conclusion,” he commented, noting that at enrollment only about half of patients had undergone disease progression, and at the close of the study only about 25% had died.
After adjusting for clinically relevant patient- and tumor-related covariates, “we found that both abemaciclib and ribociclib were more effective than palbociclib, whereas we did not find statistically significant differences between abemaciclib and ribociclib,” he reported.
Specifically, the adjusted hazard ratio (aHR) for PFS was 0.71 for abemaciclib versus palbociclib (95% CI, 0.56-0.90; P = .005), 0.81 for ribociclib versus palbociclib (95% CI, 0.65-0.99; P = .048), and 0.91 for abemaciclib versus ribociclib (95% CI, 0.70-1.19; P = .505).
“Regarding subgroup analysis, we found that abemaciclib and ribociclib were more effective than palbociclib in patients with endocrine-resistant or luminal B-like disease, as well as in premenopausal women. Abemaciclib was superior to palbociclib in patients with poorer ECOG [Eastern Cooperative Oncology Group] performance status and to both palbociclib and ribociclib in patients with de novo metastatic disease. Both ribociclib and abemaciclib showed a trend toward higher efficacy in patients with liver metastases. However, this difference only reached statistical significance in patients treated with ribociclib. And finally, the three CDK4/6 inhibitors were similarly effective in patients who were older or at bone-only disease,” he concluded.
Justifying adjustment
Speaking during the audience question period Giuseppe Del Priore, MD, from Morehouse School of Medicine in Atlanta, Georgia, said he preferred unadjusted results when examining real-world data, “because that’s the benefit,” and he questioned why the researchers had adjusted their numbers.
Dr. Vernieri explained that the adjustments were made to account for the important imbalances in the baseline characteristics of the patients.
“When we plotted unadjusted curves, we did not find statistically significant differences between these three drugs, only a trend toward the direction that I showed you today,” he said. “However, as you saw from the tables showing the characteristics of patients, there were important imbalances in terms of important prognostic factors in the three patient cohorts. So, I think that, for this kind of data and based on this level of imbalance, adjustment is necessary.
“To reinforce our conclusions, what we did was also to perform a propensity score match–based analysis,” Dr. Vernieri continued. “I did not have the time to show the results today, but these data were fully in line with the study conclusions. And we also performed a backward selection of variables. So, we basically selected variables more likely to be associated with patient prognosis. And also those models confirm the study conclusion. So I think the conclusions are quite solid.”
Dr. Del Priore, an adjunct professor of obstetrics and gynecology with a specialty in oncology, on the other hand, said he was not convinced that any of the drugs might be better or worse in the actual population treated.
“I still maintain that unadjusted real-world data should be presented and then only a limited adjusted analysis performed using the most unbalanced variables,” he said. “To do more elaborate adjustments may falsely imply a difference in drug choice and outcomes which never should be the conclusion with observational studies. Instead, the conclusions should be that, with typical use, the following similarities in PFS and OS were observed. Then point out how drug choice and important prognostic variables might be linked, thus limiting the generalizable conclusions even further.
“I would conclude that prospective studies should balance for the variables used in the PALMARES-2 analyses, which actually may have been chosen for adjustment post hoc,” Dr. Del Priore said.
The study was funded by the Italian Association for Cancer Research, the European Research Council, the Ministero della Salute, the Scientific Directorate of Fondazione IRCCS Istituto Nazionale dei Tumori, Giuliani’s Foundation and Roche. Dr. Vernieri reported consulting or advisory roles with Daiichi Sankyo/Astra Zeneca, Novartis, and Pfizer; speakers’ bureau roles with Accademia Nazionale Di Medicina (ACCMED), Istituto Gentili, Lilly and Novartis; and research funding from Roche. Dr. Del Priore reported no conflicts of interest and disclosed that he is chief medical officer at BriaCell.
Lead investigator Claudio Vernieri, MD, PhD, presented these findings of the PALMARES-2 study at the annual meeting of the American Society of Clinical Oncology.
“Along with different safety profiles, drug-drug interactions, and costs of the three available CDK4/6 inhibitor molecules, our efficacy data may help clinicians and patients in choosing the most appropriate CDK4/6 inhibitor in specific clinical contexts,” Dr. Vernieri, who is from the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, said during the meeting.
CDK4/6 inhibitors combined with ET, are the standard of care as first line treatment for this population, noted Dr. Vernieri. However, their efficacy has never been directly compared in a large clinical trial.
“Since these compounds have different pharmacokinetics, pharmacodynamics, safety profiles, costs, and drug-drug interactions, identifying which of the three CDK4/6 inhibitors may be more effective in specific clinical contexts is a highly clinically relevant issue,” he said. “Real-world data represent a key source to perform direct comparisons.”
The PALMARES-2 study was a retrospective, multicenter, population-based study, in 18 Italian cancer centers. Its two main objectives were to compare the real-world PFS of abemaciclib versus ribociclib versus palbociclib, in combination with ET, in the whole study cohort, as well as in various subgroups including patients with endocrine-resistant disease, luminal B-like disease, or in premenopausal women.
A total of 1,850 patients (median age, 63 years) were enrolled between January 1, 2016 and September 1, 2023, with 750 (40.6%) receiving palbociclib, and 676 (36.5%) and 424 (22.9%) receiving ribociclib and abemaciclib, respectively.
Baseline imbalance
Importantly, there were significant imbalances in baseline characteristics of the patients, with those receiving abemaciclib being more likely to have endocrine-resistant disease, low progesterone receptor expression, and liver metastasis, and less likely to have de novo metastatic disease, compared with other patients, said Dr. Vernieri.
The analysis showed that across the entire cohort, the median real-world PFS and overall survival (OS) were 34.7 months and 66.6 months, respectively, by a January 1, 2024, data cutoff date. “I believe that the overall survival data are still immature to make a definitive conclusion,” he commented, noting that at enrollment only about half of patients had undergone disease progression, and at the close of the study only about 25% had died.
After adjusting for clinically relevant patient- and tumor-related covariates, “we found that both abemaciclib and ribociclib were more effective than palbociclib, whereas we did not find statistically significant differences between abemaciclib and ribociclib,” he reported.
Specifically, the adjusted hazard ratio (aHR) for PFS was 0.71 for abemaciclib versus palbociclib (95% CI, 0.56-0.90; P = .005), 0.81 for ribociclib versus palbociclib (95% CI, 0.65-0.99; P = .048), and 0.91 for abemaciclib versus ribociclib (95% CI, 0.70-1.19; P = .505).
“Regarding subgroup analysis, we found that abemaciclib and ribociclib were more effective than palbociclib in patients with endocrine-resistant or luminal B-like disease, as well as in premenopausal women. Abemaciclib was superior to palbociclib in patients with poorer ECOG [Eastern Cooperative Oncology Group] performance status and to both palbociclib and ribociclib in patients with de novo metastatic disease. Both ribociclib and abemaciclib showed a trend toward higher efficacy in patients with liver metastases. However, this difference only reached statistical significance in patients treated with ribociclib. And finally, the three CDK4/6 inhibitors were similarly effective in patients who were older or at bone-only disease,” he concluded.
Justifying adjustment
Speaking during the audience question period Giuseppe Del Priore, MD, from Morehouse School of Medicine in Atlanta, Georgia, said he preferred unadjusted results when examining real-world data, “because that’s the benefit,” and he questioned why the researchers had adjusted their numbers.
Dr. Vernieri explained that the adjustments were made to account for the important imbalances in the baseline characteristics of the patients.
“When we plotted unadjusted curves, we did not find statistically significant differences between these three drugs, only a trend toward the direction that I showed you today,” he said. “However, as you saw from the tables showing the characteristics of patients, there were important imbalances in terms of important prognostic factors in the three patient cohorts. So, I think that, for this kind of data and based on this level of imbalance, adjustment is necessary.
“To reinforce our conclusions, what we did was also to perform a propensity score match–based analysis,” Dr. Vernieri continued. “I did not have the time to show the results today, but these data were fully in line with the study conclusions. And we also performed a backward selection of variables. So, we basically selected variables more likely to be associated with patient prognosis. And also those models confirm the study conclusion. So I think the conclusions are quite solid.”
Dr. Del Priore, an adjunct professor of obstetrics and gynecology with a specialty in oncology, on the other hand, said he was not convinced that any of the drugs might be better or worse in the actual population treated.
“I still maintain that unadjusted real-world data should be presented and then only a limited adjusted analysis performed using the most unbalanced variables,” he said. “To do more elaborate adjustments may falsely imply a difference in drug choice and outcomes which never should be the conclusion with observational studies. Instead, the conclusions should be that, with typical use, the following similarities in PFS and OS were observed. Then point out how drug choice and important prognostic variables might be linked, thus limiting the generalizable conclusions even further.
“I would conclude that prospective studies should balance for the variables used in the PALMARES-2 analyses, which actually may have been chosen for adjustment post hoc,” Dr. Del Priore said.
The study was funded by the Italian Association for Cancer Research, the European Research Council, the Ministero della Salute, the Scientific Directorate of Fondazione IRCCS Istituto Nazionale dei Tumori, Giuliani’s Foundation and Roche. Dr. Vernieri reported consulting or advisory roles with Daiichi Sankyo/Astra Zeneca, Novartis, and Pfizer; speakers’ bureau roles with Accademia Nazionale Di Medicina (ACCMED), Istituto Gentili, Lilly and Novartis; and research funding from Roche. Dr. Del Priore reported no conflicts of interest and disclosed that he is chief medical officer at BriaCell.
FROM ASCO 2024
Blood Biomarkers Are Highly Accurate in Diagnosing Alzheimer’s Disease
PHILADELPHIA — new research showed.
Accurate early diagnosis of Alzheimer’s disease is important because two monoclonal antibodies donanemab (Kisunla) and lecanemab (Leqembi) are now approved by the Food and Drug Administration (FDA) for early-stage Alzheimer’s disease. However, the use of these agents requires amyloid confirmation.
A key finding of the study was that primary care physicians had a diagnostic accuracy of 61%, and dementia specialists had an accuracy of 73%, after completing standard clinical evaluations and before seeing results of the blood test or other Alzheimer’s disease biomarkers, while the blood test used in the study had an accuracy of 91% for correctly classifying clinical, biomarker-verified Alzheimer’s disease.
“This underscores the potential improvement in diagnostic accuracy, especially in primary care, when implementing such a blood test,” said study investigator Sebastian Palmqvist, MD, PhD, associate professor of neurology at Lund University, Lund, and a consultant at Skåne University Hospital, Malmö, Sweden. “It also highlights the challenges in accurately identifying Alzheimer’s disease based solely on clinical evaluation and cognitive testing, even for specialists.”
The findings were presented at the 2024 Alzheimer’s Association International Conference (AAIC) and simultaneously published online in JAMA.
The study included two cohorts from primary and secondary care clinics in Sweden. Researchers analyzed plasma samples together at one time point in a single batch.
It also included two cohorts from Swedish primary and secondary care clinics where the plasma samples were analyzed prospectively (biweekly) in batches throughout the enrollment period, which more closely resembles clinical practice.
Primary care physicians and dementia specialists documented whether they believed their patients had Alzheimer’s disease pathology, basing the diagnoses on the standard evaluation that includes clinical examination, cognitive testing, and a CT scan prior to seeing any Alzheimer’s disease biomarker results.
They reported their certainty of the presence of Alzheimer’s disease pathology on a scale from 0 (not at all certain) to 10 (completely certain).
Plasma analyses were performed by personnel blinded to all clinical or biomarker data. Mass spectrometry assays were used to analyze Abeta42, Abeta40, phosphorylated tau 217 (p-tau217), and non–p-tau217.
Biomarkers used in the study included the percentage of plasma p-tau217, which is the ratio of p-tau217 relative to non–p-tau217, and the Abeta42 to Abeta40 ratio (the amyloid probability score 2 [APS2]). Researchers determined p-tau217 alone and when combined with the APS2.
The study included 1213 patients with cognitive symptoms — mean age 74.2 years and 48% women. Researchers applied biomarker cutoff values to the primary care cohort (n = 307) and the secondary care cohort (n = 300) and then evaluated the blood test prospectively in the primary care cohort (n = 208) and the secondary care cohort (n = 398).
The blood biomarker cutoff value was set at 90% specificity for Alzheimer’s disease pathology (the 1 cutoff-value approach). A 2 cutoff-value approach (using 1 upper and 1 lower cutoff value) was also used with values corresponding to 95% sensitivity and 95% specificity.
The primary outcome was presence of Alzheimer’s disease pathology. A positive finding of the Abeta biomarker was defined according to the FDA-approved cutoff value (≤ 0.072). A positive finding of the tau biomarker was defined as a p-tau217 level > 11.42 pg/mL in cerebrospinal fluid.
Researchers calculated the positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy, as well as area under the curve (AUC) values.
Accuracy in Specialty Versus Primary Care
When the plasma samples were analyzed in a single batch in the primary care cohort, the AUC was 0.97 when the APS2 was used. In the secondary care cohort, the AUC was 0.96 when the APS2 was used.
When plasma samples were analyzed prospectively (biweekly) in the primary care cohort, the AUC was 0.96 when the APS2 was used. In the secondary care cohort, the AUC was 0.97 when the APS2 was used.
The 2 cutoff-value approach achieved PPVs of 97%-99% in patients with cognitive impairment, which is the target population of currently available antiamyloid treatments.
Although NPVs were slightly lower in these patients (87%-92% using the APS2), “we argue that a very high positive predictive value is probably more important in diagnosing patients as having Alzheimer’s disease, especially before initiating costly and burdensome antiamyloid treatment,” the investigators noted.
The PPVs were less than optimal for accurate identification of Alzheimer’s disease pathology in patients with subjective cognitive decline regardless of the cutoff-value approach used. The researchers pointed out that this could be a disadvantage for clinical trials that include patients with presymptomatic Alzheimer’s disease but not in clinical practice because there are no clinical criteria for diagnosing Alzheimer’s disease at the subjective cognitive decline stage.
The NPVs were higher in patients with subjective cognitive decline (91%-94% for the APS2 or percentage of p-tau217 alone). This indicates the blood test would be more useful for ruling out underlying Alzheimer’s disease when only subtle symptoms are present, the researchers noted.
As for doctors identifying clinical Alzheimer’s disease, primary care physicians had a diagnostic accuracy of 61% (95% CI, 53%-69%) versus 91% (95% CI, 86%-96%) using the APS2. Dementia specialists had a diagnostic accuracy of 73% (95% CI, 68%-79%) versus 91% (95% CI, 86%-95%) using the APS2.
In the overall population, the diagnostic accuracy using the APS2 (90%; 95% CI, 88%-92%) was not different from that using the percentage of p-tau217 alone (90%; 95% CI, 88%-91%).
Very little was known about how a blood test would perform in a primary care setting, said Dr. Palmqvist. “Seeing that the test was just as accurate in primary care (about 90%) as it was in secondary care is really encouraging, especially since primary care is the first, and often final, point of entry into the healthcare system for cognitive evaluations.”
He said he was surprised the biomarkers performed so well in prospective, biweekly analyses throughout the study. “Previous studies have only demonstrated their effectiveness when all collected samples are analyzed at a single time point, which does not reflect how a blood test is used in clinical practice.”
He added that he was surprised that the tests were just as accurate in primary care as in a memory clinic setting with referred patients. This, despite older age and higher prevalence of comorbidities in primary care, such as chronic kidney disease (present in 26% of the primary care cohort), can be a confounding factor causing increased concentrations of p-tau217.
Next Steps
The diagnostic accuracy of the blood tests is on par with FDA-cleared cerebrospinal fluid biomarkers, noted the investigators, led by senior author Oskar Hansson, MD, PhD, Clinical Memory Research Unit, Department of Clinical Sciences Malm
As blood tests are “more time effective, cost effective, and convenient” for patients, “they could also potentially replace cerebrospinal fluid tests and PET,” they added.
Dr. Palmqvist emphasized that these tests should not be used as stand-alone diagnostic tools for Alzheimer’s disease but should complement the standard clinical evaluation that includes cognitive testing and a thorough interview with the patient and a spouse or relative.
“This is crucial because Alzheimer’s disease pathology can be asymptomatic for many years, and cognitive symptoms in some patients with Alzheimer’s disease pathology may primarily result from other conditions. Misinterpreting a positive Alzheimer’s disease blood test could lead to underdiagnosis of common non–Alzheimer’s disease conditions.”
With new antiamyloid treatments possibly slowing disease progression by 30%-40% when initiated early on, a blood test for Alzheimer’s disease could lead to more people receiving an accurate and earlier diagnosis, said Dr. Palmqvist. “This could potentially result in a better response to treatment. Results from drug trials clearly indicate that the earlier treatment begins, the more effectively it can slow disease progression.”
The test used in the study is already available in the United States, the investigators said, and a similar test will be accessible in Sweden within a few months. “However, the rollout will probably be gradual and will depend on how international and national guidelines recommend their use, so developing these guidelines will be a crucial next step for widespread implementation, particularly in primary care,” said Dr. Palmqvist.
He also underlined the importance of replicating the findings in more diverse populations. “This will help ensure the tests’ reliability and effectiveness across various demographic and clinical contexts.”
An important next research step is to examine how implementing a blood test for Alzheimer’s disease affects patient care. “This includes looking at changes in management, such as referrals, other examinations, and the initiation of appropriate treatments,” said Dr. Palmqvist.
Another study presented at the meeting showed that a highly accurate blood test could significantly reduce diagnostic wait times.
Convincing Research
In an accompanying editorial, Stephen Salloway, MD, Departments of Psychiatry and Neurology, Warren Alpert Medical School, Brown University, Providence, Rhode Island, and colleagues said the study “makes the case convincingly that highly sensitive blood measures of Alzheimer’s disease can be integrated into the clinical decision-making process, including in the primary care setting.”
These tests, they wrote, “can be used to enhance the ability of clinicians to accurately identify individuals with cognitive impairment and dementia due to Alzheimer’s disease.
“Current practice should focus on using these blood biomarkers in individuals with cognitive impairment rather than in those with normal cognition or subjective cognitive decline until further research demonstrates effective interventions for individuals considered cognitively normal with elevated levels of amyloid.”
A key limitation of the study was the lack of diversity in the study sample. This makes it difficult to generalize the results across other ethnic and racial groups, the editorialists noted. Plasma assays for Alzheimer’s disease in the United States will require approval from the FDA and coverage by the Centers for Medicare & Medicaid Services to be widely adopted.
The editorialists also pointed out that advances in the diagnosis and treatment of Alzheimer’s disease will require important changes to healthcare models, including providing additional resources and staffing.
The study was supported by the Alzheimer’s Association, National Institute on Aging, European Research Council, Swedish Research Council, the GHR Foundation, and other groups. The study was conducted as an academic collaboration between Lund University and C2N Diagnostics in the United States. Lund University or its affiliated researchers received no funding or compensation from C2N Diagnostics. C2N Diagnostics performed the plasma analyses blinded to any biomarker or clinical data and had no role in the statistical analysis or results. Dr. Palmqvist reported receiving institutional research support from ki:elements, Alzheimer’s Drug Discovery Foundation, and Avid Radiopharmaceuticals and consultancy or speaker fees from BioArctic, Biogen, Esai, Eli Lilly, and Roche. Dr. Hansson reported receiving personal fees from AC Immune, ALZpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Roche, Bristol-Myers Squibb, Merck, Novartis, Novo Nordisk, Roche, Sanofi, and Siemens and institutional research support from ADX, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche. Dr. Salloway reported receiving grants from Biogen, Roche, Lilly, Genentech, Eisai, and Novartis; personal fees from Biogen, Roche, Lilly, Genentech, Eisai, Novo Nordisk, Prothena, AbbVie, Acumen, and Kisbee; and nonfinancial support (travel expenses for conference attendance) from Biogen, Roche, Lilly, and Acumen.
A version of this article appeared on Medscape.com.
PHILADELPHIA — new research showed.
Accurate early diagnosis of Alzheimer’s disease is important because two monoclonal antibodies donanemab (Kisunla) and lecanemab (Leqembi) are now approved by the Food and Drug Administration (FDA) for early-stage Alzheimer’s disease. However, the use of these agents requires amyloid confirmation.
A key finding of the study was that primary care physicians had a diagnostic accuracy of 61%, and dementia specialists had an accuracy of 73%, after completing standard clinical evaluations and before seeing results of the blood test or other Alzheimer’s disease biomarkers, while the blood test used in the study had an accuracy of 91% for correctly classifying clinical, biomarker-verified Alzheimer’s disease.
“This underscores the potential improvement in diagnostic accuracy, especially in primary care, when implementing such a blood test,” said study investigator Sebastian Palmqvist, MD, PhD, associate professor of neurology at Lund University, Lund, and a consultant at Skåne University Hospital, Malmö, Sweden. “It also highlights the challenges in accurately identifying Alzheimer’s disease based solely on clinical evaluation and cognitive testing, even for specialists.”
The findings were presented at the 2024 Alzheimer’s Association International Conference (AAIC) and simultaneously published online in JAMA.
The study included two cohorts from primary and secondary care clinics in Sweden. Researchers analyzed plasma samples together at one time point in a single batch.
It also included two cohorts from Swedish primary and secondary care clinics where the plasma samples were analyzed prospectively (biweekly) in batches throughout the enrollment period, which more closely resembles clinical practice.
Primary care physicians and dementia specialists documented whether they believed their patients had Alzheimer’s disease pathology, basing the diagnoses on the standard evaluation that includes clinical examination, cognitive testing, and a CT scan prior to seeing any Alzheimer’s disease biomarker results.
They reported their certainty of the presence of Alzheimer’s disease pathology on a scale from 0 (not at all certain) to 10 (completely certain).
Plasma analyses were performed by personnel blinded to all clinical or biomarker data. Mass spectrometry assays were used to analyze Abeta42, Abeta40, phosphorylated tau 217 (p-tau217), and non–p-tau217.
Biomarkers used in the study included the percentage of plasma p-tau217, which is the ratio of p-tau217 relative to non–p-tau217, and the Abeta42 to Abeta40 ratio (the amyloid probability score 2 [APS2]). Researchers determined p-tau217 alone and when combined with the APS2.
The study included 1213 patients with cognitive symptoms — mean age 74.2 years and 48% women. Researchers applied biomarker cutoff values to the primary care cohort (n = 307) and the secondary care cohort (n = 300) and then evaluated the blood test prospectively in the primary care cohort (n = 208) and the secondary care cohort (n = 398).
The blood biomarker cutoff value was set at 90% specificity for Alzheimer’s disease pathology (the 1 cutoff-value approach). A 2 cutoff-value approach (using 1 upper and 1 lower cutoff value) was also used with values corresponding to 95% sensitivity and 95% specificity.
The primary outcome was presence of Alzheimer’s disease pathology. A positive finding of the Abeta biomarker was defined according to the FDA-approved cutoff value (≤ 0.072). A positive finding of the tau biomarker was defined as a p-tau217 level > 11.42 pg/mL in cerebrospinal fluid.
Researchers calculated the positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy, as well as area under the curve (AUC) values.
Accuracy in Specialty Versus Primary Care
When the plasma samples were analyzed in a single batch in the primary care cohort, the AUC was 0.97 when the APS2 was used. In the secondary care cohort, the AUC was 0.96 when the APS2 was used.
When plasma samples were analyzed prospectively (biweekly) in the primary care cohort, the AUC was 0.96 when the APS2 was used. In the secondary care cohort, the AUC was 0.97 when the APS2 was used.
The 2 cutoff-value approach achieved PPVs of 97%-99% in patients with cognitive impairment, which is the target population of currently available antiamyloid treatments.
Although NPVs were slightly lower in these patients (87%-92% using the APS2), “we argue that a very high positive predictive value is probably more important in diagnosing patients as having Alzheimer’s disease, especially before initiating costly and burdensome antiamyloid treatment,” the investigators noted.
The PPVs were less than optimal for accurate identification of Alzheimer’s disease pathology in patients with subjective cognitive decline regardless of the cutoff-value approach used. The researchers pointed out that this could be a disadvantage for clinical trials that include patients with presymptomatic Alzheimer’s disease but not in clinical practice because there are no clinical criteria for diagnosing Alzheimer’s disease at the subjective cognitive decline stage.
The NPVs were higher in patients with subjective cognitive decline (91%-94% for the APS2 or percentage of p-tau217 alone). This indicates the blood test would be more useful for ruling out underlying Alzheimer’s disease when only subtle symptoms are present, the researchers noted.
As for doctors identifying clinical Alzheimer’s disease, primary care physicians had a diagnostic accuracy of 61% (95% CI, 53%-69%) versus 91% (95% CI, 86%-96%) using the APS2. Dementia specialists had a diagnostic accuracy of 73% (95% CI, 68%-79%) versus 91% (95% CI, 86%-95%) using the APS2.
In the overall population, the diagnostic accuracy using the APS2 (90%; 95% CI, 88%-92%) was not different from that using the percentage of p-tau217 alone (90%; 95% CI, 88%-91%).
Very little was known about how a blood test would perform in a primary care setting, said Dr. Palmqvist. “Seeing that the test was just as accurate in primary care (about 90%) as it was in secondary care is really encouraging, especially since primary care is the first, and often final, point of entry into the healthcare system for cognitive evaluations.”
He said he was surprised the biomarkers performed so well in prospective, biweekly analyses throughout the study. “Previous studies have only demonstrated their effectiveness when all collected samples are analyzed at a single time point, which does not reflect how a blood test is used in clinical practice.”
He added that he was surprised that the tests were just as accurate in primary care as in a memory clinic setting with referred patients. This, despite older age and higher prevalence of comorbidities in primary care, such as chronic kidney disease (present in 26% of the primary care cohort), can be a confounding factor causing increased concentrations of p-tau217.
Next Steps
The diagnostic accuracy of the blood tests is on par with FDA-cleared cerebrospinal fluid biomarkers, noted the investigators, led by senior author Oskar Hansson, MD, PhD, Clinical Memory Research Unit, Department of Clinical Sciences Malm
As blood tests are “more time effective, cost effective, and convenient” for patients, “they could also potentially replace cerebrospinal fluid tests and PET,” they added.
Dr. Palmqvist emphasized that these tests should not be used as stand-alone diagnostic tools for Alzheimer’s disease but should complement the standard clinical evaluation that includes cognitive testing and a thorough interview with the patient and a spouse or relative.
“This is crucial because Alzheimer’s disease pathology can be asymptomatic for many years, and cognitive symptoms in some patients with Alzheimer’s disease pathology may primarily result from other conditions. Misinterpreting a positive Alzheimer’s disease blood test could lead to underdiagnosis of common non–Alzheimer’s disease conditions.”
With new antiamyloid treatments possibly slowing disease progression by 30%-40% when initiated early on, a blood test for Alzheimer’s disease could lead to more people receiving an accurate and earlier diagnosis, said Dr. Palmqvist. “This could potentially result in a better response to treatment. Results from drug trials clearly indicate that the earlier treatment begins, the more effectively it can slow disease progression.”
The test used in the study is already available in the United States, the investigators said, and a similar test will be accessible in Sweden within a few months. “However, the rollout will probably be gradual and will depend on how international and national guidelines recommend their use, so developing these guidelines will be a crucial next step for widespread implementation, particularly in primary care,” said Dr. Palmqvist.
He also underlined the importance of replicating the findings in more diverse populations. “This will help ensure the tests’ reliability and effectiveness across various demographic and clinical contexts.”
An important next research step is to examine how implementing a blood test for Alzheimer’s disease affects patient care. “This includes looking at changes in management, such as referrals, other examinations, and the initiation of appropriate treatments,” said Dr. Palmqvist.
Another study presented at the meeting showed that a highly accurate blood test could significantly reduce diagnostic wait times.
Convincing Research
In an accompanying editorial, Stephen Salloway, MD, Departments of Psychiatry and Neurology, Warren Alpert Medical School, Brown University, Providence, Rhode Island, and colleagues said the study “makes the case convincingly that highly sensitive blood measures of Alzheimer’s disease can be integrated into the clinical decision-making process, including in the primary care setting.”
These tests, they wrote, “can be used to enhance the ability of clinicians to accurately identify individuals with cognitive impairment and dementia due to Alzheimer’s disease.
“Current practice should focus on using these blood biomarkers in individuals with cognitive impairment rather than in those with normal cognition or subjective cognitive decline until further research demonstrates effective interventions for individuals considered cognitively normal with elevated levels of amyloid.”
A key limitation of the study was the lack of diversity in the study sample. This makes it difficult to generalize the results across other ethnic and racial groups, the editorialists noted. Plasma assays for Alzheimer’s disease in the United States will require approval from the FDA and coverage by the Centers for Medicare & Medicaid Services to be widely adopted.
The editorialists also pointed out that advances in the diagnosis and treatment of Alzheimer’s disease will require important changes to healthcare models, including providing additional resources and staffing.
The study was supported by the Alzheimer’s Association, National Institute on Aging, European Research Council, Swedish Research Council, the GHR Foundation, and other groups. The study was conducted as an academic collaboration between Lund University and C2N Diagnostics in the United States. Lund University or its affiliated researchers received no funding or compensation from C2N Diagnostics. C2N Diagnostics performed the plasma analyses blinded to any biomarker or clinical data and had no role in the statistical analysis or results. Dr. Palmqvist reported receiving institutional research support from ki:elements, Alzheimer’s Drug Discovery Foundation, and Avid Radiopharmaceuticals and consultancy or speaker fees from BioArctic, Biogen, Esai, Eli Lilly, and Roche. Dr. Hansson reported receiving personal fees from AC Immune, ALZpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Roche, Bristol-Myers Squibb, Merck, Novartis, Novo Nordisk, Roche, Sanofi, and Siemens and institutional research support from ADX, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche. Dr. Salloway reported receiving grants from Biogen, Roche, Lilly, Genentech, Eisai, and Novartis; personal fees from Biogen, Roche, Lilly, Genentech, Eisai, Novo Nordisk, Prothena, AbbVie, Acumen, and Kisbee; and nonfinancial support (travel expenses for conference attendance) from Biogen, Roche, Lilly, and Acumen.
A version of this article appeared on Medscape.com.
PHILADELPHIA — new research showed.
Accurate early diagnosis of Alzheimer’s disease is important because two monoclonal antibodies donanemab (Kisunla) and lecanemab (Leqembi) are now approved by the Food and Drug Administration (FDA) for early-stage Alzheimer’s disease. However, the use of these agents requires amyloid confirmation.
A key finding of the study was that primary care physicians had a diagnostic accuracy of 61%, and dementia specialists had an accuracy of 73%, after completing standard clinical evaluations and before seeing results of the blood test or other Alzheimer’s disease biomarkers, while the blood test used in the study had an accuracy of 91% for correctly classifying clinical, biomarker-verified Alzheimer’s disease.
“This underscores the potential improvement in diagnostic accuracy, especially in primary care, when implementing such a blood test,” said study investigator Sebastian Palmqvist, MD, PhD, associate professor of neurology at Lund University, Lund, and a consultant at Skåne University Hospital, Malmö, Sweden. “It also highlights the challenges in accurately identifying Alzheimer’s disease based solely on clinical evaluation and cognitive testing, even for specialists.”
The findings were presented at the 2024 Alzheimer’s Association International Conference (AAIC) and simultaneously published online in JAMA.
The study included two cohorts from primary and secondary care clinics in Sweden. Researchers analyzed plasma samples together at one time point in a single batch.
It also included two cohorts from Swedish primary and secondary care clinics where the plasma samples were analyzed prospectively (biweekly) in batches throughout the enrollment period, which more closely resembles clinical practice.
Primary care physicians and dementia specialists documented whether they believed their patients had Alzheimer’s disease pathology, basing the diagnoses on the standard evaluation that includes clinical examination, cognitive testing, and a CT scan prior to seeing any Alzheimer’s disease biomarker results.
They reported their certainty of the presence of Alzheimer’s disease pathology on a scale from 0 (not at all certain) to 10 (completely certain).
Plasma analyses were performed by personnel blinded to all clinical or biomarker data. Mass spectrometry assays were used to analyze Abeta42, Abeta40, phosphorylated tau 217 (p-tau217), and non–p-tau217.
Biomarkers used in the study included the percentage of plasma p-tau217, which is the ratio of p-tau217 relative to non–p-tau217, and the Abeta42 to Abeta40 ratio (the amyloid probability score 2 [APS2]). Researchers determined p-tau217 alone and when combined with the APS2.
The study included 1213 patients with cognitive symptoms — mean age 74.2 years and 48% women. Researchers applied biomarker cutoff values to the primary care cohort (n = 307) and the secondary care cohort (n = 300) and then evaluated the blood test prospectively in the primary care cohort (n = 208) and the secondary care cohort (n = 398).
The blood biomarker cutoff value was set at 90% specificity for Alzheimer’s disease pathology (the 1 cutoff-value approach). A 2 cutoff-value approach (using 1 upper and 1 lower cutoff value) was also used with values corresponding to 95% sensitivity and 95% specificity.
The primary outcome was presence of Alzheimer’s disease pathology. A positive finding of the Abeta biomarker was defined according to the FDA-approved cutoff value (≤ 0.072). A positive finding of the tau biomarker was defined as a p-tau217 level > 11.42 pg/mL in cerebrospinal fluid.
Researchers calculated the positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy, as well as area under the curve (AUC) values.
Accuracy in Specialty Versus Primary Care
When the plasma samples were analyzed in a single batch in the primary care cohort, the AUC was 0.97 when the APS2 was used. In the secondary care cohort, the AUC was 0.96 when the APS2 was used.
When plasma samples were analyzed prospectively (biweekly) in the primary care cohort, the AUC was 0.96 when the APS2 was used. In the secondary care cohort, the AUC was 0.97 when the APS2 was used.
The 2 cutoff-value approach achieved PPVs of 97%-99% in patients with cognitive impairment, which is the target population of currently available antiamyloid treatments.
Although NPVs were slightly lower in these patients (87%-92% using the APS2), “we argue that a very high positive predictive value is probably more important in diagnosing patients as having Alzheimer’s disease, especially before initiating costly and burdensome antiamyloid treatment,” the investigators noted.
The PPVs were less than optimal for accurate identification of Alzheimer’s disease pathology in patients with subjective cognitive decline regardless of the cutoff-value approach used. The researchers pointed out that this could be a disadvantage for clinical trials that include patients with presymptomatic Alzheimer’s disease but not in clinical practice because there are no clinical criteria for diagnosing Alzheimer’s disease at the subjective cognitive decline stage.
The NPVs were higher in patients with subjective cognitive decline (91%-94% for the APS2 or percentage of p-tau217 alone). This indicates the blood test would be more useful for ruling out underlying Alzheimer’s disease when only subtle symptoms are present, the researchers noted.
As for doctors identifying clinical Alzheimer’s disease, primary care physicians had a diagnostic accuracy of 61% (95% CI, 53%-69%) versus 91% (95% CI, 86%-96%) using the APS2. Dementia specialists had a diagnostic accuracy of 73% (95% CI, 68%-79%) versus 91% (95% CI, 86%-95%) using the APS2.
In the overall population, the diagnostic accuracy using the APS2 (90%; 95% CI, 88%-92%) was not different from that using the percentage of p-tau217 alone (90%; 95% CI, 88%-91%).
Very little was known about how a blood test would perform in a primary care setting, said Dr. Palmqvist. “Seeing that the test was just as accurate in primary care (about 90%) as it was in secondary care is really encouraging, especially since primary care is the first, and often final, point of entry into the healthcare system for cognitive evaluations.”
He said he was surprised the biomarkers performed so well in prospective, biweekly analyses throughout the study. “Previous studies have only demonstrated their effectiveness when all collected samples are analyzed at a single time point, which does not reflect how a blood test is used in clinical practice.”
He added that he was surprised that the tests were just as accurate in primary care as in a memory clinic setting with referred patients. This, despite older age and higher prevalence of comorbidities in primary care, such as chronic kidney disease (present in 26% of the primary care cohort), can be a confounding factor causing increased concentrations of p-tau217.
Next Steps
The diagnostic accuracy of the blood tests is on par with FDA-cleared cerebrospinal fluid biomarkers, noted the investigators, led by senior author Oskar Hansson, MD, PhD, Clinical Memory Research Unit, Department of Clinical Sciences Malm
As blood tests are “more time effective, cost effective, and convenient” for patients, “they could also potentially replace cerebrospinal fluid tests and PET,” they added.
Dr. Palmqvist emphasized that these tests should not be used as stand-alone diagnostic tools for Alzheimer’s disease but should complement the standard clinical evaluation that includes cognitive testing and a thorough interview with the patient and a spouse or relative.
“This is crucial because Alzheimer’s disease pathology can be asymptomatic for many years, and cognitive symptoms in some patients with Alzheimer’s disease pathology may primarily result from other conditions. Misinterpreting a positive Alzheimer’s disease blood test could lead to underdiagnosis of common non–Alzheimer’s disease conditions.”
With new antiamyloid treatments possibly slowing disease progression by 30%-40% when initiated early on, a blood test for Alzheimer’s disease could lead to more people receiving an accurate and earlier diagnosis, said Dr. Palmqvist. “This could potentially result in a better response to treatment. Results from drug trials clearly indicate that the earlier treatment begins, the more effectively it can slow disease progression.”
The test used in the study is already available in the United States, the investigators said, and a similar test will be accessible in Sweden within a few months. “However, the rollout will probably be gradual and will depend on how international and national guidelines recommend their use, so developing these guidelines will be a crucial next step for widespread implementation, particularly in primary care,” said Dr. Palmqvist.
He also underlined the importance of replicating the findings in more diverse populations. “This will help ensure the tests’ reliability and effectiveness across various demographic and clinical contexts.”
An important next research step is to examine how implementing a blood test for Alzheimer’s disease affects patient care. “This includes looking at changes in management, such as referrals, other examinations, and the initiation of appropriate treatments,” said Dr. Palmqvist.
Another study presented at the meeting showed that a highly accurate blood test could significantly reduce diagnostic wait times.
Convincing Research
In an accompanying editorial, Stephen Salloway, MD, Departments of Psychiatry and Neurology, Warren Alpert Medical School, Brown University, Providence, Rhode Island, and colleagues said the study “makes the case convincingly that highly sensitive blood measures of Alzheimer’s disease can be integrated into the clinical decision-making process, including in the primary care setting.”
These tests, they wrote, “can be used to enhance the ability of clinicians to accurately identify individuals with cognitive impairment and dementia due to Alzheimer’s disease.
“Current practice should focus on using these blood biomarkers in individuals with cognitive impairment rather than in those with normal cognition or subjective cognitive decline until further research demonstrates effective interventions for individuals considered cognitively normal with elevated levels of amyloid.”
A key limitation of the study was the lack of diversity in the study sample. This makes it difficult to generalize the results across other ethnic and racial groups, the editorialists noted. Plasma assays for Alzheimer’s disease in the United States will require approval from the FDA and coverage by the Centers for Medicare & Medicaid Services to be widely adopted.
The editorialists also pointed out that advances in the diagnosis and treatment of Alzheimer’s disease will require important changes to healthcare models, including providing additional resources and staffing.
The study was supported by the Alzheimer’s Association, National Institute on Aging, European Research Council, Swedish Research Council, the GHR Foundation, and other groups. The study was conducted as an academic collaboration between Lund University and C2N Diagnostics in the United States. Lund University or its affiliated researchers received no funding or compensation from C2N Diagnostics. C2N Diagnostics performed the plasma analyses blinded to any biomarker or clinical data and had no role in the statistical analysis or results. Dr. Palmqvist reported receiving institutional research support from ki:elements, Alzheimer’s Drug Discovery Foundation, and Avid Radiopharmaceuticals and consultancy or speaker fees from BioArctic, Biogen, Esai, Eli Lilly, and Roche. Dr. Hansson reported receiving personal fees from AC Immune, ALZpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Roche, Bristol-Myers Squibb, Merck, Novartis, Novo Nordisk, Roche, Sanofi, and Siemens and institutional research support from ADX, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche. Dr. Salloway reported receiving grants from Biogen, Roche, Lilly, Genentech, Eisai, and Novartis; personal fees from Biogen, Roche, Lilly, Genentech, Eisai, Novo Nordisk, Prothena, AbbVie, Acumen, and Kisbee; and nonfinancial support (travel expenses for conference attendance) from Biogen, Roche, Lilly, and Acumen.
A version of this article appeared on Medscape.com.
FROM AAIC 2024
Elevate Your Career: AGA Women in GI Regional Workshops Await
As a woman in a dynamic and ever-changing profession, balancing life as a powerhouse physician or scientist is no easy feat. AGA recognizes the challenges you face and is committed to addressing them directly at the AGA Women in GI Regional Workshops. The program has been expanded to six workshops in 2024.
. Participate in candid discussions regarding the challenges you face as a woman navigating the 21st century healthcare environment. Derive inspiration from your community and cultivate meaningful connections that will carry you beyond the workshop.
You may choose to join us in person or virtually, whatever fits into your busy schedule. We are also pleased to offer grants of $300 to support travel and registration fees for trainee and early career women. Additional details for the Maria Leo-Lieber Travel Award may be found in your confirmation email.
Register today for the final three workshops.
Rocky Mountain West
Saturday, Sept. 8
Colorado Springs, Colorado
Deadline to apply for a travel grant: Aug. 23
Deadline to register: Aug. 30
Southwest
Saturday, Sept. 14
Houston, Texas
Deadline to apply for a travel grant: Aug. 30
Deadline to register: Sept. 6
Southeast
Saturday, Nov. 2
Coral Gables, Florida
Deadline to apply for a travel grant: Oct. 8
Deadline to register: Oct. 25
This program is supported by Janssen.
As a woman in a dynamic and ever-changing profession, balancing life as a powerhouse physician or scientist is no easy feat. AGA recognizes the challenges you face and is committed to addressing them directly at the AGA Women in GI Regional Workshops. The program has been expanded to six workshops in 2024.
. Participate in candid discussions regarding the challenges you face as a woman navigating the 21st century healthcare environment. Derive inspiration from your community and cultivate meaningful connections that will carry you beyond the workshop.
You may choose to join us in person or virtually, whatever fits into your busy schedule. We are also pleased to offer grants of $300 to support travel and registration fees for trainee and early career women. Additional details for the Maria Leo-Lieber Travel Award may be found in your confirmation email.
Register today for the final three workshops.
Rocky Mountain West
Saturday, Sept. 8
Colorado Springs, Colorado
Deadline to apply for a travel grant: Aug. 23
Deadline to register: Aug. 30
Southwest
Saturday, Sept. 14
Houston, Texas
Deadline to apply for a travel grant: Aug. 30
Deadline to register: Sept. 6
Southeast
Saturday, Nov. 2
Coral Gables, Florida
Deadline to apply for a travel grant: Oct. 8
Deadline to register: Oct. 25
This program is supported by Janssen.
As a woman in a dynamic and ever-changing profession, balancing life as a powerhouse physician or scientist is no easy feat. AGA recognizes the challenges you face and is committed to addressing them directly at the AGA Women in GI Regional Workshops. The program has been expanded to six workshops in 2024.
. Participate in candid discussions regarding the challenges you face as a woman navigating the 21st century healthcare environment. Derive inspiration from your community and cultivate meaningful connections that will carry you beyond the workshop.
You may choose to join us in person or virtually, whatever fits into your busy schedule. We are also pleased to offer grants of $300 to support travel and registration fees for trainee and early career women. Additional details for the Maria Leo-Lieber Travel Award may be found in your confirmation email.
Register today for the final three workshops.
Rocky Mountain West
Saturday, Sept. 8
Colorado Springs, Colorado
Deadline to apply for a travel grant: Aug. 23
Deadline to register: Aug. 30
Southwest
Saturday, Sept. 14
Houston, Texas
Deadline to apply for a travel grant: Aug. 30
Deadline to register: Sept. 6
Southeast
Saturday, Nov. 2
Coral Gables, Florida
Deadline to apply for a travel grant: Oct. 8
Deadline to register: Oct. 25
This program is supported by Janssen.
Compounded Semaglutide Overdoses Tied to Hospitalizations
Patients are overdosing on compounded semaglutide due to errors in measuring and self-administering the drug and due to clinicians miscalculating doses that may differ from US Food and Drug Administration (FDA)–approved products.
The FDA published an alert on July 26 after receiving reports of dosing errors involving compounded semaglutide injectable products dispensed in multidose vials. Adverse events included gastrointestinal effects, fainting, dehydration, headache, gallstones, and acute pancreatitis. Some patients required hospitalization.
Why the Risks?
FDA-approved semaglutide injectable products are dosed in milligrams, have standard concentrations, and are currently only available in prefilled pens.
Compounded semaglutide products may differ from approved products in ways that contribute to potential errors — for example, in multidose vials and prefilled syringes. In addition, product concentrations may vary depending on the compounder, and even a single compounder may offer multiple concentrations of semaglutide.
Instructions for a compounded drug, if provided, may tell users to administer semaglutide injections in “units,” the volume of which may vary depending on the concentration — rather than in milligrams. In some instances, patients received syringes significantly larger than the prescribed volume.
Common Errors
The FDA has received reports related to patients mistakenly taking more than the prescribed dose from a multidose vial — sometimes 5-20 times more than the intended dose.
Several reports described clinicians incorrectly calculating the intended dose when converting from milligrams to units or milliliters. In one case, a patient couldn’t get clarity on dosing instructions from the telemedicine provider who prescribed the compounded semaglutide, leading the patient to search online for medical advice. This resulted in the patient taking five times the intended dose.
In another example, one clinician prescribed 20 units instead of two units, affecting three patients who, after receiving 10 times the intended dose, experienced nausea and vomiting.
Another clinician, who also takes semaglutide himself, tried to recalculate his own dose in units and ended up self-administering a dose 10 times higher than intended.
The FDA previously warned about potential risks from the use of compounded drugs during a shortage as is the case with semaglutide. While compounded drugs can “sometimes” be helpful, according to the agency, “compounded drugs pose a higher risk to patients than FDA-approved drugs because compounded drugs do not undergo FDA premarket review for safety, effectiveness, or quality.”
Patients are overdosing on compounded semaglutide due to errors in measuring and self-administering the drug and due to clinicians miscalculating doses that may differ from US Food and Drug Administration (FDA)–approved products.
The FDA published an alert on July 26 after receiving reports of dosing errors involving compounded semaglutide injectable products dispensed in multidose vials. Adverse events included gastrointestinal effects, fainting, dehydration, headache, gallstones, and acute pancreatitis. Some patients required hospitalization.
Why the Risks?
FDA-approved semaglutide injectable products are dosed in milligrams, have standard concentrations, and are currently only available in prefilled pens.
Compounded semaglutide products may differ from approved products in ways that contribute to potential errors — for example, in multidose vials and prefilled syringes. In addition, product concentrations may vary depending on the compounder, and even a single compounder may offer multiple concentrations of semaglutide.
Instructions for a compounded drug, if provided, may tell users to administer semaglutide injections in “units,” the volume of which may vary depending on the concentration — rather than in milligrams. In some instances, patients received syringes significantly larger than the prescribed volume.
Common Errors
The FDA has received reports related to patients mistakenly taking more than the prescribed dose from a multidose vial — sometimes 5-20 times more than the intended dose.
Several reports described clinicians incorrectly calculating the intended dose when converting from milligrams to units or milliliters. In one case, a patient couldn’t get clarity on dosing instructions from the telemedicine provider who prescribed the compounded semaglutide, leading the patient to search online for medical advice. This resulted in the patient taking five times the intended dose.
In another example, one clinician prescribed 20 units instead of two units, affecting three patients who, after receiving 10 times the intended dose, experienced nausea and vomiting.
Another clinician, who also takes semaglutide himself, tried to recalculate his own dose in units and ended up self-administering a dose 10 times higher than intended.
The FDA previously warned about potential risks from the use of compounded drugs during a shortage as is the case with semaglutide. While compounded drugs can “sometimes” be helpful, according to the agency, “compounded drugs pose a higher risk to patients than FDA-approved drugs because compounded drugs do not undergo FDA premarket review for safety, effectiveness, or quality.”
Patients are overdosing on compounded semaglutide due to errors in measuring and self-administering the drug and due to clinicians miscalculating doses that may differ from US Food and Drug Administration (FDA)–approved products.
The FDA published an alert on July 26 after receiving reports of dosing errors involving compounded semaglutide injectable products dispensed in multidose vials. Adverse events included gastrointestinal effects, fainting, dehydration, headache, gallstones, and acute pancreatitis. Some patients required hospitalization.
Why the Risks?
FDA-approved semaglutide injectable products are dosed in milligrams, have standard concentrations, and are currently only available in prefilled pens.
Compounded semaglutide products may differ from approved products in ways that contribute to potential errors — for example, in multidose vials and prefilled syringes. In addition, product concentrations may vary depending on the compounder, and even a single compounder may offer multiple concentrations of semaglutide.
Instructions for a compounded drug, if provided, may tell users to administer semaglutide injections in “units,” the volume of which may vary depending on the concentration — rather than in milligrams. In some instances, patients received syringes significantly larger than the prescribed volume.
Common Errors
The FDA has received reports related to patients mistakenly taking more than the prescribed dose from a multidose vial — sometimes 5-20 times more than the intended dose.
Several reports described clinicians incorrectly calculating the intended dose when converting from milligrams to units or milliliters. In one case, a patient couldn’t get clarity on dosing instructions from the telemedicine provider who prescribed the compounded semaglutide, leading the patient to search online for medical advice. This resulted in the patient taking five times the intended dose.
In another example, one clinician prescribed 20 units instead of two units, affecting three patients who, after receiving 10 times the intended dose, experienced nausea and vomiting.
Another clinician, who also takes semaglutide himself, tried to recalculate his own dose in units and ended up self-administering a dose 10 times higher than intended.
The FDA previously warned about potential risks from the use of compounded drugs during a shortage as is the case with semaglutide. While compounded drugs can “sometimes” be helpful, according to the agency, “compounded drugs pose a higher risk to patients than FDA-approved drugs because compounded drugs do not undergo FDA premarket review for safety, effectiveness, or quality.”
Breakthrough Blood Test for Colorectal Cancer Gets Green Light
The FDA on July 29 approved the test, called Shield, which can accurately detect tumors in the colon or rectum about 87% of the time when the cancer is in treatable early stages. The approval was announced July 29 by the test’s maker, Guardant Health, and comes just months after promising clinical trial results were published in The New England Journal of Medicine.
Colorectal cancer is among the most common types of cancer diagnosed in the United States each year, along with being one of the leading causes of cancer deaths. The condition is treatable in early stages, but about 1 in 3 people don’t stay up to date on regular screenings, which should begin at age 45.
The simplicity of a blood test could make it more likely for people to be screened for and, ultimately, survive the disease. Other primary screening options include feces-based tests or colonoscopy. The 5-year survival rate for colorectal cancer is 64%.
While highly accurate at detecting DNA shed by tumors during treatable stages of colorectal cancer, the Shield test was not as effective at detecting precancerous areas of tissue, which are typically removed after being detected.
In its news release, Guardant Health officials said they anticipate the test to be covered under Medicare. The out-of-pocket cost for people whose insurance does not cover the test has not yet been announced. The test is expected to be available by next week, The New York Times reported.
If someone’s Shield test comes back positive, the person would then get more tests to confirm the result. Shield was shown in trials to have a 10% false positive rate.
“I was in for a routine physical, and my doctor asked when I had my last colonoscopy,” said John Gormly, a 77-year-old business executive in Newport Beach, California, according to a Guardant Health news release. “I said it’s been a long time, so he offered to give me the Shield blood test. A few days later, the result came back positive, so he referred me for a colonoscopy. It turned out I had stage II colon cancer. The tumor was removed, and I recovered very quickly. Thank God I had taken that blood test.”
A version of this article appeared on WebMD.com.
The FDA on July 29 approved the test, called Shield, which can accurately detect tumors in the colon or rectum about 87% of the time when the cancer is in treatable early stages. The approval was announced July 29 by the test’s maker, Guardant Health, and comes just months after promising clinical trial results were published in The New England Journal of Medicine.
Colorectal cancer is among the most common types of cancer diagnosed in the United States each year, along with being one of the leading causes of cancer deaths. The condition is treatable in early stages, but about 1 in 3 people don’t stay up to date on regular screenings, which should begin at age 45.
The simplicity of a blood test could make it more likely for people to be screened for and, ultimately, survive the disease. Other primary screening options include feces-based tests or colonoscopy. The 5-year survival rate for colorectal cancer is 64%.
While highly accurate at detecting DNA shed by tumors during treatable stages of colorectal cancer, the Shield test was not as effective at detecting precancerous areas of tissue, which are typically removed after being detected.
In its news release, Guardant Health officials said they anticipate the test to be covered under Medicare. The out-of-pocket cost for people whose insurance does not cover the test has not yet been announced. The test is expected to be available by next week, The New York Times reported.
If someone’s Shield test comes back positive, the person would then get more tests to confirm the result. Shield was shown in trials to have a 10% false positive rate.
“I was in for a routine physical, and my doctor asked when I had my last colonoscopy,” said John Gormly, a 77-year-old business executive in Newport Beach, California, according to a Guardant Health news release. “I said it’s been a long time, so he offered to give me the Shield blood test. A few days later, the result came back positive, so he referred me for a colonoscopy. It turned out I had stage II colon cancer. The tumor was removed, and I recovered very quickly. Thank God I had taken that blood test.”
A version of this article appeared on WebMD.com.
The FDA on July 29 approved the test, called Shield, which can accurately detect tumors in the colon or rectum about 87% of the time when the cancer is in treatable early stages. The approval was announced July 29 by the test’s maker, Guardant Health, and comes just months after promising clinical trial results were published in The New England Journal of Medicine.
Colorectal cancer is among the most common types of cancer diagnosed in the United States each year, along with being one of the leading causes of cancer deaths. The condition is treatable in early stages, but about 1 in 3 people don’t stay up to date on regular screenings, which should begin at age 45.
The simplicity of a blood test could make it more likely for people to be screened for and, ultimately, survive the disease. Other primary screening options include feces-based tests or colonoscopy. The 5-year survival rate for colorectal cancer is 64%.
While highly accurate at detecting DNA shed by tumors during treatable stages of colorectal cancer, the Shield test was not as effective at detecting precancerous areas of tissue, which are typically removed after being detected.
In its news release, Guardant Health officials said they anticipate the test to be covered under Medicare. The out-of-pocket cost for people whose insurance does not cover the test has not yet been announced. The test is expected to be available by next week, The New York Times reported.
If someone’s Shield test comes back positive, the person would then get more tests to confirm the result. Shield was shown in trials to have a 10% false positive rate.
“I was in for a routine physical, and my doctor asked when I had my last colonoscopy,” said John Gormly, a 77-year-old business executive in Newport Beach, California, according to a Guardant Health news release. “I said it’s been a long time, so he offered to give me the Shield blood test. A few days later, the result came back positive, so he referred me for a colonoscopy. It turned out I had stage II colon cancer. The tumor was removed, and I recovered very quickly. Thank God I had taken that blood test.”
A version of this article appeared on WebMD.com.
Alzheimer’s Blood Test in Primary Care Could Slash Diagnostic, Treatment Wait Times
As disease-modifying treatments for Alzheimer’s disease (AD) become available, . Currently, the patient diagnostic journey is often prolonged owing to the limited number of AD specialists, causing concern among healthcare providers and patients alike. Now, a new study suggests that use of high-performing blood tests in primary care could identify potential patients with AD much earlier, possibly reducing wait times for specialist care and receipt of treatment.
“We need to triage in primary care and send preferentially the ones that actually could be eligible for treatment, and not those who are just worried because their grandmother reported that she has Alzheimer’s,” lead researcher Soeren Mattke, MD, DSc, told this news organization.
“By combining a brief cognitive test with an accurate blood test of Alzheimer’s pathology in primary care, we can reduce unnecessary referrals, and shorten appointment wait times,” said Dr. Mattke, director of the Brain Health Observatory at the University of Southern California in Los Angeles.
The findings were presented at the Alzheimer’s Association International Conference (AAIC) 2024.
Projected Wait Times 100 Months by 2033
The investigators used a Markov model to estimate wait times for patients eligible for AD treatment, taking into account constrained capacity for specialist visits.
The model included the projected US population of people aged 55 years or older from 2023 to 2032. It assumed that individuals would undergo a brief cognitive assessment in primary care and, if suggestive of early-stage cognitive impairment, be referred to a AD specialist under three scenarios: no blood test, blood test to rule out AD pathology, and blood test to confirm AD pathology.
According to the model, without an accurate blood test for AD pathology, projected wait times to see a specialist are about 12 months in 2024 and will increase to more than 100 months in 2033, largely owing to a lack of specialist appointments.
In contrast, with the availability of an accurate blood test to rule out AD, average wait times would be just 3 months in 2024 and increase to only about 13 months in 2033, because far fewer patients would need to see a specialist.
Availability of a blood test to rule in AD pathology in primary care would have a limited effect on wait times because 50% of patients would still undergo confirmatory testing based on expert assumptions, the model suggests.
Prioritizing Resources
“Millions of people have mild memory complaints, and if they all start coming to neurologists, it could completely flood the system and create long wait times for everybody,” Dr. Mattke told this news organization.
The problem, he said, is that brief cognitive tests performed in primary care are not particularly specific for mild cognitive impairment.
“They work pretty well for manifest advanced dementia but for mild cognitive impairment, which is a very subtle, symptomatic disease, they are only about 75% accurate. One quarter are false-positives. That’s a lot of people,” Dr. Mattke said.
He also noted that although earlier blood tests were about 75% accurate, they are now about 90% accurate, “so we are getting to a level where we can pretty much say with confidence that this is likely Alzheimer’s,” Dr. Mattke said.
Commenting on this research for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, said it is clear that blood tests, “once confirmed, could have a significant impact on the wait times” for dementia assessment.
“After an initial blood test, we might be able to rule out or rule in individuals who should go to a specialist for further follow-up and testing. This allows us to really ensure that we’re prioritizing resources accordingly,” said Dr. Snyder, who was not involved in the study.
This project was supported by a research contract from C2N Diagnostics LLC to USC. Dr. Mattke serves on the board of directors of Senscio Systems Inc. and the scientific advisory board of ALZPath and Boston Millennia Partners and has received consulting fees from Biogen, C2N, Eisai, Eli Lilly, Novartis, and Roche/Genentech. Dr. Snyder has no relevant disclosures.
A version of this article first appeared on Medscape.com.
As disease-modifying treatments for Alzheimer’s disease (AD) become available, . Currently, the patient diagnostic journey is often prolonged owing to the limited number of AD specialists, causing concern among healthcare providers and patients alike. Now, a new study suggests that use of high-performing blood tests in primary care could identify potential patients with AD much earlier, possibly reducing wait times for specialist care and receipt of treatment.
“We need to triage in primary care and send preferentially the ones that actually could be eligible for treatment, and not those who are just worried because their grandmother reported that she has Alzheimer’s,” lead researcher Soeren Mattke, MD, DSc, told this news organization.
“By combining a brief cognitive test with an accurate blood test of Alzheimer’s pathology in primary care, we can reduce unnecessary referrals, and shorten appointment wait times,” said Dr. Mattke, director of the Brain Health Observatory at the University of Southern California in Los Angeles.
The findings were presented at the Alzheimer’s Association International Conference (AAIC) 2024.
Projected Wait Times 100 Months by 2033
The investigators used a Markov model to estimate wait times for patients eligible for AD treatment, taking into account constrained capacity for specialist visits.
The model included the projected US population of people aged 55 years or older from 2023 to 2032. It assumed that individuals would undergo a brief cognitive assessment in primary care and, if suggestive of early-stage cognitive impairment, be referred to a AD specialist under three scenarios: no blood test, blood test to rule out AD pathology, and blood test to confirm AD pathology.
According to the model, without an accurate blood test for AD pathology, projected wait times to see a specialist are about 12 months in 2024 and will increase to more than 100 months in 2033, largely owing to a lack of specialist appointments.
In contrast, with the availability of an accurate blood test to rule out AD, average wait times would be just 3 months in 2024 and increase to only about 13 months in 2033, because far fewer patients would need to see a specialist.
Availability of a blood test to rule in AD pathology in primary care would have a limited effect on wait times because 50% of patients would still undergo confirmatory testing based on expert assumptions, the model suggests.
Prioritizing Resources
“Millions of people have mild memory complaints, and if they all start coming to neurologists, it could completely flood the system and create long wait times for everybody,” Dr. Mattke told this news organization.
The problem, he said, is that brief cognitive tests performed in primary care are not particularly specific for mild cognitive impairment.
“They work pretty well for manifest advanced dementia but for mild cognitive impairment, which is a very subtle, symptomatic disease, they are only about 75% accurate. One quarter are false-positives. That’s a lot of people,” Dr. Mattke said.
He also noted that although earlier blood tests were about 75% accurate, they are now about 90% accurate, “so we are getting to a level where we can pretty much say with confidence that this is likely Alzheimer’s,” Dr. Mattke said.
Commenting on this research for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, said it is clear that blood tests, “once confirmed, could have a significant impact on the wait times” for dementia assessment.
“After an initial blood test, we might be able to rule out or rule in individuals who should go to a specialist for further follow-up and testing. This allows us to really ensure that we’re prioritizing resources accordingly,” said Dr. Snyder, who was not involved in the study.
This project was supported by a research contract from C2N Diagnostics LLC to USC. Dr. Mattke serves on the board of directors of Senscio Systems Inc. and the scientific advisory board of ALZPath and Boston Millennia Partners and has received consulting fees from Biogen, C2N, Eisai, Eli Lilly, Novartis, and Roche/Genentech. Dr. Snyder has no relevant disclosures.
A version of this article first appeared on Medscape.com.
As disease-modifying treatments for Alzheimer’s disease (AD) become available, . Currently, the patient diagnostic journey is often prolonged owing to the limited number of AD specialists, causing concern among healthcare providers and patients alike. Now, a new study suggests that use of high-performing blood tests in primary care could identify potential patients with AD much earlier, possibly reducing wait times for specialist care and receipt of treatment.
“We need to triage in primary care and send preferentially the ones that actually could be eligible for treatment, and not those who are just worried because their grandmother reported that she has Alzheimer’s,” lead researcher Soeren Mattke, MD, DSc, told this news organization.
“By combining a brief cognitive test with an accurate blood test of Alzheimer’s pathology in primary care, we can reduce unnecessary referrals, and shorten appointment wait times,” said Dr. Mattke, director of the Brain Health Observatory at the University of Southern California in Los Angeles.
The findings were presented at the Alzheimer’s Association International Conference (AAIC) 2024.
Projected Wait Times 100 Months by 2033
The investigators used a Markov model to estimate wait times for patients eligible for AD treatment, taking into account constrained capacity for specialist visits.
The model included the projected US population of people aged 55 years or older from 2023 to 2032. It assumed that individuals would undergo a brief cognitive assessment in primary care and, if suggestive of early-stage cognitive impairment, be referred to a AD specialist under three scenarios: no blood test, blood test to rule out AD pathology, and blood test to confirm AD pathology.
According to the model, without an accurate blood test for AD pathology, projected wait times to see a specialist are about 12 months in 2024 and will increase to more than 100 months in 2033, largely owing to a lack of specialist appointments.
In contrast, with the availability of an accurate blood test to rule out AD, average wait times would be just 3 months in 2024 and increase to only about 13 months in 2033, because far fewer patients would need to see a specialist.
Availability of a blood test to rule in AD pathology in primary care would have a limited effect on wait times because 50% of patients would still undergo confirmatory testing based on expert assumptions, the model suggests.
Prioritizing Resources
“Millions of people have mild memory complaints, and if they all start coming to neurologists, it could completely flood the system and create long wait times for everybody,” Dr. Mattke told this news organization.
The problem, he said, is that brief cognitive tests performed in primary care are not particularly specific for mild cognitive impairment.
“They work pretty well for manifest advanced dementia but for mild cognitive impairment, which is a very subtle, symptomatic disease, they are only about 75% accurate. One quarter are false-positives. That’s a lot of people,” Dr. Mattke said.
He also noted that although earlier blood tests were about 75% accurate, they are now about 90% accurate, “so we are getting to a level where we can pretty much say with confidence that this is likely Alzheimer’s,” Dr. Mattke said.
Commenting on this research for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, said it is clear that blood tests, “once confirmed, could have a significant impact on the wait times” for dementia assessment.
“After an initial blood test, we might be able to rule out or rule in individuals who should go to a specialist for further follow-up and testing. This allows us to really ensure that we’re prioritizing resources accordingly,” said Dr. Snyder, who was not involved in the study.
This project was supported by a research contract from C2N Diagnostics LLC to USC. Dr. Mattke serves on the board of directors of Senscio Systems Inc. and the scientific advisory board of ALZPath and Boston Millennia Partners and has received consulting fees from Biogen, C2N, Eisai, Eli Lilly, Novartis, and Roche/Genentech. Dr. Snyder has no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM AAIC 2024
Undiagnosed, Untreated Tardive Dyskinesia, Hinders Adherence to Antipsychotics
This transcript has been edited for clarity.
Tardive dyskinesia is a chronic, potentially irreversible, hyperkinetic movement disorder. And the challenge with tardive dyskinesia is that it’s underdiagnosed and undertreated. With the expanded use of dopamine receptor–blocking agents, there are about 7.5 million Americans who are now exposed and at risk for tardive dyskinesia.
It’s thought that about 500,000-750,000 of these patients may in fact have tardive dyskinesia, but only 15% are treated. So why are people not being treated for tardive dyskinesia? Well, there are a number of possible answers.
Until a few years ago, there were no Food and Drug Administration (FDA)–approved treatments for tardive dyskinesia, and these antipsychotic medications that the patients were taking, in many cases, were potentially lifesaving drugs, so they couldn’t simply be stopped. As a result of that, I think physicians developed a certain psychic blindness to identifying tardive dyskinesia, because it was their drugs that were causing the disease and yet they couldn’t be stopped. So, there really wasn’t much they could do in terms of making the diagnosis.
In addition, they were trained that tardive dyskinesia doesn’t have much impact on patients. But we now know, through surveys and other studies, that tardive dyskinesia can have a tremendous impact on patients and on your ability to treat the patient’s underlying mental health issues. It’s estimated that 50% of patients with tardive dyskinesia actually reduce the amount of antipsychotic medication they’re taking on their own, and about 40% may in fact stop their antipsychotic medication altogether.
Thirty-five percent of patients stopped seeing their doctor after they developed tardive dyskinesia, and about 20% of patients actually told other patients not to take their antipsychotic medication. So, tardive dyskinesia is impacting your ability to treat patients. In addition, it impacts the patients themselves. Nearly three out of four patients with tardive dyskinesia said, in surveys, that it caused severe impact on their psychosocial functioning.
It also impacted caregivers, with 70% of caregivers saying that the patients with tardive dyskinesia made them more anxious and limited them socially. So, we have this tremendous impact from tardive dyskinesia.
In addition, physicians sometimes don’t identify tardive dyskinesia correctly. They mistake it for another movement disorder: drug-induced parkinsonism. Or it falls under the rubric of extrapyramidal symptoms (EPS), and they were trained that you treat EPS with benztropine. The challenge with that is that benztropine is only indicated for acute dystonia or for drug-induced parkinsonism. It actually makes tardive dyskinesia worse. And, in the product insert for benztropine, it’s recommended that it should not be used in tardive dyskinesia. So if you have a patient whom you suspect has tardive dyskinesia, you have to discontinue the benztropine. That’s a really important first step.
And then, what else should you do? There are now two FDA-approved treatments for tardive dyskinesia. These are valbenazine and deutetrabenazine. Both of these drugs have been demonstrated in large double-blind, placebo-controlled studies to reduce tardive dyskinesia, as measured by the Abnormal Involuntary Movement Scale, by about 30%. These drugs have been demonstrated to be safe and well tolerated, with the main side effect being somnolence.
Some people can also develop parkinsonism. Why could there be Parkinsonism? This is because vesicular monoamine transporter 2 (VMAT2) inhibitors work by reducing the amount of dopamine that can be packaged in the presynaptic neuron. That means that less dopamine is available to the synapse, and this reduces movement. The American Psychiatric Association has issued guidelines for the treatment of tardive dyskinesia and has said that moderate to severe tardive dyskinesia should be treated first-line with VMAT2 inhibitors and that mild tardive dyskinesia should also be treated with VMAT2 inhibitors if the tardive dyskinesia is impacting the patient.
Given the impact that tardive dyskinesia has on patients and caregivers, and the physician’s ability to treat these patients’ mental health issues, we need to become aggressive and treat the tardive dyskinesia so that patients can improve and be able to have their movements treated without impacting their underlying mental health issues.
Daniel Kremens, professor, Department of Neurology, Sidney Kimmel Medical College, Thomas Jefferson University, codirector, Parkinson’s Disease and Movement Disorders Division, Jack and Vickie Farber Center for Neuroscience, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, has disclosed relevant financial relationships with Teva Pharmaceuticals, AbbVie, Merz, Allergan, Bial, Cerevel, Amneal, Acadia, Supernus, Adamas, Acorda, Kyowa Kirin, and Neurocrine.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Tardive dyskinesia is a chronic, potentially irreversible, hyperkinetic movement disorder. And the challenge with tardive dyskinesia is that it’s underdiagnosed and undertreated. With the expanded use of dopamine receptor–blocking agents, there are about 7.5 million Americans who are now exposed and at risk for tardive dyskinesia.
It’s thought that about 500,000-750,000 of these patients may in fact have tardive dyskinesia, but only 15% are treated. So why are people not being treated for tardive dyskinesia? Well, there are a number of possible answers.
Until a few years ago, there were no Food and Drug Administration (FDA)–approved treatments for tardive dyskinesia, and these antipsychotic medications that the patients were taking, in many cases, were potentially lifesaving drugs, so they couldn’t simply be stopped. As a result of that, I think physicians developed a certain psychic blindness to identifying tardive dyskinesia, because it was their drugs that were causing the disease and yet they couldn’t be stopped. So, there really wasn’t much they could do in terms of making the diagnosis.
In addition, they were trained that tardive dyskinesia doesn’t have much impact on patients. But we now know, through surveys and other studies, that tardive dyskinesia can have a tremendous impact on patients and on your ability to treat the patient’s underlying mental health issues. It’s estimated that 50% of patients with tardive dyskinesia actually reduce the amount of antipsychotic medication they’re taking on their own, and about 40% may in fact stop their antipsychotic medication altogether.
Thirty-five percent of patients stopped seeing their doctor after they developed tardive dyskinesia, and about 20% of patients actually told other patients not to take their antipsychotic medication. So, tardive dyskinesia is impacting your ability to treat patients. In addition, it impacts the patients themselves. Nearly three out of four patients with tardive dyskinesia said, in surveys, that it caused severe impact on their psychosocial functioning.
It also impacted caregivers, with 70% of caregivers saying that the patients with tardive dyskinesia made them more anxious and limited them socially. So, we have this tremendous impact from tardive dyskinesia.
In addition, physicians sometimes don’t identify tardive dyskinesia correctly. They mistake it for another movement disorder: drug-induced parkinsonism. Or it falls under the rubric of extrapyramidal symptoms (EPS), and they were trained that you treat EPS with benztropine. The challenge with that is that benztropine is only indicated for acute dystonia or for drug-induced parkinsonism. It actually makes tardive dyskinesia worse. And, in the product insert for benztropine, it’s recommended that it should not be used in tardive dyskinesia. So if you have a patient whom you suspect has tardive dyskinesia, you have to discontinue the benztropine. That’s a really important first step.
And then, what else should you do? There are now two FDA-approved treatments for tardive dyskinesia. These are valbenazine and deutetrabenazine. Both of these drugs have been demonstrated in large double-blind, placebo-controlled studies to reduce tardive dyskinesia, as measured by the Abnormal Involuntary Movement Scale, by about 30%. These drugs have been demonstrated to be safe and well tolerated, with the main side effect being somnolence.
Some people can also develop parkinsonism. Why could there be Parkinsonism? This is because vesicular monoamine transporter 2 (VMAT2) inhibitors work by reducing the amount of dopamine that can be packaged in the presynaptic neuron. That means that less dopamine is available to the synapse, and this reduces movement. The American Psychiatric Association has issued guidelines for the treatment of tardive dyskinesia and has said that moderate to severe tardive dyskinesia should be treated first-line with VMAT2 inhibitors and that mild tardive dyskinesia should also be treated with VMAT2 inhibitors if the tardive dyskinesia is impacting the patient.
Given the impact that tardive dyskinesia has on patients and caregivers, and the physician’s ability to treat these patients’ mental health issues, we need to become aggressive and treat the tardive dyskinesia so that patients can improve and be able to have their movements treated without impacting their underlying mental health issues.
Daniel Kremens, professor, Department of Neurology, Sidney Kimmel Medical College, Thomas Jefferson University, codirector, Parkinson’s Disease and Movement Disorders Division, Jack and Vickie Farber Center for Neuroscience, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, has disclosed relevant financial relationships with Teva Pharmaceuticals, AbbVie, Merz, Allergan, Bial, Cerevel, Amneal, Acadia, Supernus, Adamas, Acorda, Kyowa Kirin, and Neurocrine.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Tardive dyskinesia is a chronic, potentially irreversible, hyperkinetic movement disorder. And the challenge with tardive dyskinesia is that it’s underdiagnosed and undertreated. With the expanded use of dopamine receptor–blocking agents, there are about 7.5 million Americans who are now exposed and at risk for tardive dyskinesia.
It’s thought that about 500,000-750,000 of these patients may in fact have tardive dyskinesia, but only 15% are treated. So why are people not being treated for tardive dyskinesia? Well, there are a number of possible answers.
Until a few years ago, there were no Food and Drug Administration (FDA)–approved treatments for tardive dyskinesia, and these antipsychotic medications that the patients were taking, in many cases, were potentially lifesaving drugs, so they couldn’t simply be stopped. As a result of that, I think physicians developed a certain psychic blindness to identifying tardive dyskinesia, because it was their drugs that were causing the disease and yet they couldn’t be stopped. So, there really wasn’t much they could do in terms of making the diagnosis.
In addition, they were trained that tardive dyskinesia doesn’t have much impact on patients. But we now know, through surveys and other studies, that tardive dyskinesia can have a tremendous impact on patients and on your ability to treat the patient’s underlying mental health issues. It’s estimated that 50% of patients with tardive dyskinesia actually reduce the amount of antipsychotic medication they’re taking on their own, and about 40% may in fact stop their antipsychotic medication altogether.
Thirty-five percent of patients stopped seeing their doctor after they developed tardive dyskinesia, and about 20% of patients actually told other patients not to take their antipsychotic medication. So, tardive dyskinesia is impacting your ability to treat patients. In addition, it impacts the patients themselves. Nearly three out of four patients with tardive dyskinesia said, in surveys, that it caused severe impact on their psychosocial functioning.
It also impacted caregivers, with 70% of caregivers saying that the patients with tardive dyskinesia made them more anxious and limited them socially. So, we have this tremendous impact from tardive dyskinesia.
In addition, physicians sometimes don’t identify tardive dyskinesia correctly. They mistake it for another movement disorder: drug-induced parkinsonism. Or it falls under the rubric of extrapyramidal symptoms (EPS), and they were trained that you treat EPS with benztropine. The challenge with that is that benztropine is only indicated for acute dystonia or for drug-induced parkinsonism. It actually makes tardive dyskinesia worse. And, in the product insert for benztropine, it’s recommended that it should not be used in tardive dyskinesia. So if you have a patient whom you suspect has tardive dyskinesia, you have to discontinue the benztropine. That’s a really important first step.
And then, what else should you do? There are now two FDA-approved treatments for tardive dyskinesia. These are valbenazine and deutetrabenazine. Both of these drugs have been demonstrated in large double-blind, placebo-controlled studies to reduce tardive dyskinesia, as measured by the Abnormal Involuntary Movement Scale, by about 30%. These drugs have been demonstrated to be safe and well tolerated, with the main side effect being somnolence.
Some people can also develop parkinsonism. Why could there be Parkinsonism? This is because vesicular monoamine transporter 2 (VMAT2) inhibitors work by reducing the amount of dopamine that can be packaged in the presynaptic neuron. That means that less dopamine is available to the synapse, and this reduces movement. The American Psychiatric Association has issued guidelines for the treatment of tardive dyskinesia and has said that moderate to severe tardive dyskinesia should be treated first-line with VMAT2 inhibitors and that mild tardive dyskinesia should also be treated with VMAT2 inhibitors if the tardive dyskinesia is impacting the patient.
Given the impact that tardive dyskinesia has on patients and caregivers, and the physician’s ability to treat these patients’ mental health issues, we need to become aggressive and treat the tardive dyskinesia so that patients can improve and be able to have their movements treated without impacting their underlying mental health issues.
Daniel Kremens, professor, Department of Neurology, Sidney Kimmel Medical College, Thomas Jefferson University, codirector, Parkinson’s Disease and Movement Disorders Division, Jack and Vickie Farber Center for Neuroscience, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, has disclosed relevant financial relationships with Teva Pharmaceuticals, AbbVie, Merz, Allergan, Bial, Cerevel, Amneal, Acadia, Supernus, Adamas, Acorda, Kyowa Kirin, and Neurocrine.
A version of this article first appeared on Medscape.com.
How To Navigate Your First Job
In a special episode live from Digestive Disease Week® (DDW) 2024, host Dr. Matthew Whitson talks with returning guest Dr. Janice Jou. Dr. Jou is a transplant hematologist at the Portland VA and currently serves as professor of medicine and fellowship program director at Oregon Health & Science University. Don’t miss her insight as she shares advice all about what she wishes she knew when going into her first job in gastroenterology. Dr. Jou also answers questions from the audience on topics including “when to say no” and the importance of encouraging emotional transparency with fellows and faculty.
Catch up with past episodes and subscribe wherever you listen to podcasts. You can also listen by clicking on the episode name below.
- Episode 5: Janice Jou: Live from #DDW2024 with tips for your first job
- Episode 4: Loren Rabinowitz and Rachel Issaka: Building research collaborations
- Episode 3: Andy Tau: How to treat GI emergencies
- Episode 2: Laurel Fisher and Asma Khapra: Advancing and advocating for women in GI
- Episode 1: Barbara Jung: Unpacking mentorship with AGA’s president
In a special episode live from Digestive Disease Week® (DDW) 2024, host Dr. Matthew Whitson talks with returning guest Dr. Janice Jou. Dr. Jou is a transplant hematologist at the Portland VA and currently serves as professor of medicine and fellowship program director at Oregon Health & Science University. Don’t miss her insight as she shares advice all about what she wishes she knew when going into her first job in gastroenterology. Dr. Jou also answers questions from the audience on topics including “when to say no” and the importance of encouraging emotional transparency with fellows and faculty.
Catch up with past episodes and subscribe wherever you listen to podcasts. You can also listen by clicking on the episode name below.
- Episode 5: Janice Jou: Live from #DDW2024 with tips for your first job
- Episode 4: Loren Rabinowitz and Rachel Issaka: Building research collaborations
- Episode 3: Andy Tau: How to treat GI emergencies
- Episode 2: Laurel Fisher and Asma Khapra: Advancing and advocating for women in GI
- Episode 1: Barbara Jung: Unpacking mentorship with AGA’s president
In a special episode live from Digestive Disease Week® (DDW) 2024, host Dr. Matthew Whitson talks with returning guest Dr. Janice Jou. Dr. Jou is a transplant hematologist at the Portland VA and currently serves as professor of medicine and fellowship program director at Oregon Health & Science University. Don’t miss her insight as she shares advice all about what she wishes she knew when going into her first job in gastroenterology. Dr. Jou also answers questions from the audience on topics including “when to say no” and the importance of encouraging emotional transparency with fellows and faculty.
Catch up with past episodes and subscribe wherever you listen to podcasts. You can also listen by clicking on the episode name below.
- Episode 5: Janice Jou: Live from #DDW2024 with tips for your first job
- Episode 4: Loren Rabinowitz and Rachel Issaka: Building research collaborations
- Episode 3: Andy Tau: How to treat GI emergencies
- Episode 2: Laurel Fisher and Asma Khapra: Advancing and advocating for women in GI
- Episode 1: Barbara Jung: Unpacking mentorship with AGA’s president
Pruritic Rash on the Neck and Back
The Diagnosis: Prurigo Pigmentosa
A comprehensive metabolic panel collected from our patient 1 month earlier did not reveal any abnormalities. Serum methylmalonic acid and homocysteine were both elevated at 417 nmol/L (reference range [for those aged 2–59 years], 55–335 nmol/L) and 23 μmol/L (reference range, 5–15 μmol/L), respectively. Serum folate and 25-hydroxyvitamin D were low at 3.1 ng/mL (reference range, >4.8 ng/mL) and 5 ng/mL (reference range, 30–80 ng/mL), respectively. Vitamin B12 was within reference range. Two 4-mm punch biopsies collected from the upper back showed spongiotic dermatitis.
Our patient’s histopathology results along with the rash distribution and medical history of anorexia increased suspicion for prurigo pigmentosa. A trial of oral doxycycline 100 mg twice daily for 2 weeks was prescribed. At 2-week follow-up, the patient’s mother revealed a history of ketosis in her daughter, solidifying the diagnosis. The patient was counseled on maintaining a healthy diet to prevent future breakouts. The patient’s rash resolved with diet modification and doxycycline; however, it recurred upon relapse of anorexia 4 months later.
Prurigo pigmentosa, originally identified in Japan by Nagashima et al,1 is an uncommon recurrent inflammatory disorder predominantly observed in young adults of Asian descent. Subsequently, it was reported to occur among individuals from different ethnic backgrounds, indicating potential underdiagnosis or misdiagnosis in Western countries.2 Although a direct pathogenic cause for prurigo pigmentosa has not been identified, a strong association has been linked to diet, specifically when ketosis is induced, such as in ketogenic diets and anorexia nervosa.3-5 Other possible causes include sunlight exposure, clothing friction, and sweating.1,5 The disease course is characterized by intermittent flares and spontaneous resolution, with recurrence in most cases. During the active phase, intensely pruritic, papulovesicular or urticarial papules are predominant and most often are localized to the upper body and torso, including the back, shoulders, neck, and chest.5 These flares can persist for several days but eventually subside, leaving behind a characteristic reticular pigmentation that can persist for months.5 First-line treatment often involves the use of tetracycline antibiotics, such as minocycline or doxycycline. 2,4,5 Dapsone often is used with successful resolution. 6 Dietary modifications also have been found to be effective in treating prurigo pigmentosa, particularly in patients presenting with dietary insufficiency.6,7 Increased carbohydrate intake has been shown to promote resolution. 6 Topical corticosteroids demonstrate limited efficacy in controlling flares.6,8
Histopathology has been variably described, with initial findings reported as nonspecific.1 However, it was later described as a distinct inflammatory disease of the skin with histologically distinct stages.2,9 Early stages reveal scattered dermal, dermal papillary, and perivascular neutrophilic infiltration.9 The lesions then progress and become fully developed, at which point neutrophilic infiltration becomes more prominent, accompanied by the presence of intraepidermal neutrophils and spongiosis. As the lesions resolve, the infiltration transitions to lymphocytic, and lichenoid changes can sometimes be appreciated along with epidermal hyperplasia, hyperpigmentation, and dermal melanophages.9 Although these findings aid in the diagnosis of prurigo pigmentosa, a clinicopathologic correlation is necessary to establish a definitive diagnosis.
Because prurigo pigmentosa is rare, it often is misdiagnosed as another condition with a similar presentation and nonspecific biopsy findings.6 Allergic contact dermatitis is a common type IV delayed hypersensitivity reaction that manifests similar to prurigo pigmentosa with pruritus and a well-demarcated distribution10 that is related to the pattern of allergen exposure; in the case of allergic contact dermatitis related to textiles, a well-demarcated rash will appear in the distribution area of the associated clothing (eg, shirt, pants, shorts).11 Development of allergy involves exposure and sensitization to an allergen, followed by subsequent re-exposure that results in cutaneous T-cell activation and inflammation. 10 Histopathology shows nonspecific spongiotic inflammation, and the gold standard for diagnosis is patch testing to identify the causative substance(s). Definitive treatment includes avoidance of identified allergies; however, if patients are unable to avoid the allergen or the cause is unknown, then corticosteroids, antihistamines, and/or calcineurin inhibitors are beneficial in controlling symptoms and flares.10
Pityrosporum folliculitis (also known as Malassezia folliculitis) is a fungal acneform condition that arises from overgrowth of normal skin flora Malassezia yeast,12 which may be due to occlusion of follicles or disruption of the normal flora composition. Clinically, the manifestation may resemble prurigo pigmentosa in distribution and presence of intense pruritus. However, pustular lesions and involvement of the face can aid in differentiating Pityrosporum from prurigo pigmentosa, which can be confirmed via periodic acid–Schiff staining with numerous round yeasts within affected follicles. Oral antifungal therapy typically yields rapid improvement and resolution of symptoms.12
Urticaria and prurigo pigmentosa share similar clinical characteristics, with symptoms of intense pruritus and urticarial lesions on the trunk.2,13 Urticaria is an IgEmediated type I hypersensitivity reaction characterized by wheals (ie, edematous red or pink lesions of variable size and shape that typically resolve spontaneously within 24–48 hours).13 Notably, urticaria will improve and in some cases completely resolve with antihistamines or anti-IgE antibody treatment, which may aid in distinguishing it from prurigo pigmentosa, as the latter typically exhibits limited response to such treatment.2 Histopathology also can assist in the diagnosis by ruling out other causes of similar rash; however, biopsies are not routinely done unless other inflammatory conditions are of high suspicion.13
Bullous pemphigoid is an autoimmune, subepidermal, blistering dermatosis that is most common among the elderly.14 It is characterized by the presence of IgG antibodies that target BP180 and BP230, which initiate inflammatory cascades that lead to tissue damage and blister formation. It typically manifests as pruritic blistering eruptions, primarily on the limbs and trunk, but may involve the head, neck, or palmoplantar regions.14 Although blistering eruptions are the prodrome of the disease, some cases may present with nonspecific urticarial or eczematous lesions14,15 that may resemble prurigo pigmentosa. The diagnosis is confirmed through direct immunofluorescence microscopy of biopsied lesions, which reveals IgG and/or C3 deposits along the dermoepidermal junction.14 Management of bullous pemphigoid involves timely initiation of dapsone or systemic corticosteroids, which have demonstrated high efficacy in controlling the disease and its associated symptoms.15
Our patient achieved a favorable response to diet modification and doxycycline therapy consistent with the diagnosis of prurigo pigmentosa. Unfortunately, the condition recurred following a relapse of anorexia. Management of prurigo pigmentosa necessitates not only accurate diagnosis but also addressing any underlying factors that may contribute to disease exacerbation. We anticipate the eating disorder will pose a major challenge in achieving long-term control of prurigo pigmentosa.
- Nagashima M, Ohshiro A, Shimizu N. A peculiar pruriginous dermatosis with gross reticular pigmentation. Jpn J Dermatol. 1971;81:38-39.
- Boer A, Asgari M. Prurigo pigmentosa: an underdiagnosed disease? Indian J Dermatol Venereol Leprol. 2006;72:405-409. doi:10.4103/0378-6323.29334
- Michaels JD, Hoss E, DiCaudo DJ, et al. Prurigo pigmentosa after a strict ketogenic diet. Pediatr Dermatol. 2013;32:248-251. doi:10.1111/pde.12275
- Teraki Y, Teraki E, Kawashima M, et al. Ketosis is involved in the origin of prurigo pigmentosa. J Am Acad Dermatol. 1996;34:509-511. doi:10.1016/s0190-9622(96)90460-0
- Böer A, Misago N, Wolter M, et al. Prurigo pigmentosa: a distinctive inflammatory disease of the skin. Am J Dermatopathol. 2003;25:117-129. doi:10.1097/00000372-200304000-00005
- Mufti A, Mirali S, Abduelmula A, et al. Clinical manifestations and treatment outcomes in prurigo pigmentosa (Nagashima disease): a systematic review of the literature. JAAD Int. 2021;3:79-87. doi:10.1016/j.jdin.2021.03.003
- Wong M, Lee E, Wu Y, et al. Treatment of prurigo pigmentosa with diet modification: a medical case study. Hawaii J Med Public Health. 2018;77:114-117.
- Almaani N, Al-Tarawneh AH, Msallam H. Prurigo pigmentosa: a clinicopathological report of three Middle Eastern patients. Case Rep Dermatol Med. 2018;2018:9406797. doi:10.1155/2018/9406797
- Kim JK, Chung WK, Chang SE, et al. Prurigo pigmentosa: clinicopathological study and analysis of 50 cases in Korea. J Dermatol. 2012;39:891-897. doi:10.1111/j.1346-8138.2012.01640.x
- Mowad CM, Anderson B, Scheinman P, et al. Allergic contact dermatitis: patient diagnosis and evaluation. J Am Acad Dermatol. 2016;74:1029-1040. doi:10.1016/j.jaad.2015.02.1139
- Lazarov A, Cordoba M, Plosk N, et al. Atypical and unusual clinical manifestations of contact dermatitis to clothing (textile contact dermatitis)—case presentation and review of the literature. Dermatol Online J. 2003;9. doi:10.5070/d30kd1d259
- Rubenstein RM, Malerich SA. Malassezia (Pityrosporum) folliculitis. J Clin Aesthet Dermatol. 2014;7:37-41.
- Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014;133:1270-1277. doi:10.1016/j.jaci.2014.02.036
- della Torre R, Combescure C, Cortés B, et al. Clinical presentation and diagnostic delay in bullous pemphigoid: a prospective nationwide cohort. Br J Dermatol. 2012;167:1111-1117. doi:10.1111/j.1365-2133.2012.11108.x
- Alonso-Llamazares J, Rogers RS 3rd, Oursler JR, et al. Bullous pemphigoid presenting as generalized pruritus: observations in six patients. Int J Dermatol. 1998;37:508-514.
The Diagnosis: Prurigo Pigmentosa
A comprehensive metabolic panel collected from our patient 1 month earlier did not reveal any abnormalities. Serum methylmalonic acid and homocysteine were both elevated at 417 nmol/L (reference range [for those aged 2–59 years], 55–335 nmol/L) and 23 μmol/L (reference range, 5–15 μmol/L), respectively. Serum folate and 25-hydroxyvitamin D were low at 3.1 ng/mL (reference range, >4.8 ng/mL) and 5 ng/mL (reference range, 30–80 ng/mL), respectively. Vitamin B12 was within reference range. Two 4-mm punch biopsies collected from the upper back showed spongiotic dermatitis.
Our patient’s histopathology results along with the rash distribution and medical history of anorexia increased suspicion for prurigo pigmentosa. A trial of oral doxycycline 100 mg twice daily for 2 weeks was prescribed. At 2-week follow-up, the patient’s mother revealed a history of ketosis in her daughter, solidifying the diagnosis. The patient was counseled on maintaining a healthy diet to prevent future breakouts. The patient’s rash resolved with diet modification and doxycycline; however, it recurred upon relapse of anorexia 4 months later.
Prurigo pigmentosa, originally identified in Japan by Nagashima et al,1 is an uncommon recurrent inflammatory disorder predominantly observed in young adults of Asian descent. Subsequently, it was reported to occur among individuals from different ethnic backgrounds, indicating potential underdiagnosis or misdiagnosis in Western countries.2 Although a direct pathogenic cause for prurigo pigmentosa has not been identified, a strong association has been linked to diet, specifically when ketosis is induced, such as in ketogenic diets and anorexia nervosa.3-5 Other possible causes include sunlight exposure, clothing friction, and sweating.1,5 The disease course is characterized by intermittent flares and spontaneous resolution, with recurrence in most cases. During the active phase, intensely pruritic, papulovesicular or urticarial papules are predominant and most often are localized to the upper body and torso, including the back, shoulders, neck, and chest.5 These flares can persist for several days but eventually subside, leaving behind a characteristic reticular pigmentation that can persist for months.5 First-line treatment often involves the use of tetracycline antibiotics, such as minocycline or doxycycline. 2,4,5 Dapsone often is used with successful resolution. 6 Dietary modifications also have been found to be effective in treating prurigo pigmentosa, particularly in patients presenting with dietary insufficiency.6,7 Increased carbohydrate intake has been shown to promote resolution. 6 Topical corticosteroids demonstrate limited efficacy in controlling flares.6,8
Histopathology has been variably described, with initial findings reported as nonspecific.1 However, it was later described as a distinct inflammatory disease of the skin with histologically distinct stages.2,9 Early stages reveal scattered dermal, dermal papillary, and perivascular neutrophilic infiltration.9 The lesions then progress and become fully developed, at which point neutrophilic infiltration becomes more prominent, accompanied by the presence of intraepidermal neutrophils and spongiosis. As the lesions resolve, the infiltration transitions to lymphocytic, and lichenoid changes can sometimes be appreciated along with epidermal hyperplasia, hyperpigmentation, and dermal melanophages.9 Although these findings aid in the diagnosis of prurigo pigmentosa, a clinicopathologic correlation is necessary to establish a definitive diagnosis.
Because prurigo pigmentosa is rare, it often is misdiagnosed as another condition with a similar presentation and nonspecific biopsy findings.6 Allergic contact dermatitis is a common type IV delayed hypersensitivity reaction that manifests similar to prurigo pigmentosa with pruritus and a well-demarcated distribution10 that is related to the pattern of allergen exposure; in the case of allergic contact dermatitis related to textiles, a well-demarcated rash will appear in the distribution area of the associated clothing (eg, shirt, pants, shorts).11 Development of allergy involves exposure and sensitization to an allergen, followed by subsequent re-exposure that results in cutaneous T-cell activation and inflammation. 10 Histopathology shows nonspecific spongiotic inflammation, and the gold standard for diagnosis is patch testing to identify the causative substance(s). Definitive treatment includes avoidance of identified allergies; however, if patients are unable to avoid the allergen or the cause is unknown, then corticosteroids, antihistamines, and/or calcineurin inhibitors are beneficial in controlling symptoms and flares.10
Pityrosporum folliculitis (also known as Malassezia folliculitis) is a fungal acneform condition that arises from overgrowth of normal skin flora Malassezia yeast,12 which may be due to occlusion of follicles or disruption of the normal flora composition. Clinically, the manifestation may resemble prurigo pigmentosa in distribution and presence of intense pruritus. However, pustular lesions and involvement of the face can aid in differentiating Pityrosporum from prurigo pigmentosa, which can be confirmed via periodic acid–Schiff staining with numerous round yeasts within affected follicles. Oral antifungal therapy typically yields rapid improvement and resolution of symptoms.12
Urticaria and prurigo pigmentosa share similar clinical characteristics, with symptoms of intense pruritus and urticarial lesions on the trunk.2,13 Urticaria is an IgEmediated type I hypersensitivity reaction characterized by wheals (ie, edematous red or pink lesions of variable size and shape that typically resolve spontaneously within 24–48 hours).13 Notably, urticaria will improve and in some cases completely resolve with antihistamines or anti-IgE antibody treatment, which may aid in distinguishing it from prurigo pigmentosa, as the latter typically exhibits limited response to such treatment.2 Histopathology also can assist in the diagnosis by ruling out other causes of similar rash; however, biopsies are not routinely done unless other inflammatory conditions are of high suspicion.13
Bullous pemphigoid is an autoimmune, subepidermal, blistering dermatosis that is most common among the elderly.14 It is characterized by the presence of IgG antibodies that target BP180 and BP230, which initiate inflammatory cascades that lead to tissue damage and blister formation. It typically manifests as pruritic blistering eruptions, primarily on the limbs and trunk, but may involve the head, neck, or palmoplantar regions.14 Although blistering eruptions are the prodrome of the disease, some cases may present with nonspecific urticarial or eczematous lesions14,15 that may resemble prurigo pigmentosa. The diagnosis is confirmed through direct immunofluorescence microscopy of biopsied lesions, which reveals IgG and/or C3 deposits along the dermoepidermal junction.14 Management of bullous pemphigoid involves timely initiation of dapsone or systemic corticosteroids, which have demonstrated high efficacy in controlling the disease and its associated symptoms.15
Our patient achieved a favorable response to diet modification and doxycycline therapy consistent with the diagnosis of prurigo pigmentosa. Unfortunately, the condition recurred following a relapse of anorexia. Management of prurigo pigmentosa necessitates not only accurate diagnosis but also addressing any underlying factors that may contribute to disease exacerbation. We anticipate the eating disorder will pose a major challenge in achieving long-term control of prurigo pigmentosa.
The Diagnosis: Prurigo Pigmentosa
A comprehensive metabolic panel collected from our patient 1 month earlier did not reveal any abnormalities. Serum methylmalonic acid and homocysteine were both elevated at 417 nmol/L (reference range [for those aged 2–59 years], 55–335 nmol/L) and 23 μmol/L (reference range, 5–15 μmol/L), respectively. Serum folate and 25-hydroxyvitamin D were low at 3.1 ng/mL (reference range, >4.8 ng/mL) and 5 ng/mL (reference range, 30–80 ng/mL), respectively. Vitamin B12 was within reference range. Two 4-mm punch biopsies collected from the upper back showed spongiotic dermatitis.
Our patient’s histopathology results along with the rash distribution and medical history of anorexia increased suspicion for prurigo pigmentosa. A trial of oral doxycycline 100 mg twice daily for 2 weeks was prescribed. At 2-week follow-up, the patient’s mother revealed a history of ketosis in her daughter, solidifying the diagnosis. The patient was counseled on maintaining a healthy diet to prevent future breakouts. The patient’s rash resolved with diet modification and doxycycline; however, it recurred upon relapse of anorexia 4 months later.
Prurigo pigmentosa, originally identified in Japan by Nagashima et al,1 is an uncommon recurrent inflammatory disorder predominantly observed in young adults of Asian descent. Subsequently, it was reported to occur among individuals from different ethnic backgrounds, indicating potential underdiagnosis or misdiagnosis in Western countries.2 Although a direct pathogenic cause for prurigo pigmentosa has not been identified, a strong association has been linked to diet, specifically when ketosis is induced, such as in ketogenic diets and anorexia nervosa.3-5 Other possible causes include sunlight exposure, clothing friction, and sweating.1,5 The disease course is characterized by intermittent flares and spontaneous resolution, with recurrence in most cases. During the active phase, intensely pruritic, papulovesicular or urticarial papules are predominant and most often are localized to the upper body and torso, including the back, shoulders, neck, and chest.5 These flares can persist for several days but eventually subside, leaving behind a characteristic reticular pigmentation that can persist for months.5 First-line treatment often involves the use of tetracycline antibiotics, such as minocycline or doxycycline. 2,4,5 Dapsone often is used with successful resolution. 6 Dietary modifications also have been found to be effective in treating prurigo pigmentosa, particularly in patients presenting with dietary insufficiency.6,7 Increased carbohydrate intake has been shown to promote resolution. 6 Topical corticosteroids demonstrate limited efficacy in controlling flares.6,8
Histopathology has been variably described, with initial findings reported as nonspecific.1 However, it was later described as a distinct inflammatory disease of the skin with histologically distinct stages.2,9 Early stages reveal scattered dermal, dermal papillary, and perivascular neutrophilic infiltration.9 The lesions then progress and become fully developed, at which point neutrophilic infiltration becomes more prominent, accompanied by the presence of intraepidermal neutrophils and spongiosis. As the lesions resolve, the infiltration transitions to lymphocytic, and lichenoid changes can sometimes be appreciated along with epidermal hyperplasia, hyperpigmentation, and dermal melanophages.9 Although these findings aid in the diagnosis of prurigo pigmentosa, a clinicopathologic correlation is necessary to establish a definitive diagnosis.
Because prurigo pigmentosa is rare, it often is misdiagnosed as another condition with a similar presentation and nonspecific biopsy findings.6 Allergic contact dermatitis is a common type IV delayed hypersensitivity reaction that manifests similar to prurigo pigmentosa with pruritus and a well-demarcated distribution10 that is related to the pattern of allergen exposure; in the case of allergic contact dermatitis related to textiles, a well-demarcated rash will appear in the distribution area of the associated clothing (eg, shirt, pants, shorts).11 Development of allergy involves exposure and sensitization to an allergen, followed by subsequent re-exposure that results in cutaneous T-cell activation and inflammation. 10 Histopathology shows nonspecific spongiotic inflammation, and the gold standard for diagnosis is patch testing to identify the causative substance(s). Definitive treatment includes avoidance of identified allergies; however, if patients are unable to avoid the allergen or the cause is unknown, then corticosteroids, antihistamines, and/or calcineurin inhibitors are beneficial in controlling symptoms and flares.10
Pityrosporum folliculitis (also known as Malassezia folliculitis) is a fungal acneform condition that arises from overgrowth of normal skin flora Malassezia yeast,12 which may be due to occlusion of follicles or disruption of the normal flora composition. Clinically, the manifestation may resemble prurigo pigmentosa in distribution and presence of intense pruritus. However, pustular lesions and involvement of the face can aid in differentiating Pityrosporum from prurigo pigmentosa, which can be confirmed via periodic acid–Schiff staining with numerous round yeasts within affected follicles. Oral antifungal therapy typically yields rapid improvement and resolution of symptoms.12
Urticaria and prurigo pigmentosa share similar clinical characteristics, with symptoms of intense pruritus and urticarial lesions on the trunk.2,13 Urticaria is an IgEmediated type I hypersensitivity reaction characterized by wheals (ie, edematous red or pink lesions of variable size and shape that typically resolve spontaneously within 24–48 hours).13 Notably, urticaria will improve and in some cases completely resolve with antihistamines or anti-IgE antibody treatment, which may aid in distinguishing it from prurigo pigmentosa, as the latter typically exhibits limited response to such treatment.2 Histopathology also can assist in the diagnosis by ruling out other causes of similar rash; however, biopsies are not routinely done unless other inflammatory conditions are of high suspicion.13
Bullous pemphigoid is an autoimmune, subepidermal, blistering dermatosis that is most common among the elderly.14 It is characterized by the presence of IgG antibodies that target BP180 and BP230, which initiate inflammatory cascades that lead to tissue damage and blister formation. It typically manifests as pruritic blistering eruptions, primarily on the limbs and trunk, but may involve the head, neck, or palmoplantar regions.14 Although blistering eruptions are the prodrome of the disease, some cases may present with nonspecific urticarial or eczematous lesions14,15 that may resemble prurigo pigmentosa. The diagnosis is confirmed through direct immunofluorescence microscopy of biopsied lesions, which reveals IgG and/or C3 deposits along the dermoepidermal junction.14 Management of bullous pemphigoid involves timely initiation of dapsone or systemic corticosteroids, which have demonstrated high efficacy in controlling the disease and its associated symptoms.15
Our patient achieved a favorable response to diet modification and doxycycline therapy consistent with the diagnosis of prurigo pigmentosa. Unfortunately, the condition recurred following a relapse of anorexia. Management of prurigo pigmentosa necessitates not only accurate diagnosis but also addressing any underlying factors that may contribute to disease exacerbation. We anticipate the eating disorder will pose a major challenge in achieving long-term control of prurigo pigmentosa.
- Nagashima M, Ohshiro A, Shimizu N. A peculiar pruriginous dermatosis with gross reticular pigmentation. Jpn J Dermatol. 1971;81:38-39.
- Boer A, Asgari M. Prurigo pigmentosa: an underdiagnosed disease? Indian J Dermatol Venereol Leprol. 2006;72:405-409. doi:10.4103/0378-6323.29334
- Michaels JD, Hoss E, DiCaudo DJ, et al. Prurigo pigmentosa after a strict ketogenic diet. Pediatr Dermatol. 2013;32:248-251. doi:10.1111/pde.12275
- Teraki Y, Teraki E, Kawashima M, et al. Ketosis is involved in the origin of prurigo pigmentosa. J Am Acad Dermatol. 1996;34:509-511. doi:10.1016/s0190-9622(96)90460-0
- Böer A, Misago N, Wolter M, et al. Prurigo pigmentosa: a distinctive inflammatory disease of the skin. Am J Dermatopathol. 2003;25:117-129. doi:10.1097/00000372-200304000-00005
- Mufti A, Mirali S, Abduelmula A, et al. Clinical manifestations and treatment outcomes in prurigo pigmentosa (Nagashima disease): a systematic review of the literature. JAAD Int. 2021;3:79-87. doi:10.1016/j.jdin.2021.03.003
- Wong M, Lee E, Wu Y, et al. Treatment of prurigo pigmentosa with diet modification: a medical case study. Hawaii J Med Public Health. 2018;77:114-117.
- Almaani N, Al-Tarawneh AH, Msallam H. Prurigo pigmentosa: a clinicopathological report of three Middle Eastern patients. Case Rep Dermatol Med. 2018;2018:9406797. doi:10.1155/2018/9406797
- Kim JK, Chung WK, Chang SE, et al. Prurigo pigmentosa: clinicopathological study and analysis of 50 cases in Korea. J Dermatol. 2012;39:891-897. doi:10.1111/j.1346-8138.2012.01640.x
- Mowad CM, Anderson B, Scheinman P, et al. Allergic contact dermatitis: patient diagnosis and evaluation. J Am Acad Dermatol. 2016;74:1029-1040. doi:10.1016/j.jaad.2015.02.1139
- Lazarov A, Cordoba M, Plosk N, et al. Atypical and unusual clinical manifestations of contact dermatitis to clothing (textile contact dermatitis)—case presentation and review of the literature. Dermatol Online J. 2003;9. doi:10.5070/d30kd1d259
- Rubenstein RM, Malerich SA. Malassezia (Pityrosporum) folliculitis. J Clin Aesthet Dermatol. 2014;7:37-41.
- Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014;133:1270-1277. doi:10.1016/j.jaci.2014.02.036
- della Torre R, Combescure C, Cortés B, et al. Clinical presentation and diagnostic delay in bullous pemphigoid: a prospective nationwide cohort. Br J Dermatol. 2012;167:1111-1117. doi:10.1111/j.1365-2133.2012.11108.x
- Alonso-Llamazares J, Rogers RS 3rd, Oursler JR, et al. Bullous pemphigoid presenting as generalized pruritus: observations in six patients. Int J Dermatol. 1998;37:508-514.
- Nagashima M, Ohshiro A, Shimizu N. A peculiar pruriginous dermatosis with gross reticular pigmentation. Jpn J Dermatol. 1971;81:38-39.
- Boer A, Asgari M. Prurigo pigmentosa: an underdiagnosed disease? Indian J Dermatol Venereol Leprol. 2006;72:405-409. doi:10.4103/0378-6323.29334
- Michaels JD, Hoss E, DiCaudo DJ, et al. Prurigo pigmentosa after a strict ketogenic diet. Pediatr Dermatol. 2013;32:248-251. doi:10.1111/pde.12275
- Teraki Y, Teraki E, Kawashima M, et al. Ketosis is involved in the origin of prurigo pigmentosa. J Am Acad Dermatol. 1996;34:509-511. doi:10.1016/s0190-9622(96)90460-0
- Böer A, Misago N, Wolter M, et al. Prurigo pigmentosa: a distinctive inflammatory disease of the skin. Am J Dermatopathol. 2003;25:117-129. doi:10.1097/00000372-200304000-00005
- Mufti A, Mirali S, Abduelmula A, et al. Clinical manifestations and treatment outcomes in prurigo pigmentosa (Nagashima disease): a systematic review of the literature. JAAD Int. 2021;3:79-87. doi:10.1016/j.jdin.2021.03.003
- Wong M, Lee E, Wu Y, et al. Treatment of prurigo pigmentosa with diet modification: a medical case study. Hawaii J Med Public Health. 2018;77:114-117.
- Almaani N, Al-Tarawneh AH, Msallam H. Prurigo pigmentosa: a clinicopathological report of three Middle Eastern patients. Case Rep Dermatol Med. 2018;2018:9406797. doi:10.1155/2018/9406797
- Kim JK, Chung WK, Chang SE, et al. Prurigo pigmentosa: clinicopathological study and analysis of 50 cases in Korea. J Dermatol. 2012;39:891-897. doi:10.1111/j.1346-8138.2012.01640.x
- Mowad CM, Anderson B, Scheinman P, et al. Allergic contact dermatitis: patient diagnosis and evaluation. J Am Acad Dermatol. 2016;74:1029-1040. doi:10.1016/j.jaad.2015.02.1139
- Lazarov A, Cordoba M, Plosk N, et al. Atypical and unusual clinical manifestations of contact dermatitis to clothing (textile contact dermatitis)—case presentation and review of the literature. Dermatol Online J. 2003;9. doi:10.5070/d30kd1d259
- Rubenstein RM, Malerich SA. Malassezia (Pityrosporum) folliculitis. J Clin Aesthet Dermatol. 2014;7:37-41.
- Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014;133:1270-1277. doi:10.1016/j.jaci.2014.02.036
- della Torre R, Combescure C, Cortés B, et al. Clinical presentation and diagnostic delay in bullous pemphigoid: a prospective nationwide cohort. Br J Dermatol. 2012;167:1111-1117. doi:10.1111/j.1365-2133.2012.11108.x
- Alonso-Llamazares J, Rogers RS 3rd, Oursler JR, et al. Bullous pemphigoid presenting as generalized pruritus: observations in six patients. Int J Dermatol. 1998;37:508-514.
A 43-year-old woman presented with a pruritic rash across the neck and back of 6 months’ duration that progressively worsened. She had a medical history of anorexia nervosa, herpes zoster with a recent flare, and peripheral neuropathy. Physical examination showed numerous red scaly papules across the upper back and shoulders that coalesced in a reticular pattern. No similar papules were seen elsewhere on the body.
New Models Predict Time From Mild Cognitive Impairment to Dementia
Using a large, real-world population, researchers have developed models that predict cognitive decline in amyloid-positive patients with either mild cognitive impairment (MCI) or mild dementia.
The models may help clinicians better answer common questions from their patients about their rate of cognitive decline, noted the investigators, led by Pieter J. van der Veere, MD, Alzheimer Center and Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands.
The findings were published online in Neurology.
Easy-to-Use Prototype
On average, it takes 4 years for MCI to progress to dementia. While new disease-modifying drugs targeting amyloid may slow progression, whether this effect is clinically meaningful is debatable, the investigators noted.
Earlier published models predicting cognitive decline either are limited to patients with MCI or haven’t been developed for easy clinical use, they added.
For the single-center study, researchers selected 961 amyloid-positive patients, mean age 65 years, who had at least two longitudinal Mini-Mental State Examinations (MMSEs). Of these, 310 had MCI, and 651 had mild dementia; 48% were women, and over 90% were White.
Researchers used linear mixed modeling to predict MMSE over time. They included age, sex, baseline MMSE, apolipoprotein E epsilon 4 status, cerebrospinal fluid (CSF) beta-amyloid (Aß) 1-42 and plasma phosphorylated-tau markers, and MRI total brain and hippocampal volume measures in the various models, including the final biomarker prediction models.
At follow-up, investigators found that the yearly decline in MMSEs increased in patients with both MCI and mild dementia. In MCI, the average MMSE declined from 26.4 (95% confidence interval [CI], 26.2-26.7) at baseline to 21.0 (95% CI, 20.2-21.7) after 5 years.
In mild dementia, the average MMSE declined from 22.4 (95% CI, 22.0-22.7) to 7.8 (95% CI, 6.8-8.9) at 5 years.
The predicted mean time to reach an MMSE of 20 (indicating mild dementia) for a hypothetical patient with MCI and a baseline MMSE of 28 and CSF Aß 1-42 of 925 pg/mL was 6 years (95% CI, 5.4-6.7 years).
However, with a hypothetical drug treatment that reduces the rate of decline by 30%, the patient would not reach the stage of moderate dementia for 8.6 years.
For a hypothetical patient with mild dementia with a baseline MMSE of 20 and CSF Aß 1-42 of 625 pg/mL, the predicted mean time to reach an MMSE of 15 was 2.3 years (95% CI, 2.1-2.5), or 3.3 years if decline is reduced by 30% with drug treatment.
External validation of the prediction models using data from the Alzheimer’s Disease Neuroimaging Initiative, a longitudinal cohort of patients not cognitively impaired or with MCI or dementia, showed comparable performance between the model-building approaches.
Researchers have incorporated the models in an easy-to-use calculator as a prototype tool that physicians can use to discuss prognosis, the uncertainty surrounding the predictions, and the impact of intervention strategies with patients.
Future prediction models may be able to predict patient-reported outcomes such as quality of life and daily functioning, the researchers noted.
“Until then, there is an important role for clinicians in translating the observed and predicted cognitive functions,” they wrote.
Compared with other studies predicting the MMSE decline using different statistical techniques, these new models showed similar or even better predictive performance while requiring less or similar information, the investigators noted.
The study used MMSE as a measure of cognition, but there may be intraindividual variation in these measures among cognitively normal patients, and those with cognitive decline may score lower if measurements are taken later in the day. Another study limitation was that the models were built for use in memory clinics, so generalizability to the general population could be limited.
The study was supported by Eisai, ZonMW, and Health~Holland Top Sector Life Sciences & Health. See paper for financial disclosures.
A version of this article first appeared on Medscape.com.
Using a large, real-world population, researchers have developed models that predict cognitive decline in amyloid-positive patients with either mild cognitive impairment (MCI) or mild dementia.
The models may help clinicians better answer common questions from their patients about their rate of cognitive decline, noted the investigators, led by Pieter J. van der Veere, MD, Alzheimer Center and Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands.
The findings were published online in Neurology.
Easy-to-Use Prototype
On average, it takes 4 years for MCI to progress to dementia. While new disease-modifying drugs targeting amyloid may slow progression, whether this effect is clinically meaningful is debatable, the investigators noted.
Earlier published models predicting cognitive decline either are limited to patients with MCI or haven’t been developed for easy clinical use, they added.
For the single-center study, researchers selected 961 amyloid-positive patients, mean age 65 years, who had at least two longitudinal Mini-Mental State Examinations (MMSEs). Of these, 310 had MCI, and 651 had mild dementia; 48% were women, and over 90% were White.
Researchers used linear mixed modeling to predict MMSE over time. They included age, sex, baseline MMSE, apolipoprotein E epsilon 4 status, cerebrospinal fluid (CSF) beta-amyloid (Aß) 1-42 and plasma phosphorylated-tau markers, and MRI total brain and hippocampal volume measures in the various models, including the final biomarker prediction models.
At follow-up, investigators found that the yearly decline in MMSEs increased in patients with both MCI and mild dementia. In MCI, the average MMSE declined from 26.4 (95% confidence interval [CI], 26.2-26.7) at baseline to 21.0 (95% CI, 20.2-21.7) after 5 years.
In mild dementia, the average MMSE declined from 22.4 (95% CI, 22.0-22.7) to 7.8 (95% CI, 6.8-8.9) at 5 years.
The predicted mean time to reach an MMSE of 20 (indicating mild dementia) for a hypothetical patient with MCI and a baseline MMSE of 28 and CSF Aß 1-42 of 925 pg/mL was 6 years (95% CI, 5.4-6.7 years).
However, with a hypothetical drug treatment that reduces the rate of decline by 30%, the patient would not reach the stage of moderate dementia for 8.6 years.
For a hypothetical patient with mild dementia with a baseline MMSE of 20 and CSF Aß 1-42 of 625 pg/mL, the predicted mean time to reach an MMSE of 15 was 2.3 years (95% CI, 2.1-2.5), or 3.3 years if decline is reduced by 30% with drug treatment.
External validation of the prediction models using data from the Alzheimer’s Disease Neuroimaging Initiative, a longitudinal cohort of patients not cognitively impaired or with MCI or dementia, showed comparable performance between the model-building approaches.
Researchers have incorporated the models in an easy-to-use calculator as a prototype tool that physicians can use to discuss prognosis, the uncertainty surrounding the predictions, and the impact of intervention strategies with patients.
Future prediction models may be able to predict patient-reported outcomes such as quality of life and daily functioning, the researchers noted.
“Until then, there is an important role for clinicians in translating the observed and predicted cognitive functions,” they wrote.
Compared with other studies predicting the MMSE decline using different statistical techniques, these new models showed similar or even better predictive performance while requiring less or similar information, the investigators noted.
The study used MMSE as a measure of cognition, but there may be intraindividual variation in these measures among cognitively normal patients, and those with cognitive decline may score lower if measurements are taken later in the day. Another study limitation was that the models were built for use in memory clinics, so generalizability to the general population could be limited.
The study was supported by Eisai, ZonMW, and Health~Holland Top Sector Life Sciences & Health. See paper for financial disclosures.
A version of this article first appeared on Medscape.com.
Using a large, real-world population, researchers have developed models that predict cognitive decline in amyloid-positive patients with either mild cognitive impairment (MCI) or mild dementia.
The models may help clinicians better answer common questions from their patients about their rate of cognitive decline, noted the investigators, led by Pieter J. van der Veere, MD, Alzheimer Center and Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands.
The findings were published online in Neurology.
Easy-to-Use Prototype
On average, it takes 4 years for MCI to progress to dementia. While new disease-modifying drugs targeting amyloid may slow progression, whether this effect is clinically meaningful is debatable, the investigators noted.
Earlier published models predicting cognitive decline either are limited to patients with MCI or haven’t been developed for easy clinical use, they added.
For the single-center study, researchers selected 961 amyloid-positive patients, mean age 65 years, who had at least two longitudinal Mini-Mental State Examinations (MMSEs). Of these, 310 had MCI, and 651 had mild dementia; 48% were women, and over 90% were White.
Researchers used linear mixed modeling to predict MMSE over time. They included age, sex, baseline MMSE, apolipoprotein E epsilon 4 status, cerebrospinal fluid (CSF) beta-amyloid (Aß) 1-42 and plasma phosphorylated-tau markers, and MRI total brain and hippocampal volume measures in the various models, including the final biomarker prediction models.
At follow-up, investigators found that the yearly decline in MMSEs increased in patients with both MCI and mild dementia. In MCI, the average MMSE declined from 26.4 (95% confidence interval [CI], 26.2-26.7) at baseline to 21.0 (95% CI, 20.2-21.7) after 5 years.
In mild dementia, the average MMSE declined from 22.4 (95% CI, 22.0-22.7) to 7.8 (95% CI, 6.8-8.9) at 5 years.
The predicted mean time to reach an MMSE of 20 (indicating mild dementia) for a hypothetical patient with MCI and a baseline MMSE of 28 and CSF Aß 1-42 of 925 pg/mL was 6 years (95% CI, 5.4-6.7 years).
However, with a hypothetical drug treatment that reduces the rate of decline by 30%, the patient would not reach the stage of moderate dementia for 8.6 years.
For a hypothetical patient with mild dementia with a baseline MMSE of 20 and CSF Aß 1-42 of 625 pg/mL, the predicted mean time to reach an MMSE of 15 was 2.3 years (95% CI, 2.1-2.5), or 3.3 years if decline is reduced by 30% with drug treatment.
External validation of the prediction models using data from the Alzheimer’s Disease Neuroimaging Initiative, a longitudinal cohort of patients not cognitively impaired or with MCI or dementia, showed comparable performance between the model-building approaches.
Researchers have incorporated the models in an easy-to-use calculator as a prototype tool that physicians can use to discuss prognosis, the uncertainty surrounding the predictions, and the impact of intervention strategies with patients.
Future prediction models may be able to predict patient-reported outcomes such as quality of life and daily functioning, the researchers noted.
“Until then, there is an important role for clinicians in translating the observed and predicted cognitive functions,” they wrote.
Compared with other studies predicting the MMSE decline using different statistical techniques, these new models showed similar or even better predictive performance while requiring less or similar information, the investigators noted.
The study used MMSE as a measure of cognition, but there may be intraindividual variation in these measures among cognitively normal patients, and those with cognitive decline may score lower if measurements are taken later in the day. Another study limitation was that the models were built for use in memory clinics, so generalizability to the general population could be limited.
The study was supported by Eisai, ZonMW, and Health~Holland Top Sector Life Sciences & Health. See paper for financial disclosures.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY