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AI detects hidden, potentially curable pancreatic cancers
TOPLINE:
new research suggests.
METHODOLOGY:
- The researchers utilized a diverse dataset of 3,014 CT scans: 1,105 diagnostic CT scans with pancreatic ductal adenocarcinoma (PDA) and 1,909 control CT scans.
- Of the total, 696 diagnostic CT scans with PDA and 1,080 control CT scans were used as an AI model training subset, and 409 CT scans with PDA and 829 control CT scans were used as an intramural hold-out test subset.
- The model was also tested on a simulated cohort that evaluated the risk for PDA in new-onset diabetes; multicenter public datasets (194 CT scans with PDA and 80 controls); and a cohort of 100 prediagnostic CT scans, incidentally acquired 3-36 months prior to PDA being diagnosed, and 134 controls.
TAKEAWAY:
- The model correctly classified 360 CT scans with PDA (88%) and 783 control CT scans (94%) in the intramural test subset. The mean accuracy was 0.92, the area under the receiver operating characteristic curve was 0.97, sensitivity was 0.88, and specificity was 0.95.
- On heat maps, activation areas overlapped with the tumor in 350 of 360 CT scans (97%).
- Performance was high across tumor stages, with sensitivities of 0.80, 0.87, 0.95, and 1.0 on T1 through T4 stages, respectively. Performance was comparable for hypodense versus isodense tumors (sensitivity of 0.90 vs. 0.82, respectively), patient demographics, CT slice thicknesses, and vendors.
- Findings were generalizable on both the simulated cohort (accuracy, 0.95; area under the ROC curve, 0.97) and public datasets (accuracy, 0.86; AUROC, 0.9).
- Occult PDA was detected on prediagnostic CT scans at a median 475 days before clinical diagnosis. Accuracy was 0.84, AUROC was 0.91, sensitivity was 0.75, and specificity was 0.9.
IN PRACTICE:
“Artificial intelligence model could mitigate the inadequacies of imaging and the diagnostic errors in interpretation, which often contribute to delayed diagnosis of pancreas cancer. In combination with emerging blood-based biomarkers, such a model could be evaluated to screen for sporadic cancer in ongoing trials of high-risk cohorts such as the Early Detection Initiative (NCT04662879).”
SOURCE:
Panagiotis Korfiatis, PhD, of Mayo Clinic, Rochester, Minn., led the study, which was published online in Gastroenterology.
LIMITATIONS:
The retrospective design is prone to selection bias. Results are presented dichotomously as either cancer or control. These are preliminary insights, and prospective clinical trials that incorporate epidemiological risk factors and emerging blood-based biomarkers are needed to further evaluate the model’s performance.
DISCLOSURES:
The research was supported by the National Cancer Institute, the Centene Charitable Foundation, and the Champions for Hope Pancreatic Cancer Research Program of the Funk Zitiello Foundation. One author received an institutional research grant from Sofie Biosciences and Clovis Oncology, is on the BlueStar Genomics advisory board (ad hoc), and is a consultant for Bayer Healthcare, Candel Therapeutics, and UWorld. The remaining authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
TOPLINE:
new research suggests.
METHODOLOGY:
- The researchers utilized a diverse dataset of 3,014 CT scans: 1,105 diagnostic CT scans with pancreatic ductal adenocarcinoma (PDA) and 1,909 control CT scans.
- Of the total, 696 diagnostic CT scans with PDA and 1,080 control CT scans were used as an AI model training subset, and 409 CT scans with PDA and 829 control CT scans were used as an intramural hold-out test subset.
- The model was also tested on a simulated cohort that evaluated the risk for PDA in new-onset diabetes; multicenter public datasets (194 CT scans with PDA and 80 controls); and a cohort of 100 prediagnostic CT scans, incidentally acquired 3-36 months prior to PDA being diagnosed, and 134 controls.
TAKEAWAY:
- The model correctly classified 360 CT scans with PDA (88%) and 783 control CT scans (94%) in the intramural test subset. The mean accuracy was 0.92, the area under the receiver operating characteristic curve was 0.97, sensitivity was 0.88, and specificity was 0.95.
- On heat maps, activation areas overlapped with the tumor in 350 of 360 CT scans (97%).
- Performance was high across tumor stages, with sensitivities of 0.80, 0.87, 0.95, and 1.0 on T1 through T4 stages, respectively. Performance was comparable for hypodense versus isodense tumors (sensitivity of 0.90 vs. 0.82, respectively), patient demographics, CT slice thicknesses, and vendors.
- Findings were generalizable on both the simulated cohort (accuracy, 0.95; area under the ROC curve, 0.97) and public datasets (accuracy, 0.86; AUROC, 0.9).
- Occult PDA was detected on prediagnostic CT scans at a median 475 days before clinical diagnosis. Accuracy was 0.84, AUROC was 0.91, sensitivity was 0.75, and specificity was 0.9.
IN PRACTICE:
“Artificial intelligence model could mitigate the inadequacies of imaging and the diagnostic errors in interpretation, which often contribute to delayed diagnosis of pancreas cancer. In combination with emerging blood-based biomarkers, such a model could be evaluated to screen for sporadic cancer in ongoing trials of high-risk cohorts such as the Early Detection Initiative (NCT04662879).”
SOURCE:
Panagiotis Korfiatis, PhD, of Mayo Clinic, Rochester, Minn., led the study, which was published online in Gastroenterology.
LIMITATIONS:
The retrospective design is prone to selection bias. Results are presented dichotomously as either cancer or control. These are preliminary insights, and prospective clinical trials that incorporate epidemiological risk factors and emerging blood-based biomarkers are needed to further evaluate the model’s performance.
DISCLOSURES:
The research was supported by the National Cancer Institute, the Centene Charitable Foundation, and the Champions for Hope Pancreatic Cancer Research Program of the Funk Zitiello Foundation. One author received an institutional research grant from Sofie Biosciences and Clovis Oncology, is on the BlueStar Genomics advisory board (ad hoc), and is a consultant for Bayer Healthcare, Candel Therapeutics, and UWorld. The remaining authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
TOPLINE:
new research suggests.
METHODOLOGY:
- The researchers utilized a diverse dataset of 3,014 CT scans: 1,105 diagnostic CT scans with pancreatic ductal adenocarcinoma (PDA) and 1,909 control CT scans.
- Of the total, 696 diagnostic CT scans with PDA and 1,080 control CT scans were used as an AI model training subset, and 409 CT scans with PDA and 829 control CT scans were used as an intramural hold-out test subset.
- The model was also tested on a simulated cohort that evaluated the risk for PDA in new-onset diabetes; multicenter public datasets (194 CT scans with PDA and 80 controls); and a cohort of 100 prediagnostic CT scans, incidentally acquired 3-36 months prior to PDA being diagnosed, and 134 controls.
TAKEAWAY:
- The model correctly classified 360 CT scans with PDA (88%) and 783 control CT scans (94%) in the intramural test subset. The mean accuracy was 0.92, the area under the receiver operating characteristic curve was 0.97, sensitivity was 0.88, and specificity was 0.95.
- On heat maps, activation areas overlapped with the tumor in 350 of 360 CT scans (97%).
- Performance was high across tumor stages, with sensitivities of 0.80, 0.87, 0.95, and 1.0 on T1 through T4 stages, respectively. Performance was comparable for hypodense versus isodense tumors (sensitivity of 0.90 vs. 0.82, respectively), patient demographics, CT slice thicknesses, and vendors.
- Findings were generalizable on both the simulated cohort (accuracy, 0.95; area under the ROC curve, 0.97) and public datasets (accuracy, 0.86; AUROC, 0.9).
- Occult PDA was detected on prediagnostic CT scans at a median 475 days before clinical diagnosis. Accuracy was 0.84, AUROC was 0.91, sensitivity was 0.75, and specificity was 0.9.
IN PRACTICE:
“Artificial intelligence model could mitigate the inadequacies of imaging and the diagnostic errors in interpretation, which often contribute to delayed diagnosis of pancreas cancer. In combination with emerging blood-based biomarkers, such a model could be evaluated to screen for sporadic cancer in ongoing trials of high-risk cohorts such as the Early Detection Initiative (NCT04662879).”
SOURCE:
Panagiotis Korfiatis, PhD, of Mayo Clinic, Rochester, Minn., led the study, which was published online in Gastroenterology.
LIMITATIONS:
The retrospective design is prone to selection bias. Results are presented dichotomously as either cancer or control. These are preliminary insights, and prospective clinical trials that incorporate epidemiological risk factors and emerging blood-based biomarkers are needed to further evaluate the model’s performance.
DISCLOSURES:
The research was supported by the National Cancer Institute, the Centene Charitable Foundation, and the Champions for Hope Pancreatic Cancer Research Program of the Funk Zitiello Foundation. One author received an institutional research grant from Sofie Biosciences and Clovis Oncology, is on the BlueStar Genomics advisory board (ad hoc), and is a consultant for Bayer Healthcare, Candel Therapeutics, and UWorld. The remaining authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
GLP-1 agonists linked to higher risk for rare but serious GI complications
Patients taking either of these glucagonlike peptide-1 (GLP-1) receptor agonists had a 9-fold elevation in risk for pancreatitis. They were also 4 times more likely to develop bowel obstruction and over 3.5 times more likely to experience gastroparesis.
The research letter was published online in JAMA.
Investigators say their findings are not about scaring people off the weight-loss drugs, but instead about increasing awareness that these potential adverse outcomes can happen.
“Given the wide use of these drugs, these adverse events, although rare, must be considered by patients thinking about using them for weight loss,” said lead author Mohit Sodhi, MSc, in a news release about the study. Mr. Sodhi is a graduate of the experimental medicine program at the University of British Columbia in Vancouver, and also a 4th-year medical student at UBC.
People taking a GLP-1 agonist to treat diabetes might be more willing to accept the risks, given their potential advantages, especially that of lowering the risk for heart problems, said Mahyar Etminan, PharmD, MSc, the study’s senior author and an expert in drug safety and pharmacoepidemiology at UBC. “But those who are otherwise healthy and just taking them for weight loss might want to be more careful in weighing the risk–benefit equation.”
People taking these drugs for weight loss have an approximately 1%-2% chance of experiencing these events, including a 1% risk for gastroparesis, Dr. Etminan said.
Key findings
The study included 4,144 people taking liraglutide, 613 taking semaglutide, and 654 taking naltrexone/bupropion based on medical records between 2006 and 2020.
They included patients with a recent history of obesity but excluded those with diabetes or who had been prescribed another diabetes medication.
The use of GLP-1 agonists, compared with naltrexone/bupropion, was associated with an increased risk for pancreatitis (adjusted hazard ratio, 9.09; 95% confidence interval, 1.25-66.00), bowel obstruction (HR, 4.22; 95% CI, 1.02-17.40), and gastroparesis (HR, 3.67; 95% CI, 1.15-11.90).
The study also found a higher incidence of biliary disease, but the difference was not statistically significant (HR, 1.50; 95% CI, 0.89-2.53). The incidence of biliary disease (per 1,000 person-years) was 11.7 for semaglutide, 18.6 for liraglutide, and 12.6 for naltrexone/bupropion.
Not the first report of GI issues
“This important paper confirms the safety signals hinted at in previous randomized controlled trials,” said Carel Le Roux, MBChB, PhD, professor of metabolic medicine, Ulster University, Coleraine, Ireland, and professor of experimental pathology at University College Dublin.
“The limitations of the paper are acknowledged but do not detract from the value of the robust data,” Dr. Le Roux said. “Patients should be informed of the low risk of serious complications, such as pancreatitis, gastroparesis, and bowel obstruction, before they start semaglutide or liraglutide.”
This is not the first report of GI issues associated with GLP-1 agonists, but it’s one of the largest. Most reports have been anecdotal. The U.S. Food and Drug Administration announced on Sept. 28 that it would require manufacturers to include a warning about gastrointestinal ileus on the Ozempic (semaglutide) label.
“The results from this study highlight how important it is that patients access these drugs only through trusted medical professionals, and only with ongoing support and monitoring,” noted Simon Cork, PhD, senior lecturer in physiology, Anglia Ruskin University in Cambridge, England.
Dr. Cork added that “it’s important to look at this in the proper context.” Obesity significantly increases the risk for developing cardiovascular disease, type 2 diabetes, cancer, gallbladder disease, and stroke, risks that fall dramatically with clinically meaningful and sustained weight loss, he said.
“For the overwhelming majority of patients for whom these drugs are targeted (those with the most severe forms of obesity), the benefits of weight loss far outweigh the risks,” Dr. Cork said.
The study was independently supported. Mr. Sodhi, Dr. Etminan, and Dr. Cork report no relevant financial relationships. Dr. Le Roux is a consultant and has received research funding and reimbursement of travel expenses from Novo Nordisk.
A version of this article first appeared on Medscape.com.
Patients taking either of these glucagonlike peptide-1 (GLP-1) receptor agonists had a 9-fold elevation in risk for pancreatitis. They were also 4 times more likely to develop bowel obstruction and over 3.5 times more likely to experience gastroparesis.
The research letter was published online in JAMA.
Investigators say their findings are not about scaring people off the weight-loss drugs, but instead about increasing awareness that these potential adverse outcomes can happen.
“Given the wide use of these drugs, these adverse events, although rare, must be considered by patients thinking about using them for weight loss,” said lead author Mohit Sodhi, MSc, in a news release about the study. Mr. Sodhi is a graduate of the experimental medicine program at the University of British Columbia in Vancouver, and also a 4th-year medical student at UBC.
People taking a GLP-1 agonist to treat diabetes might be more willing to accept the risks, given their potential advantages, especially that of lowering the risk for heart problems, said Mahyar Etminan, PharmD, MSc, the study’s senior author and an expert in drug safety and pharmacoepidemiology at UBC. “But those who are otherwise healthy and just taking them for weight loss might want to be more careful in weighing the risk–benefit equation.”
People taking these drugs for weight loss have an approximately 1%-2% chance of experiencing these events, including a 1% risk for gastroparesis, Dr. Etminan said.
Key findings
The study included 4,144 people taking liraglutide, 613 taking semaglutide, and 654 taking naltrexone/bupropion based on medical records between 2006 and 2020.
They included patients with a recent history of obesity but excluded those with diabetes or who had been prescribed another diabetes medication.
The use of GLP-1 agonists, compared with naltrexone/bupropion, was associated with an increased risk for pancreatitis (adjusted hazard ratio, 9.09; 95% confidence interval, 1.25-66.00), bowel obstruction (HR, 4.22; 95% CI, 1.02-17.40), and gastroparesis (HR, 3.67; 95% CI, 1.15-11.90).
The study also found a higher incidence of biliary disease, but the difference was not statistically significant (HR, 1.50; 95% CI, 0.89-2.53). The incidence of biliary disease (per 1,000 person-years) was 11.7 for semaglutide, 18.6 for liraglutide, and 12.6 for naltrexone/bupropion.
Not the first report of GI issues
“This important paper confirms the safety signals hinted at in previous randomized controlled trials,” said Carel Le Roux, MBChB, PhD, professor of metabolic medicine, Ulster University, Coleraine, Ireland, and professor of experimental pathology at University College Dublin.
“The limitations of the paper are acknowledged but do not detract from the value of the robust data,” Dr. Le Roux said. “Patients should be informed of the low risk of serious complications, such as pancreatitis, gastroparesis, and bowel obstruction, before they start semaglutide or liraglutide.”
This is not the first report of GI issues associated with GLP-1 agonists, but it’s one of the largest. Most reports have been anecdotal. The U.S. Food and Drug Administration announced on Sept. 28 that it would require manufacturers to include a warning about gastrointestinal ileus on the Ozempic (semaglutide) label.
“The results from this study highlight how important it is that patients access these drugs only through trusted medical professionals, and only with ongoing support and monitoring,” noted Simon Cork, PhD, senior lecturer in physiology, Anglia Ruskin University in Cambridge, England.
Dr. Cork added that “it’s important to look at this in the proper context.” Obesity significantly increases the risk for developing cardiovascular disease, type 2 diabetes, cancer, gallbladder disease, and stroke, risks that fall dramatically with clinically meaningful and sustained weight loss, he said.
“For the overwhelming majority of patients for whom these drugs are targeted (those with the most severe forms of obesity), the benefits of weight loss far outweigh the risks,” Dr. Cork said.
The study was independently supported. Mr. Sodhi, Dr. Etminan, and Dr. Cork report no relevant financial relationships. Dr. Le Roux is a consultant and has received research funding and reimbursement of travel expenses from Novo Nordisk.
A version of this article first appeared on Medscape.com.
Patients taking either of these glucagonlike peptide-1 (GLP-1) receptor agonists had a 9-fold elevation in risk for pancreatitis. They were also 4 times more likely to develop bowel obstruction and over 3.5 times more likely to experience gastroparesis.
The research letter was published online in JAMA.
Investigators say their findings are not about scaring people off the weight-loss drugs, but instead about increasing awareness that these potential adverse outcomes can happen.
“Given the wide use of these drugs, these adverse events, although rare, must be considered by patients thinking about using them for weight loss,” said lead author Mohit Sodhi, MSc, in a news release about the study. Mr. Sodhi is a graduate of the experimental medicine program at the University of British Columbia in Vancouver, and also a 4th-year medical student at UBC.
People taking a GLP-1 agonist to treat diabetes might be more willing to accept the risks, given their potential advantages, especially that of lowering the risk for heart problems, said Mahyar Etminan, PharmD, MSc, the study’s senior author and an expert in drug safety and pharmacoepidemiology at UBC. “But those who are otherwise healthy and just taking them for weight loss might want to be more careful in weighing the risk–benefit equation.”
People taking these drugs for weight loss have an approximately 1%-2% chance of experiencing these events, including a 1% risk for gastroparesis, Dr. Etminan said.
Key findings
The study included 4,144 people taking liraglutide, 613 taking semaglutide, and 654 taking naltrexone/bupropion based on medical records between 2006 and 2020.
They included patients with a recent history of obesity but excluded those with diabetes or who had been prescribed another diabetes medication.
The use of GLP-1 agonists, compared with naltrexone/bupropion, was associated with an increased risk for pancreatitis (adjusted hazard ratio, 9.09; 95% confidence interval, 1.25-66.00), bowel obstruction (HR, 4.22; 95% CI, 1.02-17.40), and gastroparesis (HR, 3.67; 95% CI, 1.15-11.90).
The study also found a higher incidence of biliary disease, but the difference was not statistically significant (HR, 1.50; 95% CI, 0.89-2.53). The incidence of biliary disease (per 1,000 person-years) was 11.7 for semaglutide, 18.6 for liraglutide, and 12.6 for naltrexone/bupropion.
Not the first report of GI issues
“This important paper confirms the safety signals hinted at in previous randomized controlled trials,” said Carel Le Roux, MBChB, PhD, professor of metabolic medicine, Ulster University, Coleraine, Ireland, and professor of experimental pathology at University College Dublin.
“The limitations of the paper are acknowledged but do not detract from the value of the robust data,” Dr. Le Roux said. “Patients should be informed of the low risk of serious complications, such as pancreatitis, gastroparesis, and bowel obstruction, before they start semaglutide or liraglutide.”
This is not the first report of GI issues associated with GLP-1 agonists, but it’s one of the largest. Most reports have been anecdotal. The U.S. Food and Drug Administration announced on Sept. 28 that it would require manufacturers to include a warning about gastrointestinal ileus on the Ozempic (semaglutide) label.
“The results from this study highlight how important it is that patients access these drugs only through trusted medical professionals, and only with ongoing support and monitoring,” noted Simon Cork, PhD, senior lecturer in physiology, Anglia Ruskin University in Cambridge, England.
Dr. Cork added that “it’s important to look at this in the proper context.” Obesity significantly increases the risk for developing cardiovascular disease, type 2 diabetes, cancer, gallbladder disease, and stroke, risks that fall dramatically with clinically meaningful and sustained weight loss, he said.
“For the overwhelming majority of patients for whom these drugs are targeted (those with the most severe forms of obesity), the benefits of weight loss far outweigh the risks,” Dr. Cork said.
The study was independently supported. Mr. Sodhi, Dr. Etminan, and Dr. Cork report no relevant financial relationships. Dr. Le Roux is a consultant and has received research funding and reimbursement of travel expenses from Novo Nordisk.
A version of this article first appeared on Medscape.com.
FROM JAMA
Obesity linked to multiple ills in MS study
MILAN – Swedish researchers reported at the 9th Joint ECTRIMS-ACTRIMS meeting.
In a group of 3,249 subjects tracked for up to 5 years (74% female; mean age, 37.8 years), patients who were obese at diagnosis were 1.41 times more likely than normal-weight patients to reach an Expanded Disability Status Scale (EDSS) score of 3. About 35% of 355 obese subjects (body mass index > 30 kg/m2) reached that level versus 29% of 713 overweight patients (BMI, 25-30) and 28% of 1,475 normal-weight patients (BMI, 18.5-24.99).
Among subjects whose BMI category didn’t change over follow-up, those who were obese at diagnosis were more likely to develop cognitive worsening than those who weren’t obese (hazard ratio, 1.47, 95% confidence interval, 1.08-2.01).
Lars Alfredsson, PhD, a professor at the Karolinska Institutet, Stockholm, who presented the study findings, said in an interview that they fill a gap in knowledge about obesity and MS. “It is known that obesity around the age of 20 or in adolescence is a risk factor for developing MS. But much less is known in regard to progression, and the studies have been very inconclusive.”
The researchers tracked patients via the Swedish MS registry: 1,475 of normal weight, 713 overweight, and 355 obese. Before adjustment for factors such as age, gender, and baseline EDSS, obese subjects were 1.51 times more likely to reach EDSS score 3 than normal-weight subjects.
Obese subjects whose BMI level didn’t change over time were 1.70 times more likely than the nonobese to develop physical worsening as measured by an increased Multiple Sclerosis Impact Scale physical score of 7.5 points or more, and they were 1.36 times more likely to have psychological worsening as measured by increased MSIS-28 psychological score of 7.5 points or more.
Also, among subjects whose BMI didn’t change over time, the likelihood of cognitive disability worsening was 1.47 times higher among obese participants versus nonobese participants. Worsening was defined as an increased Symbol Digit Modalities Test score of 8 points or more.
The level of excess cognitive decline “will affect people significantly,” Dr. Alfredsson said.
While obesity can counterintuitively provide a protective effect in some diseases, he said there’s no sign of such an effect in the subjects.
As for limitations, Dr. Alfredsson noted in his presentation that BMI data is self-reported, and it’s possible that the researchers didn’t adjust their statistics to reflect important confounders.
A 2023 German study of outcomes in MS patients with obesity came to similar conclusions. It tracked 1,066 subjects for up to 6 years and found that “median time to reach EDSS 3 was 0.99 years for patients with BMI of 30 or higher and 1.46 years for nonobese patients. Risk to reach EDSS 3 over 6 years was significantly increased in patients with BMI of at least 30, compared with patients with BMI less than 30 after adjustment for sex, age, smoking (HR, 1.87; 95% CI, 1.3-2.6; P < .001), and independent of disease-modifying therapies.”
However, the German researchers found no link between obesity and higher levels of relapse, contrast-enhancing MRI lesions, or MRI T2 lesion burden.
Interpretation and commentary
Could obesity be causing worse outcomes? The new study doesn’t provide insight into cause and effect. However, obesity may speed up progression via low-grade inflammation, Dr. Alfredsson said.
What can clinicians do with the information from the study? If patients are obese, it can be a good idea to more carefully monitor them and use reliable tools to improve their progression, Dr. Alfredsson said.
In an interview, Michael D. Kornberg, MD, PhD, an assistant professor of neurology at Johns Hopkins University, Baltimore, who was not involved with the study, agreed with Dr. Alfredsson that other research has linked obesity early in life to higher rates of MS. He added that “a number of studies have shown that comorbidities in general are usually associated with a higher rate of disability.”
Dr. Kornberg said the new research is important, and he noted that it has a “robust” cohort because of its larger size.
Could patients with MS reverse the risk of progression and other poor outcomes by losing weight? “It’s hard to say,” Dr. Kornberg said. “We have to be cautious when we assume causation. There’s a plausible rationale that obesity might worsen progression in MS, but it could just be a marker of some other factor that reflects a different phenotype of MS.”
He doesn’t think it’s likely that weight loss would “dramatically reverse the biology of MS,” but he said reversing the obesity epidemic would still be a good thing. An interventional study could examine the effects of weight-loss intervention on disability measures, he said, “and that’s the next step.”
Also contacted for commentary, Adil Harroud, MD, a neurologist at McGill University who studies obesity in MS, said research suggests that “obesity seems to exacerbate MS disability. While some studies show no effect, the majority indicate a detrimental impact.”
However, “the effect of obesity on MS progression remains unclear. Animal studies suggest that shifts in immune cell subsets and functions may play a role, but the relevance to humans is yet to be determined,” he said.
Dr. Harroud, who did not take part in the new study, said it’s “one of the largest examining the impact of obesity on MS disability.” He added that “the cohort was relatively early in their disease course, suggesting that obesity impacts even the early stages of MS. This underscores the importance of obesity as a modifiable risk factor for disability accumulation.”
As for why obesity affects MS, he said one theory is that obesity plays a role through its impact on vitamin D levels. “However, using a genetic approach, we have demonstrated that, at least for MS risk, the effect of obesity is independent of vitamin D. This is also likely true for MS progression, as recent trials of vitamin D supplementation have not shown a meaningful impact on MS outcomes.”
According to Dr. Harroud, “other theories suggest that obesity leads to a pro-inflammatory immune shift. Additionally, it has been proposed that obesity may influence the response to disease-modifying therapy by reducing drug bioavailability, potentially necessitating weight-based dosing for some therapies.”
Dr. Alfredsson reported receiving grants from the Swedish Research Council, the Swedish Research Council for Health Working Life and Welfare, and the Swedish Brain Foundation and personal fees from Teva and Biogene Idec. Some of the other study authors reported various disclosures. Dr. Kornberg and Dr. Harroud reported no relevant disclosures.
This article was updated 10/20/23.
MILAN – Swedish researchers reported at the 9th Joint ECTRIMS-ACTRIMS meeting.
In a group of 3,249 subjects tracked for up to 5 years (74% female; mean age, 37.8 years), patients who were obese at diagnosis were 1.41 times more likely than normal-weight patients to reach an Expanded Disability Status Scale (EDSS) score of 3. About 35% of 355 obese subjects (body mass index > 30 kg/m2) reached that level versus 29% of 713 overweight patients (BMI, 25-30) and 28% of 1,475 normal-weight patients (BMI, 18.5-24.99).
Among subjects whose BMI category didn’t change over follow-up, those who were obese at diagnosis were more likely to develop cognitive worsening than those who weren’t obese (hazard ratio, 1.47, 95% confidence interval, 1.08-2.01).
Lars Alfredsson, PhD, a professor at the Karolinska Institutet, Stockholm, who presented the study findings, said in an interview that they fill a gap in knowledge about obesity and MS. “It is known that obesity around the age of 20 or in adolescence is a risk factor for developing MS. But much less is known in regard to progression, and the studies have been very inconclusive.”
The researchers tracked patients via the Swedish MS registry: 1,475 of normal weight, 713 overweight, and 355 obese. Before adjustment for factors such as age, gender, and baseline EDSS, obese subjects were 1.51 times more likely to reach EDSS score 3 than normal-weight subjects.
Obese subjects whose BMI level didn’t change over time were 1.70 times more likely than the nonobese to develop physical worsening as measured by an increased Multiple Sclerosis Impact Scale physical score of 7.5 points or more, and they were 1.36 times more likely to have psychological worsening as measured by increased MSIS-28 psychological score of 7.5 points or more.
Also, among subjects whose BMI didn’t change over time, the likelihood of cognitive disability worsening was 1.47 times higher among obese participants versus nonobese participants. Worsening was defined as an increased Symbol Digit Modalities Test score of 8 points or more.
The level of excess cognitive decline “will affect people significantly,” Dr. Alfredsson said.
While obesity can counterintuitively provide a protective effect in some diseases, he said there’s no sign of such an effect in the subjects.
As for limitations, Dr. Alfredsson noted in his presentation that BMI data is self-reported, and it’s possible that the researchers didn’t adjust their statistics to reflect important confounders.
A 2023 German study of outcomes in MS patients with obesity came to similar conclusions. It tracked 1,066 subjects for up to 6 years and found that “median time to reach EDSS 3 was 0.99 years for patients with BMI of 30 or higher and 1.46 years for nonobese patients. Risk to reach EDSS 3 over 6 years was significantly increased in patients with BMI of at least 30, compared with patients with BMI less than 30 after adjustment for sex, age, smoking (HR, 1.87; 95% CI, 1.3-2.6; P < .001), and independent of disease-modifying therapies.”
However, the German researchers found no link between obesity and higher levels of relapse, contrast-enhancing MRI lesions, or MRI T2 lesion burden.
Interpretation and commentary
Could obesity be causing worse outcomes? The new study doesn’t provide insight into cause and effect. However, obesity may speed up progression via low-grade inflammation, Dr. Alfredsson said.
What can clinicians do with the information from the study? If patients are obese, it can be a good idea to more carefully monitor them and use reliable tools to improve their progression, Dr. Alfredsson said.
In an interview, Michael D. Kornberg, MD, PhD, an assistant professor of neurology at Johns Hopkins University, Baltimore, who was not involved with the study, agreed with Dr. Alfredsson that other research has linked obesity early in life to higher rates of MS. He added that “a number of studies have shown that comorbidities in general are usually associated with a higher rate of disability.”
Dr. Kornberg said the new research is important, and he noted that it has a “robust” cohort because of its larger size.
Could patients with MS reverse the risk of progression and other poor outcomes by losing weight? “It’s hard to say,” Dr. Kornberg said. “We have to be cautious when we assume causation. There’s a plausible rationale that obesity might worsen progression in MS, but it could just be a marker of some other factor that reflects a different phenotype of MS.”
He doesn’t think it’s likely that weight loss would “dramatically reverse the biology of MS,” but he said reversing the obesity epidemic would still be a good thing. An interventional study could examine the effects of weight-loss intervention on disability measures, he said, “and that’s the next step.”
Also contacted for commentary, Adil Harroud, MD, a neurologist at McGill University who studies obesity in MS, said research suggests that “obesity seems to exacerbate MS disability. While some studies show no effect, the majority indicate a detrimental impact.”
However, “the effect of obesity on MS progression remains unclear. Animal studies suggest that shifts in immune cell subsets and functions may play a role, but the relevance to humans is yet to be determined,” he said.
Dr. Harroud, who did not take part in the new study, said it’s “one of the largest examining the impact of obesity on MS disability.” He added that “the cohort was relatively early in their disease course, suggesting that obesity impacts even the early stages of MS. This underscores the importance of obesity as a modifiable risk factor for disability accumulation.”
As for why obesity affects MS, he said one theory is that obesity plays a role through its impact on vitamin D levels. “However, using a genetic approach, we have demonstrated that, at least for MS risk, the effect of obesity is independent of vitamin D. This is also likely true for MS progression, as recent trials of vitamin D supplementation have not shown a meaningful impact on MS outcomes.”
According to Dr. Harroud, “other theories suggest that obesity leads to a pro-inflammatory immune shift. Additionally, it has been proposed that obesity may influence the response to disease-modifying therapy by reducing drug bioavailability, potentially necessitating weight-based dosing for some therapies.”
Dr. Alfredsson reported receiving grants from the Swedish Research Council, the Swedish Research Council for Health Working Life and Welfare, and the Swedish Brain Foundation and personal fees from Teva and Biogene Idec. Some of the other study authors reported various disclosures. Dr. Kornberg and Dr. Harroud reported no relevant disclosures.
This article was updated 10/20/23.
MILAN – Swedish researchers reported at the 9th Joint ECTRIMS-ACTRIMS meeting.
In a group of 3,249 subjects tracked for up to 5 years (74% female; mean age, 37.8 years), patients who were obese at diagnosis were 1.41 times more likely than normal-weight patients to reach an Expanded Disability Status Scale (EDSS) score of 3. About 35% of 355 obese subjects (body mass index > 30 kg/m2) reached that level versus 29% of 713 overweight patients (BMI, 25-30) and 28% of 1,475 normal-weight patients (BMI, 18.5-24.99).
Among subjects whose BMI category didn’t change over follow-up, those who were obese at diagnosis were more likely to develop cognitive worsening than those who weren’t obese (hazard ratio, 1.47, 95% confidence interval, 1.08-2.01).
Lars Alfredsson, PhD, a professor at the Karolinska Institutet, Stockholm, who presented the study findings, said in an interview that they fill a gap in knowledge about obesity and MS. “It is known that obesity around the age of 20 or in adolescence is a risk factor for developing MS. But much less is known in regard to progression, and the studies have been very inconclusive.”
The researchers tracked patients via the Swedish MS registry: 1,475 of normal weight, 713 overweight, and 355 obese. Before adjustment for factors such as age, gender, and baseline EDSS, obese subjects were 1.51 times more likely to reach EDSS score 3 than normal-weight subjects.
Obese subjects whose BMI level didn’t change over time were 1.70 times more likely than the nonobese to develop physical worsening as measured by an increased Multiple Sclerosis Impact Scale physical score of 7.5 points or more, and they were 1.36 times more likely to have psychological worsening as measured by increased MSIS-28 psychological score of 7.5 points or more.
Also, among subjects whose BMI didn’t change over time, the likelihood of cognitive disability worsening was 1.47 times higher among obese participants versus nonobese participants. Worsening was defined as an increased Symbol Digit Modalities Test score of 8 points or more.
The level of excess cognitive decline “will affect people significantly,” Dr. Alfredsson said.
While obesity can counterintuitively provide a protective effect in some diseases, he said there’s no sign of such an effect in the subjects.
As for limitations, Dr. Alfredsson noted in his presentation that BMI data is self-reported, and it’s possible that the researchers didn’t adjust their statistics to reflect important confounders.
A 2023 German study of outcomes in MS patients with obesity came to similar conclusions. It tracked 1,066 subjects for up to 6 years and found that “median time to reach EDSS 3 was 0.99 years for patients with BMI of 30 or higher and 1.46 years for nonobese patients. Risk to reach EDSS 3 over 6 years was significantly increased in patients with BMI of at least 30, compared with patients with BMI less than 30 after adjustment for sex, age, smoking (HR, 1.87; 95% CI, 1.3-2.6; P < .001), and independent of disease-modifying therapies.”
However, the German researchers found no link between obesity and higher levels of relapse, contrast-enhancing MRI lesions, or MRI T2 lesion burden.
Interpretation and commentary
Could obesity be causing worse outcomes? The new study doesn’t provide insight into cause and effect. However, obesity may speed up progression via low-grade inflammation, Dr. Alfredsson said.
What can clinicians do with the information from the study? If patients are obese, it can be a good idea to more carefully monitor them and use reliable tools to improve their progression, Dr. Alfredsson said.
In an interview, Michael D. Kornberg, MD, PhD, an assistant professor of neurology at Johns Hopkins University, Baltimore, who was not involved with the study, agreed with Dr. Alfredsson that other research has linked obesity early in life to higher rates of MS. He added that “a number of studies have shown that comorbidities in general are usually associated with a higher rate of disability.”
Dr. Kornberg said the new research is important, and he noted that it has a “robust” cohort because of its larger size.
Could patients with MS reverse the risk of progression and other poor outcomes by losing weight? “It’s hard to say,” Dr. Kornberg said. “We have to be cautious when we assume causation. There’s a plausible rationale that obesity might worsen progression in MS, but it could just be a marker of some other factor that reflects a different phenotype of MS.”
He doesn’t think it’s likely that weight loss would “dramatically reverse the biology of MS,” but he said reversing the obesity epidemic would still be a good thing. An interventional study could examine the effects of weight-loss intervention on disability measures, he said, “and that’s the next step.”
Also contacted for commentary, Adil Harroud, MD, a neurologist at McGill University who studies obesity in MS, said research suggests that “obesity seems to exacerbate MS disability. While some studies show no effect, the majority indicate a detrimental impact.”
However, “the effect of obesity on MS progression remains unclear. Animal studies suggest that shifts in immune cell subsets and functions may play a role, but the relevance to humans is yet to be determined,” he said.
Dr. Harroud, who did not take part in the new study, said it’s “one of the largest examining the impact of obesity on MS disability.” He added that “the cohort was relatively early in their disease course, suggesting that obesity impacts even the early stages of MS. This underscores the importance of obesity as a modifiable risk factor for disability accumulation.”
As for why obesity affects MS, he said one theory is that obesity plays a role through its impact on vitamin D levels. “However, using a genetic approach, we have demonstrated that, at least for MS risk, the effect of obesity is independent of vitamin D. This is also likely true for MS progression, as recent trials of vitamin D supplementation have not shown a meaningful impact on MS outcomes.”
According to Dr. Harroud, “other theories suggest that obesity leads to a pro-inflammatory immune shift. Additionally, it has been proposed that obesity may influence the response to disease-modifying therapy by reducing drug bioavailability, potentially necessitating weight-based dosing for some therapies.”
Dr. Alfredsson reported receiving grants from the Swedish Research Council, the Swedish Research Council for Health Working Life and Welfare, and the Swedish Brain Foundation and personal fees from Teva and Biogene Idec. Some of the other study authors reported various disclosures. Dr. Kornberg and Dr. Harroud reported no relevant disclosures.
This article was updated 10/20/23.
AT ECTRIMS 2023
Repetitive primary care screenings may miss depression and anxiety
Routine screening for depression and anxiety at each primary care clinical encounter in order to meet performance metrics could compromise accuracy and clinical care, based on data from more than 380,000 individuals in primary care.
“Prioritizing repetition of intake screening questionnaires at primary care visits may have unintended consequences such as administrative burden, provision of low-value care, and reduced clinical capacity to deliver other, high-value services,” but the accuracy of workflow-based intake screening on subsequent diagnosis has not been explored, wrote Jodi Simon, DrPH, of AllianceChicago, Ill., and colleagues.
In a study published in the Annals of Family Medicine, the researchers reviewed data from screenings performed on 380,057 patients in primary care settings. They examined the accuracy and utility of the Patient Health Questionnaire (PHQ-2) for depression and the Generalized Anxiety Disorder 2 (GAD-2) for anxiety.
The data included 1,883,317 screenings with PHQ-2s and 1,573,107 with GAD-2s. Of these, 92.3% of PHQ-2 screenings and 91.4% of GAD-2 screenings indicated low likelihood of depression or anxiety (defined as cumulative scores of 0 or 1). Mean scores for the PHQ-2 and GAD-2 in the study population were 0.29 and 0.35, respectively.
In the current study, 11% of patients had positive PHQ-2 scores (defined as 2 or higher) vs. 47%-53% seen in previous studies and census data.
In an analysis of new diagnoses of depression and anxiety, the researchers found that 42.3% of patients with a new depression diagnosis were not identified on intake screening; they had scores of 0 or 1 on the PHQ-2 in the past 30 days. Similarly, 42.7% of patients with a new anxiety diagnosis had scores of 0 or 1 on the GAD-2 in the past 30 days.
In other words, “Screening only detected risk in 57.7% of patients subsequently diagnosed with depression and 57.3% of patients subsequently diagnosed with anxiety,” the researchers said. This low positivity rate in patients diagnosed within 30 days merits further research, they added.
More studies are needed, but preliminary interviews with patients, clinicians, and staff indicate that time constraints and variation in the administration of questionnaires are among the factors contributing to inaccurate screening, the researchers noted.
The current study results suggest that screenings for anxiety and depression may occur in a perfunctory or inconsistent manner that might compromise accuracy when they are part of the workflow for each clinical visit in order to meet performance metrics, they said. “Ineffective screening may unintentionally detract from clinical care because care teams and patients have less time and cognitive energy to focus on other priorities during busy clinical encounters,” they added.
Alternatively, , the researchers concluded.
The study was funded by the American Medical Association Transformation Initiative. The researchers had no financial conflicts to disclose.
Routine screening for depression and anxiety at each primary care clinical encounter in order to meet performance metrics could compromise accuracy and clinical care, based on data from more than 380,000 individuals in primary care.
“Prioritizing repetition of intake screening questionnaires at primary care visits may have unintended consequences such as administrative burden, provision of low-value care, and reduced clinical capacity to deliver other, high-value services,” but the accuracy of workflow-based intake screening on subsequent diagnosis has not been explored, wrote Jodi Simon, DrPH, of AllianceChicago, Ill., and colleagues.
In a study published in the Annals of Family Medicine, the researchers reviewed data from screenings performed on 380,057 patients in primary care settings. They examined the accuracy and utility of the Patient Health Questionnaire (PHQ-2) for depression and the Generalized Anxiety Disorder 2 (GAD-2) for anxiety.
The data included 1,883,317 screenings with PHQ-2s and 1,573,107 with GAD-2s. Of these, 92.3% of PHQ-2 screenings and 91.4% of GAD-2 screenings indicated low likelihood of depression or anxiety (defined as cumulative scores of 0 or 1). Mean scores for the PHQ-2 and GAD-2 in the study population were 0.29 and 0.35, respectively.
In the current study, 11% of patients had positive PHQ-2 scores (defined as 2 or higher) vs. 47%-53% seen in previous studies and census data.
In an analysis of new diagnoses of depression and anxiety, the researchers found that 42.3% of patients with a new depression diagnosis were not identified on intake screening; they had scores of 0 or 1 on the PHQ-2 in the past 30 days. Similarly, 42.7% of patients with a new anxiety diagnosis had scores of 0 or 1 on the GAD-2 in the past 30 days.
In other words, “Screening only detected risk in 57.7% of patients subsequently diagnosed with depression and 57.3% of patients subsequently diagnosed with anxiety,” the researchers said. This low positivity rate in patients diagnosed within 30 days merits further research, they added.
More studies are needed, but preliminary interviews with patients, clinicians, and staff indicate that time constraints and variation in the administration of questionnaires are among the factors contributing to inaccurate screening, the researchers noted.
The current study results suggest that screenings for anxiety and depression may occur in a perfunctory or inconsistent manner that might compromise accuracy when they are part of the workflow for each clinical visit in order to meet performance metrics, they said. “Ineffective screening may unintentionally detract from clinical care because care teams and patients have less time and cognitive energy to focus on other priorities during busy clinical encounters,” they added.
Alternatively, , the researchers concluded.
The study was funded by the American Medical Association Transformation Initiative. The researchers had no financial conflicts to disclose.
Routine screening for depression and anxiety at each primary care clinical encounter in order to meet performance metrics could compromise accuracy and clinical care, based on data from more than 380,000 individuals in primary care.
“Prioritizing repetition of intake screening questionnaires at primary care visits may have unintended consequences such as administrative burden, provision of low-value care, and reduced clinical capacity to deliver other, high-value services,” but the accuracy of workflow-based intake screening on subsequent diagnosis has not been explored, wrote Jodi Simon, DrPH, of AllianceChicago, Ill., and colleagues.
In a study published in the Annals of Family Medicine, the researchers reviewed data from screenings performed on 380,057 patients in primary care settings. They examined the accuracy and utility of the Patient Health Questionnaire (PHQ-2) for depression and the Generalized Anxiety Disorder 2 (GAD-2) for anxiety.
The data included 1,883,317 screenings with PHQ-2s and 1,573,107 with GAD-2s. Of these, 92.3% of PHQ-2 screenings and 91.4% of GAD-2 screenings indicated low likelihood of depression or anxiety (defined as cumulative scores of 0 or 1). Mean scores for the PHQ-2 and GAD-2 in the study population were 0.29 and 0.35, respectively.
In the current study, 11% of patients had positive PHQ-2 scores (defined as 2 or higher) vs. 47%-53% seen in previous studies and census data.
In an analysis of new diagnoses of depression and anxiety, the researchers found that 42.3% of patients with a new depression diagnosis were not identified on intake screening; they had scores of 0 or 1 on the PHQ-2 in the past 30 days. Similarly, 42.7% of patients with a new anxiety diagnosis had scores of 0 or 1 on the GAD-2 in the past 30 days.
In other words, “Screening only detected risk in 57.7% of patients subsequently diagnosed with depression and 57.3% of patients subsequently diagnosed with anxiety,” the researchers said. This low positivity rate in patients diagnosed within 30 days merits further research, they added.
More studies are needed, but preliminary interviews with patients, clinicians, and staff indicate that time constraints and variation in the administration of questionnaires are among the factors contributing to inaccurate screening, the researchers noted.
The current study results suggest that screenings for anxiety and depression may occur in a perfunctory or inconsistent manner that might compromise accuracy when they are part of the workflow for each clinical visit in order to meet performance metrics, they said. “Ineffective screening may unintentionally detract from clinical care because care teams and patients have less time and cognitive energy to focus on other priorities during busy clinical encounters,” they added.
Alternatively, , the researchers concluded.
The study was funded by the American Medical Association Transformation Initiative. The researchers had no financial conflicts to disclose.
FROM THE ANNALS OF FAMILY MEDICINE
Male patients with breast cancer: Special considerations and gender-specific concerns
This transcript has been edited for clarity.
Fatima Cardoso, MD: Today we will be discussing breast cancer in male patients. To join me in this discussion, I have Sharon Giordano and Oliver Bogler. I will ask, to start, that we briefly introduce ourselves.
I’m Fatima Cardoso. I’m a medical oncologist based in Lisbon, Portugal. I have had a special interest in this topic for a couple of years. Sharon?
Sharon H. Giordano, MD, MPH, FASCO: I’m Sharon Giordano. I practice at the University of Texas MD Anderson Cancer Center. I’m also a medical oncologist and treat most of the male breast cancer patients that are seen here.
Oliver Bogler, PhD: I’m Oliver Bogler. I’m a cancer biologist by background and an 11-year survivor of breast cancer. Dr. Giordano was my oncologist during the active phase of my treatment. It’s great to be here with you.
Special considerations surrounding male patients
- Dr. Cardoso: Sharon, when you are treating breast cancer in a male patient, what specific considerations do you have?
- Dr. Giordano: As we all know, breast cancer in men is a rare disease. It makes up about 1 in 1,000 cases of breast cancer.
Often, what we need to do and what we end up doing is extrapolating as much as possible from clinical trials that were conducted in female patients with breast cancer. I think that’s one of the major challenges we face in treating the disease. There have been international efforts to try to put together standardized treatment approaches.
For example, ASCO has created guidelines for the management of male breast cancer. NCCN also has a special page on considerations for treatment of men with breast cancer. I would encourage people to look at those resources if questions do come up on the topic.
Dr. Cardoso: Perhaps we can also mention that the latest clinical trials fortunately have been allowing for male patients to be included, which is very important so that we can start having some data on the new drugs. I think that’s also relevant.
Dr. Giordano: That’s a great point because, historically, most of the trials explicitly excluded men. I don’t know if it was intentional or they just wrote the trials saying “women with breast cancer,” because that’s what most people thought of. I think it’s a great effort by the FDA and by investigators to make sure now that men are included in the trials. That will help build our evidence base.
Dr. Cardoso: Oliver, 11 years ago, you faced the diagnosis and you went through this. Can you speak a little bit about this challenge of going through what is considered a rare disease, but also a disease that is very much associated with the female gender traditionally?
Dr. Bogler: Gladly. For me, it was particularly odd because my wife, at the time that I was diagnosed, was a 5-year survivor of breast cancer. It took me some time to even think that the lump I felt might be the same disease. That seemed very unlikely, statistically, and also odd.
I have to say that I was protected from much of the fish-out-of-water experience that many men have because I both worked and was treated at MD Anderson, where Dr Giordano has a large practice, so my colleagues and my friends were not surprised that a man could get this disease.
Many of the patients I met had that experience, difficulty convincing their primary care physician or even their first-line oncologist that this could be the case. I just want to connect to what you both said, which is that 10 years ago, inclusion of men in clinical trials was not standard. It is a fantastic development to see that because unless we include men, we won’t learn about that type of breast cancer.
Dr. Cardoso: Even if only a few are entering each trial, at least it allows us to see if the drug behaves the same way or if there is any strange behavior of the drug in a male patient. It’s already one step forward. You were going to mention something, Sharon?
Dr. Giordano: I was going to say that, anecdotally, I’ve heard the experience that Oliver referred to, of many men feeling not so much uncomfortable with the diagnosis – although that does happen – but not having an obvious fit within the health care system.
For example, going to get their mammogram as part of their diagnostic workup and whoever might be taking them back saying, “Oh, no, this is Mrs. Jones, not Mr.,” and trying to argue with them that it’s not really meant for them. I had a patient – and this guy had a great sense of humor – who had a biopsy done and the instructions were to place this pink, floral ice pack inside your bra.
Even the materials that we have are gender specific. I think those things all together can certainly contribute to a man feeling like a fish out of water.
Dr. Cardoso: Actually, I fought in my institution because they wanted to call the Breast and Gynecology Unit the Women’s Unit. I said that there is no way you can call it the Women’s Unit because we have male patients. There are small things that we can do in our institutions to try to decrease the stigma and to make it less awkward for a man to be in a waiting room that says Women’s Clinic or something similar to that.
The importance of a support system
Dr. Cardoso: I wanted Oliver, perhaps, to mention experiences that you may have heard from other men. Some men do not feel that comfortable speaking about the disease. Also, some of them do not feel comfortable after treatment to go to the beach, to show the scar, and to show what happens after you have radiation.
Some men actually take it quite heavily, psychologically speaking. Have you encountered some of these men?
Dr. Bogler: Definitely. I think it leads to men not accessing the support opportunities – their family, their friends, or the support groups – and staying away from those because of this feeling of not wanting to share about it. That can be damaging. Cancer treatment is usually a tough road for most people, and the long-term consequences of hormone therapy – most men have hormone-driven disease – can be significant. I agree with you.
I participated in the male breast cancer SCAR Project by David Jay, a famous photographer. One of the high points of my life has been appearing in The New York Times topless, right after my radiation treatment, showing my scar. There are quite a few of us out there who’ve done that.
I’ll just mention in passing the Male Breast Cancer Global Alliance, which is a patient support supergroup, if you will. We’ve got a symposium coming up in November. That’s a great place for men who are early in the stage of their disease, or at any stage, to connect to others who are facing this issue.
Dr. Cardoso: They can also find specific information. This is a really good website where you can find information. One of the most important topics that I’ve heard from my patients is, “I never thought that I could have this disease. I never heard that men could have breast cancer as well.” Information is very crucial.
I believe that if you are well informed, you will also be less scared of the disease. Sources of reliable information are really crucial for patients. Since you mentioned the SCAR Project, we have a similar project here in Portugal that really called attention to the disease. It was very visual and really interesting.
Discussions during and after treatment
Dr. Cardoso: I wanted to say something, and I don’t know if both of you would agree. I think only recently surgeons have started to pay attention to the way they operate on men with breast cancer, and even in considering techniques of breast conservation and oncoplastic surgery. I had the feeling, looking at those photos, that some years ago, it wouldn’t have mattered how they do with the mastectomy scar just because it was a man. This was biased, right?
Just because it was a man, there was no need to pay attention to the aesthetic outcome. That is wrong, in my perspective. I’m very happy to see that now there are surgeons considering other types of breast surgery to conserve as much as possible the aesthetic outcome.
Dr. Bogler: I have to say that I was offered reconstruction at MD Anderson. I declined it. It wasn’t that big a part of my body image. When I raised this issue at home, my kids, who were quite young at the time, just suggested, “Well, Dad, why don’t you just wear a swim shirt?” They came up with a very practical solution for this issue.
I agree with you that it should be an option. I was also offered a nipple tattoo. I have yet to take that up, but maybe one day.
Dr. Cardoso: I’m not sure that we need to go into reconstruction. It also depends on whether a man has gynecomastia, if it’s going to be very asymmetric. There are other techniques to do, and depending on the size of the tumor, we can also do breast conservation, which we have done here in a couple of patients.
It’s quite an interesting approach where, for example, a skin-sparing mastectomy would be less aggressive, let’s say. Sharon?
Dr. Giordano: I completely agree. I’ve noticed increasing attention to the issue over the years that I’ve been in practice. I do think that it’s more front-and-center when the surgeons are having discussions with the patients now.
Also, although it’s still a minority, some do choose to have reconstructive surgery; some have more extensive surgeries, and some maybe have nipple reconstruction or a nipple tattoo. In a few men, like you mentioned, who are somewhat asymmetric, it actually can make a difference even when they’re dressed.
For many men, it’s more that they want to take off their shirt to play basketball or go swimming, and to decrease the feeling of awkwardness or like they have to make an explanation for why they have a nipple missing and a scar across their chest.
Biological aspects of male patients
Dr. Cardoso: Let’s switch gears now to the management, and before that, the biology. Oliver, with your other hat of biology, speak a little bit on what we know so far – whether it is exactly the same disease or there are biological specific characteristics of breast cancer in men.
Dr. Bogler: I should preface this by saying that I spent my career studying brain tumors. That was clearly a mistake.
Dr. Cardoso: It starts with a B. ...
Dr. Bogler: It starts with a B, but it’s the wrong part of the body. The reality is that we don’t really know that much fundamental biology yet, though the picture is changing and it has changed in recent years. Part of the reason is we don’t have many of the tools that we’ve had for the female disease for many years, particularly laboratory models.
On the genetic and transcriptomics front, there has been some really good activity. There was a comprehensive systematic review by Professor Val Speirs from the University of Aberdeen earlier this year that summarized much of the recent data. It showed that there are a handful of molecular hallmarks of the male disease, compared with the female disease, that are worth exploring.
Interestingly enough, one of them is the androgen receptor. It does beg the question of whether hormone-driven disease might not show up quite differently in males and females, where the hormone picture is a little different. I think there’s increasing evidence that there’s information out there to go after.
I will say that I was treated by Dr. Giordano and her colleagues very much like a woman would have been with my disease, and actually, very similarly to my wife. I’ve done well with it, so I would say, in most cases, the current standard of care is very effective but it falls a little short of personalized medicine, particularly when it comes to the hormone component.
Dr. Cardoso: Sharon?
Dr. Giordano: I would add that when I think about it as a clinician, although there’s a large amount of overlap and many similarities, when we’re treating men with breast cancer, almost all of the men have hormone receptor–positive disease, which I think Oliver mentioned earlier. We’re really thinking about endocrine therapy as one of the mainstays of treatment.
Obviously, as he also mentioned, it’s a different biologic background of hormones in a male vs. a female patient. There’s reason to think that some of those treatments could differ. In general, the subtypes are a little bit different. We see very, very few cases of triple-negative breast cancer in men. I think I’ve seen only one or two in my career. The ones I remember were probably radiation induced. They were cancer survivors who’d had chest-wall radiation for previous diseases. Those patients are very uncommon.
We also tend to see that the histology patterns are a little bit different. We tend to see more ductal cancers in men than we do in women as a relative proportion.
One thing that I always try to remember is that the risk for BRCA mutations or underlying germline genetic mutations is higher in men than in women. Just having a diagnosis of male breast cancer is an indication to consider genetic testing or meet with a genetic counselor to look for a BRCA1 or BRCA2 mutation.
Now, most men will not have that. Only roughly 10% of male patients, or maybe a little less, will have a BRCA2 mutation; for BRCA1, it’s more like only 1% or 2%. They’re not that common. Certainly, male breast cancer is recognized as being associated with the BRCA mutations.
Dr. Cardoso: If I have to give a take-home message in terms of biology, it would be that if there is a diagnosis of hormone receptor–negative or HER2-positive disease in a male patient, I would ask for a confirmation of the diagnosis. It’s not that it cannot exist, but it’s so rare that it’s worthwhile to confirm.
You mentioned that triple-negative disease is less than 1%, at about 0.5%, and HER2-positive disease is about 9%-10%. I think it will be very important to keep this in mind and confirm the biology if you have a different diagnosis than ER-positive, HER2-negative. Unfortunately, I received some cases where this was not done, and in fact, it ended up being a technical problem. People can receive the wrong treatment based on that.
Dr. Giordano: I’ve also seen that happen when it’s a metastasis to the breast rather than a primary breast cancer. I completely agree. That’s an excellent point.
Management approaches
Dr. Cardoso: Let’s go now to management and focus on early breast cancer first. Sharon, what are your main take-home messages for a professional who doesn’t see this very often? What does someone need to remember when they manage a male patient who has early breast cancer?
Dr. Giordano: In general, in terms of chemotherapy, we essentially use the same guidelines as we do for women. Most of the male patients will have tumors that are hormone receptor positive. For endocrine therapy, we typically rely on tamoxifen as the standard of care for adjuvant endocrine treatment for breast cancer.
There are some data suggesting that there can be some efficacy of aromatase inhibitors as single agents. In general, and extrapolated from some population-based registry data, the outcomes for men treated with single-agent aromatase inhibitors don’t tend to be as good as for those treated with tamoxifen.
I know that these are not randomized data so there are all the caveats of that, but the best information we have suggests that tamoxifen appears to likely be more effective. Typically, we stay with tamoxifen. If, for some reason, a man cannot tolerate tamoxifen or has a contraindication, then we could use a GnRH agonist along with an aromatase inhibitor.
Dr. Cardoso: I would like to mention that, because it’s ER-positive, HER2-negative disease most of the time, there will be the question as to whether we can use genomic tests. I think it is important that people know that we have much less data regarding the use of Oncotype DX, MammaPrint, or any of the genomic tests in male patients.
We have some data on the distribution of, for example, Oncotype DX or MammaPrint scores. Whether we can use these tests for the decision of chemotherapy, we don’t have much data on that. I’ve seen many people making exactly the same decisions as with female patients, but that’s not really based on very strong evidence.
Dr. Giordano: It’s hard to know what to do with that. There are prognostic data on Oncotype, so the higher-risk tumors do seem to have a worse outcome than the lower-score tumors. You’re right, though; I don’t think we have any predictive information to really show that the Oncotype DX score predicts benefit to chemotherapy.
Having said that, I will sometimes order the test in my practice. If somebody comes back with a score of 5 or a very low-risk score, I will use that in my decision-making.
Dr. Cardoso: There is something we didn’t exactly mention in the diagnosis that may be important. We discussed most men not knowing that they can have breast cancer, and Oliver, you mentioned that sometimes the first-line physicians can think that very often. Usually, we have late diagnosis and that means a higher tumor burden.
Sometimes we have to go to chemotherapy because of locally advanced or very positive axillas and not really because of the biology. That’s one of the reasons to go for chemotherapy in this setting, right?
Dr. Bogler: Yes. I remember that conversation with you, Dr. Giordano. I asked you whether I should do one of these tests. You said, “Don’t worry about it. At stage III, you’re going to have chemo anyway.”
Dr. Cardoso: The problem of these rare diagnoses is the not thinking about it, even from the health professional side, and then having the diagnosis quite late that will demand chemotherapy use.
To clarify to everybody, in terms of distinguishing luminal A–like, luminal B–like, and what that implies in a male patient, we really don’t know if it’s the same as in a female. There have been some very interesting studies from our Nordic country colleagues showing that maybe the subtyping is different. There is likely a male-specific subtype that does not exist in female breast cancer and that probably behaves differently. We still have a large amount of research to do to understand that.
Is there anything else you would like to mention about early breast cancer management?
Dr. Bogler: One of the things that’s probably underexplored is adherence to tamoxifen therapy in men. I do know anecdotally that this is the discussion among men because of the impact on quality of life. I do worry that sometimes men perhaps make the wrong choice, and I think that’s an opportunity for more research. Again, if there were alternative therapies that were perhaps a little less impactful on things like libido, that might be an advance in the field.
Dr. Cardoso: We have been seeing more studies on the issue of quality of life. Noncompliance is also an issue in female patients. We have to acknowledge that. Not everybody is able to keep taking the treatments. Interestingly, when there is a relapse and people had stopped taking the tamoxifen, most of them say, “I stopped because I had not understood exactly how important it is.”
We come back to the importance of explaining that it is the most crucial treatment for this subtype of breast cancer. Again, information is really key.
Sometimes I also use the argument with my patients that the alternative is even worse because if you use an aromatase inhibitor, and you have to use an LHRH agonist, then the implications for your sexual life are even worse. That’s how I try to convince them to stay on tamoxifen.
Let’s finalize with a couple of words on metastatic breast cancer in male patients. Sharon, I’ll start with you again. Is there any difference in the management if you have a patient with metastatic, ER-positive, HER2-negative disease? How do you treat? How do you sequence the available therapies? Is it different from the female patient?
Dr. Giordano: I’d say that, big picture, it’s quite similar. Again, most of the men have hormone receptor–positive disease, so really, the mainstay of treatment and the first treatments are going to be endocrine therapies. We’ll sequence through the endocrine therapies like we do in women. When using aromatase inhibitors, I typically would add a GnRH agonist to that, and I have had that be a very successful therapy, along now with the CDK inhibitors that are also approved.
I don’t think the studies of CDK inhibitors included male patients, but at least palbociclib actually was approved in the United States, based on some real-world evidence of its efficacy. Anecdotally, again, in my clinical practice, that tends to be a really powerful combination of leuprolide, an aromatase inhibitor, and a CDK inhibitor.
I think there’s less information about drugs like fulvestrant, whether that would benefit from combination with a GnRH agonist or whether those should be given as single agents. We just don’t really know. We have a few case series out there.
Similar to the early breast cancer setting, I think it’s really important to remember to check for BRCA1 and BRCA2 mutations. PARP inhibitors could be a part of the treatment plan if those underlying germline mutations are found. Generally, we’re following a similar sequence of endocrine therapies and then, eventually, chemotherapy.
Dr. Cardoso: Maybe, Oliver, you’re also seeing that one consistent finding in the biology study is the importance of the AKT/PI3K/mTOR pathway in male patients with breast cancer, because we now have at least two classes of agents to tackle this pathway. Again, anecdotally – we’re not talking about trials – I’ve been seeing quite interesting responses, for example, to everolimus combined with endocrine therapy.
We have a little less experience with the PI3K inhibitor, but that’s just because of accessibility to the drug. I think this combination is also something to keep in mind that can be quite effective in these patients.
Dr. Bogler: I agree. Those findings are exciting in the context of dealing with something as difficult as metastatic breast cancer. It’s good to know that there’s some information coming and opportunities and options, hopefully, down the road for men facing that problem.
Dr. Cardoso: Sharon, although small numbers, in these cases where there is HER2-positive disease, you would also use the new anti-HER2 agents and more or less the same sequence, right?
Dr. Giordano: Absolutely. It’s not particularly data driven, but yes, I would. If it’s a HER2-positive tumor, I would use the same HER2-targeted therapies that are used for women with breast cancer.
Working toward a balance in patient care
Dr. Cardoso: I would like to add something for all of us to be united in the fight. I don’t know if it happens in the U.S., but in many countries, access to these new agents for male patients is very difficult because of the approval and the labeling. This is why I’m always fighting with those who are proposing that the labeling, again, says “women with breast cancer.”
It is really important that we keep on lobbying and pushing for the labeling to say “patients with breast cancer” so that nobody can withhold access to these new therapies because of gender. In the U.S., maybe you don’t have this problem. There are many European countries where men cannot access, for example, fulvestrant because it has been approved for women with breast cancer.
Dr. Giordano: Thankfully, I have not faced that issue very often. I’ve had occasional issues with getting GnRH agonists approved. Generally, in the U.S., if I provide, for example, the NCCN guideline recommendations, most insurers will cover it. I think it’s often just lack of knowledge.
Dr. Cardoso: It’s something to keep working hard on because for the old drugs that were approved with the wording that still said “women,” we have to keep fighting for accessibility.
I think we had a really nice discussion. I’m going to give you an opportunity for any last words that you want to say on this topic. Perhaps we’ll start with you, Sharon, and we’ll leave the very last word to Oliver.
Dr. Giordano: I would just emphasize the importance of doing research in this area. Hopefully, we will be able to get clinical trials. There are reasons to think that endocrine therapies may behave differently in men and women. We need to continue to work together as a community to collect the data so that we can ultimately improve the outcomes for our patients.
Dr. Bogler: I would echo what you just said, Dr. Giordano. I would like to express my gratitude to both of you. Dr. Giordano, you have a huge practice of men at MD Anderson. You took care of me and many other people I know.
Dr. Cardoso, you are a pioneer of a big registry trial that I am privileged to be working on, trying to gather data on men. You’re both pioneers in this field of working on behalf of people like me. I’m just very grateful for what you do.
Dr. Giordano: Thank you.
Dr. Cardoso: Thank you both for accepting this invitation. We hope that everybody takes more interest in this field. Who knows? Maybe we can find enough funds to run a specific trial for male patients with breast cancer.
Dr. Cardoso is director of the breast unit at Champalimaud Clinical Centre/Champalimaud Foundation, Lisbon. Dr. Giordano is professor of breast medical oncology and chair of health services research at the University of Texas MD Anderson Cancer Center, Houston. Dr. Bogler is a cancer biologist at the Randolph (Vt.) Center. Dr. Cardoso reported conflicts of interest with numerous pharmaceutical companies; Dr. Giordano and Dr. Bogler reported no conflicts of interest.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Fatima Cardoso, MD: Today we will be discussing breast cancer in male patients. To join me in this discussion, I have Sharon Giordano and Oliver Bogler. I will ask, to start, that we briefly introduce ourselves.
I’m Fatima Cardoso. I’m a medical oncologist based in Lisbon, Portugal. I have had a special interest in this topic for a couple of years. Sharon?
Sharon H. Giordano, MD, MPH, FASCO: I’m Sharon Giordano. I practice at the University of Texas MD Anderson Cancer Center. I’m also a medical oncologist and treat most of the male breast cancer patients that are seen here.
Oliver Bogler, PhD: I’m Oliver Bogler. I’m a cancer biologist by background and an 11-year survivor of breast cancer. Dr. Giordano was my oncologist during the active phase of my treatment. It’s great to be here with you.
Special considerations surrounding male patients
- Dr. Cardoso: Sharon, when you are treating breast cancer in a male patient, what specific considerations do you have?
- Dr. Giordano: As we all know, breast cancer in men is a rare disease. It makes up about 1 in 1,000 cases of breast cancer.
Often, what we need to do and what we end up doing is extrapolating as much as possible from clinical trials that were conducted in female patients with breast cancer. I think that’s one of the major challenges we face in treating the disease. There have been international efforts to try to put together standardized treatment approaches.
For example, ASCO has created guidelines for the management of male breast cancer. NCCN also has a special page on considerations for treatment of men with breast cancer. I would encourage people to look at those resources if questions do come up on the topic.
Dr. Cardoso: Perhaps we can also mention that the latest clinical trials fortunately have been allowing for male patients to be included, which is very important so that we can start having some data on the new drugs. I think that’s also relevant.
Dr. Giordano: That’s a great point because, historically, most of the trials explicitly excluded men. I don’t know if it was intentional or they just wrote the trials saying “women with breast cancer,” because that’s what most people thought of. I think it’s a great effort by the FDA and by investigators to make sure now that men are included in the trials. That will help build our evidence base.
Dr. Cardoso: Oliver, 11 years ago, you faced the diagnosis and you went through this. Can you speak a little bit about this challenge of going through what is considered a rare disease, but also a disease that is very much associated with the female gender traditionally?
Dr. Bogler: Gladly. For me, it was particularly odd because my wife, at the time that I was diagnosed, was a 5-year survivor of breast cancer. It took me some time to even think that the lump I felt might be the same disease. That seemed very unlikely, statistically, and also odd.
I have to say that I was protected from much of the fish-out-of-water experience that many men have because I both worked and was treated at MD Anderson, where Dr Giordano has a large practice, so my colleagues and my friends were not surprised that a man could get this disease.
Many of the patients I met had that experience, difficulty convincing their primary care physician or even their first-line oncologist that this could be the case. I just want to connect to what you both said, which is that 10 years ago, inclusion of men in clinical trials was not standard. It is a fantastic development to see that because unless we include men, we won’t learn about that type of breast cancer.
Dr. Cardoso: Even if only a few are entering each trial, at least it allows us to see if the drug behaves the same way or if there is any strange behavior of the drug in a male patient. It’s already one step forward. You were going to mention something, Sharon?
Dr. Giordano: I was going to say that, anecdotally, I’ve heard the experience that Oliver referred to, of many men feeling not so much uncomfortable with the diagnosis – although that does happen – but not having an obvious fit within the health care system.
For example, going to get their mammogram as part of their diagnostic workup and whoever might be taking them back saying, “Oh, no, this is Mrs. Jones, not Mr.,” and trying to argue with them that it’s not really meant for them. I had a patient – and this guy had a great sense of humor – who had a biopsy done and the instructions were to place this pink, floral ice pack inside your bra.
Even the materials that we have are gender specific. I think those things all together can certainly contribute to a man feeling like a fish out of water.
Dr. Cardoso: Actually, I fought in my institution because they wanted to call the Breast and Gynecology Unit the Women’s Unit. I said that there is no way you can call it the Women’s Unit because we have male patients. There are small things that we can do in our institutions to try to decrease the stigma and to make it less awkward for a man to be in a waiting room that says Women’s Clinic or something similar to that.
The importance of a support system
Dr. Cardoso: I wanted Oliver, perhaps, to mention experiences that you may have heard from other men. Some men do not feel that comfortable speaking about the disease. Also, some of them do not feel comfortable after treatment to go to the beach, to show the scar, and to show what happens after you have radiation.
Some men actually take it quite heavily, psychologically speaking. Have you encountered some of these men?
Dr. Bogler: Definitely. I think it leads to men not accessing the support opportunities – their family, their friends, or the support groups – and staying away from those because of this feeling of not wanting to share about it. That can be damaging. Cancer treatment is usually a tough road for most people, and the long-term consequences of hormone therapy – most men have hormone-driven disease – can be significant. I agree with you.
I participated in the male breast cancer SCAR Project by David Jay, a famous photographer. One of the high points of my life has been appearing in The New York Times topless, right after my radiation treatment, showing my scar. There are quite a few of us out there who’ve done that.
I’ll just mention in passing the Male Breast Cancer Global Alliance, which is a patient support supergroup, if you will. We’ve got a symposium coming up in November. That’s a great place for men who are early in the stage of their disease, or at any stage, to connect to others who are facing this issue.
Dr. Cardoso: They can also find specific information. This is a really good website where you can find information. One of the most important topics that I’ve heard from my patients is, “I never thought that I could have this disease. I never heard that men could have breast cancer as well.” Information is very crucial.
I believe that if you are well informed, you will also be less scared of the disease. Sources of reliable information are really crucial for patients. Since you mentioned the SCAR Project, we have a similar project here in Portugal that really called attention to the disease. It was very visual and really interesting.
Discussions during and after treatment
Dr. Cardoso: I wanted to say something, and I don’t know if both of you would agree. I think only recently surgeons have started to pay attention to the way they operate on men with breast cancer, and even in considering techniques of breast conservation and oncoplastic surgery. I had the feeling, looking at those photos, that some years ago, it wouldn’t have mattered how they do with the mastectomy scar just because it was a man. This was biased, right?
Just because it was a man, there was no need to pay attention to the aesthetic outcome. That is wrong, in my perspective. I’m very happy to see that now there are surgeons considering other types of breast surgery to conserve as much as possible the aesthetic outcome.
Dr. Bogler: I have to say that I was offered reconstruction at MD Anderson. I declined it. It wasn’t that big a part of my body image. When I raised this issue at home, my kids, who were quite young at the time, just suggested, “Well, Dad, why don’t you just wear a swim shirt?” They came up with a very practical solution for this issue.
I agree with you that it should be an option. I was also offered a nipple tattoo. I have yet to take that up, but maybe one day.
Dr. Cardoso: I’m not sure that we need to go into reconstruction. It also depends on whether a man has gynecomastia, if it’s going to be very asymmetric. There are other techniques to do, and depending on the size of the tumor, we can also do breast conservation, which we have done here in a couple of patients.
It’s quite an interesting approach where, for example, a skin-sparing mastectomy would be less aggressive, let’s say. Sharon?
Dr. Giordano: I completely agree. I’ve noticed increasing attention to the issue over the years that I’ve been in practice. I do think that it’s more front-and-center when the surgeons are having discussions with the patients now.
Also, although it’s still a minority, some do choose to have reconstructive surgery; some have more extensive surgeries, and some maybe have nipple reconstruction or a nipple tattoo. In a few men, like you mentioned, who are somewhat asymmetric, it actually can make a difference even when they’re dressed.
For many men, it’s more that they want to take off their shirt to play basketball or go swimming, and to decrease the feeling of awkwardness or like they have to make an explanation for why they have a nipple missing and a scar across their chest.
Biological aspects of male patients
Dr. Cardoso: Let’s switch gears now to the management, and before that, the biology. Oliver, with your other hat of biology, speak a little bit on what we know so far – whether it is exactly the same disease or there are biological specific characteristics of breast cancer in men.
Dr. Bogler: I should preface this by saying that I spent my career studying brain tumors. That was clearly a mistake.
Dr. Cardoso: It starts with a B. ...
Dr. Bogler: It starts with a B, but it’s the wrong part of the body. The reality is that we don’t really know that much fundamental biology yet, though the picture is changing and it has changed in recent years. Part of the reason is we don’t have many of the tools that we’ve had for the female disease for many years, particularly laboratory models.
On the genetic and transcriptomics front, there has been some really good activity. There was a comprehensive systematic review by Professor Val Speirs from the University of Aberdeen earlier this year that summarized much of the recent data. It showed that there are a handful of molecular hallmarks of the male disease, compared with the female disease, that are worth exploring.
Interestingly enough, one of them is the androgen receptor. It does beg the question of whether hormone-driven disease might not show up quite differently in males and females, where the hormone picture is a little different. I think there’s increasing evidence that there’s information out there to go after.
I will say that I was treated by Dr. Giordano and her colleagues very much like a woman would have been with my disease, and actually, very similarly to my wife. I’ve done well with it, so I would say, in most cases, the current standard of care is very effective but it falls a little short of personalized medicine, particularly when it comes to the hormone component.
Dr. Cardoso: Sharon?
Dr. Giordano: I would add that when I think about it as a clinician, although there’s a large amount of overlap and many similarities, when we’re treating men with breast cancer, almost all of the men have hormone receptor–positive disease, which I think Oliver mentioned earlier. We’re really thinking about endocrine therapy as one of the mainstays of treatment.
Obviously, as he also mentioned, it’s a different biologic background of hormones in a male vs. a female patient. There’s reason to think that some of those treatments could differ. In general, the subtypes are a little bit different. We see very, very few cases of triple-negative breast cancer in men. I think I’ve seen only one or two in my career. The ones I remember were probably radiation induced. They were cancer survivors who’d had chest-wall radiation for previous diseases. Those patients are very uncommon.
We also tend to see that the histology patterns are a little bit different. We tend to see more ductal cancers in men than we do in women as a relative proportion.
One thing that I always try to remember is that the risk for BRCA mutations or underlying germline genetic mutations is higher in men than in women. Just having a diagnosis of male breast cancer is an indication to consider genetic testing or meet with a genetic counselor to look for a BRCA1 or BRCA2 mutation.
Now, most men will not have that. Only roughly 10% of male patients, or maybe a little less, will have a BRCA2 mutation; for BRCA1, it’s more like only 1% or 2%. They’re not that common. Certainly, male breast cancer is recognized as being associated with the BRCA mutations.
Dr. Cardoso: If I have to give a take-home message in terms of biology, it would be that if there is a diagnosis of hormone receptor–negative or HER2-positive disease in a male patient, I would ask for a confirmation of the diagnosis. It’s not that it cannot exist, but it’s so rare that it’s worthwhile to confirm.
You mentioned that triple-negative disease is less than 1%, at about 0.5%, and HER2-positive disease is about 9%-10%. I think it will be very important to keep this in mind and confirm the biology if you have a different diagnosis than ER-positive, HER2-negative. Unfortunately, I received some cases where this was not done, and in fact, it ended up being a technical problem. People can receive the wrong treatment based on that.
Dr. Giordano: I’ve also seen that happen when it’s a metastasis to the breast rather than a primary breast cancer. I completely agree. That’s an excellent point.
Management approaches
Dr. Cardoso: Let’s go now to management and focus on early breast cancer first. Sharon, what are your main take-home messages for a professional who doesn’t see this very often? What does someone need to remember when they manage a male patient who has early breast cancer?
Dr. Giordano: In general, in terms of chemotherapy, we essentially use the same guidelines as we do for women. Most of the male patients will have tumors that are hormone receptor positive. For endocrine therapy, we typically rely on tamoxifen as the standard of care for adjuvant endocrine treatment for breast cancer.
There are some data suggesting that there can be some efficacy of aromatase inhibitors as single agents. In general, and extrapolated from some population-based registry data, the outcomes for men treated with single-agent aromatase inhibitors don’t tend to be as good as for those treated with tamoxifen.
I know that these are not randomized data so there are all the caveats of that, but the best information we have suggests that tamoxifen appears to likely be more effective. Typically, we stay with tamoxifen. If, for some reason, a man cannot tolerate tamoxifen or has a contraindication, then we could use a GnRH agonist along with an aromatase inhibitor.
Dr. Cardoso: I would like to mention that, because it’s ER-positive, HER2-negative disease most of the time, there will be the question as to whether we can use genomic tests. I think it is important that people know that we have much less data regarding the use of Oncotype DX, MammaPrint, or any of the genomic tests in male patients.
We have some data on the distribution of, for example, Oncotype DX or MammaPrint scores. Whether we can use these tests for the decision of chemotherapy, we don’t have much data on that. I’ve seen many people making exactly the same decisions as with female patients, but that’s not really based on very strong evidence.
Dr. Giordano: It’s hard to know what to do with that. There are prognostic data on Oncotype, so the higher-risk tumors do seem to have a worse outcome than the lower-score tumors. You’re right, though; I don’t think we have any predictive information to really show that the Oncotype DX score predicts benefit to chemotherapy.
Having said that, I will sometimes order the test in my practice. If somebody comes back with a score of 5 or a very low-risk score, I will use that in my decision-making.
Dr. Cardoso: There is something we didn’t exactly mention in the diagnosis that may be important. We discussed most men not knowing that they can have breast cancer, and Oliver, you mentioned that sometimes the first-line physicians can think that very often. Usually, we have late diagnosis and that means a higher tumor burden.
Sometimes we have to go to chemotherapy because of locally advanced or very positive axillas and not really because of the biology. That’s one of the reasons to go for chemotherapy in this setting, right?
Dr. Bogler: Yes. I remember that conversation with you, Dr. Giordano. I asked you whether I should do one of these tests. You said, “Don’t worry about it. At stage III, you’re going to have chemo anyway.”
Dr. Cardoso: The problem of these rare diagnoses is the not thinking about it, even from the health professional side, and then having the diagnosis quite late that will demand chemotherapy use.
To clarify to everybody, in terms of distinguishing luminal A–like, luminal B–like, and what that implies in a male patient, we really don’t know if it’s the same as in a female. There have been some very interesting studies from our Nordic country colleagues showing that maybe the subtyping is different. There is likely a male-specific subtype that does not exist in female breast cancer and that probably behaves differently. We still have a large amount of research to do to understand that.
Is there anything else you would like to mention about early breast cancer management?
Dr. Bogler: One of the things that’s probably underexplored is adherence to tamoxifen therapy in men. I do know anecdotally that this is the discussion among men because of the impact on quality of life. I do worry that sometimes men perhaps make the wrong choice, and I think that’s an opportunity for more research. Again, if there were alternative therapies that were perhaps a little less impactful on things like libido, that might be an advance in the field.
Dr. Cardoso: We have been seeing more studies on the issue of quality of life. Noncompliance is also an issue in female patients. We have to acknowledge that. Not everybody is able to keep taking the treatments. Interestingly, when there is a relapse and people had stopped taking the tamoxifen, most of them say, “I stopped because I had not understood exactly how important it is.”
We come back to the importance of explaining that it is the most crucial treatment for this subtype of breast cancer. Again, information is really key.
Sometimes I also use the argument with my patients that the alternative is even worse because if you use an aromatase inhibitor, and you have to use an LHRH agonist, then the implications for your sexual life are even worse. That’s how I try to convince them to stay on tamoxifen.
Let’s finalize with a couple of words on metastatic breast cancer in male patients. Sharon, I’ll start with you again. Is there any difference in the management if you have a patient with metastatic, ER-positive, HER2-negative disease? How do you treat? How do you sequence the available therapies? Is it different from the female patient?
Dr. Giordano: I’d say that, big picture, it’s quite similar. Again, most of the men have hormone receptor–positive disease, so really, the mainstay of treatment and the first treatments are going to be endocrine therapies. We’ll sequence through the endocrine therapies like we do in women. When using aromatase inhibitors, I typically would add a GnRH agonist to that, and I have had that be a very successful therapy, along now with the CDK inhibitors that are also approved.
I don’t think the studies of CDK inhibitors included male patients, but at least palbociclib actually was approved in the United States, based on some real-world evidence of its efficacy. Anecdotally, again, in my clinical practice, that tends to be a really powerful combination of leuprolide, an aromatase inhibitor, and a CDK inhibitor.
I think there’s less information about drugs like fulvestrant, whether that would benefit from combination with a GnRH agonist or whether those should be given as single agents. We just don’t really know. We have a few case series out there.
Similar to the early breast cancer setting, I think it’s really important to remember to check for BRCA1 and BRCA2 mutations. PARP inhibitors could be a part of the treatment plan if those underlying germline mutations are found. Generally, we’re following a similar sequence of endocrine therapies and then, eventually, chemotherapy.
Dr. Cardoso: Maybe, Oliver, you’re also seeing that one consistent finding in the biology study is the importance of the AKT/PI3K/mTOR pathway in male patients with breast cancer, because we now have at least two classes of agents to tackle this pathway. Again, anecdotally – we’re not talking about trials – I’ve been seeing quite interesting responses, for example, to everolimus combined with endocrine therapy.
We have a little less experience with the PI3K inhibitor, but that’s just because of accessibility to the drug. I think this combination is also something to keep in mind that can be quite effective in these patients.
Dr. Bogler: I agree. Those findings are exciting in the context of dealing with something as difficult as metastatic breast cancer. It’s good to know that there’s some information coming and opportunities and options, hopefully, down the road for men facing that problem.
Dr. Cardoso: Sharon, although small numbers, in these cases where there is HER2-positive disease, you would also use the new anti-HER2 agents and more or less the same sequence, right?
Dr. Giordano: Absolutely. It’s not particularly data driven, but yes, I would. If it’s a HER2-positive tumor, I would use the same HER2-targeted therapies that are used for women with breast cancer.
Working toward a balance in patient care
Dr. Cardoso: I would like to add something for all of us to be united in the fight. I don’t know if it happens in the U.S., but in many countries, access to these new agents for male patients is very difficult because of the approval and the labeling. This is why I’m always fighting with those who are proposing that the labeling, again, says “women with breast cancer.”
It is really important that we keep on lobbying and pushing for the labeling to say “patients with breast cancer” so that nobody can withhold access to these new therapies because of gender. In the U.S., maybe you don’t have this problem. There are many European countries where men cannot access, for example, fulvestrant because it has been approved for women with breast cancer.
Dr. Giordano: Thankfully, I have not faced that issue very often. I’ve had occasional issues with getting GnRH agonists approved. Generally, in the U.S., if I provide, for example, the NCCN guideline recommendations, most insurers will cover it. I think it’s often just lack of knowledge.
Dr. Cardoso: It’s something to keep working hard on because for the old drugs that were approved with the wording that still said “women,” we have to keep fighting for accessibility.
I think we had a really nice discussion. I’m going to give you an opportunity for any last words that you want to say on this topic. Perhaps we’ll start with you, Sharon, and we’ll leave the very last word to Oliver.
Dr. Giordano: I would just emphasize the importance of doing research in this area. Hopefully, we will be able to get clinical trials. There are reasons to think that endocrine therapies may behave differently in men and women. We need to continue to work together as a community to collect the data so that we can ultimately improve the outcomes for our patients.
Dr. Bogler: I would echo what you just said, Dr. Giordano. I would like to express my gratitude to both of you. Dr. Giordano, you have a huge practice of men at MD Anderson. You took care of me and many other people I know.
Dr. Cardoso, you are a pioneer of a big registry trial that I am privileged to be working on, trying to gather data on men. You’re both pioneers in this field of working on behalf of people like me. I’m just very grateful for what you do.
Dr. Giordano: Thank you.
Dr. Cardoso: Thank you both for accepting this invitation. We hope that everybody takes more interest in this field. Who knows? Maybe we can find enough funds to run a specific trial for male patients with breast cancer.
Dr. Cardoso is director of the breast unit at Champalimaud Clinical Centre/Champalimaud Foundation, Lisbon. Dr. Giordano is professor of breast medical oncology and chair of health services research at the University of Texas MD Anderson Cancer Center, Houston. Dr. Bogler is a cancer biologist at the Randolph (Vt.) Center. Dr. Cardoso reported conflicts of interest with numerous pharmaceutical companies; Dr. Giordano and Dr. Bogler reported no conflicts of interest.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Fatima Cardoso, MD: Today we will be discussing breast cancer in male patients. To join me in this discussion, I have Sharon Giordano and Oliver Bogler. I will ask, to start, that we briefly introduce ourselves.
I’m Fatima Cardoso. I’m a medical oncologist based in Lisbon, Portugal. I have had a special interest in this topic for a couple of years. Sharon?
Sharon H. Giordano, MD, MPH, FASCO: I’m Sharon Giordano. I practice at the University of Texas MD Anderson Cancer Center. I’m also a medical oncologist and treat most of the male breast cancer patients that are seen here.
Oliver Bogler, PhD: I’m Oliver Bogler. I’m a cancer biologist by background and an 11-year survivor of breast cancer. Dr. Giordano was my oncologist during the active phase of my treatment. It’s great to be here with you.
Special considerations surrounding male patients
- Dr. Cardoso: Sharon, when you are treating breast cancer in a male patient, what specific considerations do you have?
- Dr. Giordano: As we all know, breast cancer in men is a rare disease. It makes up about 1 in 1,000 cases of breast cancer.
Often, what we need to do and what we end up doing is extrapolating as much as possible from clinical trials that were conducted in female patients with breast cancer. I think that’s one of the major challenges we face in treating the disease. There have been international efforts to try to put together standardized treatment approaches.
For example, ASCO has created guidelines for the management of male breast cancer. NCCN also has a special page on considerations for treatment of men with breast cancer. I would encourage people to look at those resources if questions do come up on the topic.
Dr. Cardoso: Perhaps we can also mention that the latest clinical trials fortunately have been allowing for male patients to be included, which is very important so that we can start having some data on the new drugs. I think that’s also relevant.
Dr. Giordano: That’s a great point because, historically, most of the trials explicitly excluded men. I don’t know if it was intentional or they just wrote the trials saying “women with breast cancer,” because that’s what most people thought of. I think it’s a great effort by the FDA and by investigators to make sure now that men are included in the trials. That will help build our evidence base.
Dr. Cardoso: Oliver, 11 years ago, you faced the diagnosis and you went through this. Can you speak a little bit about this challenge of going through what is considered a rare disease, but also a disease that is very much associated with the female gender traditionally?
Dr. Bogler: Gladly. For me, it was particularly odd because my wife, at the time that I was diagnosed, was a 5-year survivor of breast cancer. It took me some time to even think that the lump I felt might be the same disease. That seemed very unlikely, statistically, and also odd.
I have to say that I was protected from much of the fish-out-of-water experience that many men have because I both worked and was treated at MD Anderson, where Dr Giordano has a large practice, so my colleagues and my friends were not surprised that a man could get this disease.
Many of the patients I met had that experience, difficulty convincing their primary care physician or even their first-line oncologist that this could be the case. I just want to connect to what you both said, which is that 10 years ago, inclusion of men in clinical trials was not standard. It is a fantastic development to see that because unless we include men, we won’t learn about that type of breast cancer.
Dr. Cardoso: Even if only a few are entering each trial, at least it allows us to see if the drug behaves the same way or if there is any strange behavior of the drug in a male patient. It’s already one step forward. You were going to mention something, Sharon?
Dr. Giordano: I was going to say that, anecdotally, I’ve heard the experience that Oliver referred to, of many men feeling not so much uncomfortable with the diagnosis – although that does happen – but not having an obvious fit within the health care system.
For example, going to get their mammogram as part of their diagnostic workup and whoever might be taking them back saying, “Oh, no, this is Mrs. Jones, not Mr.,” and trying to argue with them that it’s not really meant for them. I had a patient – and this guy had a great sense of humor – who had a biopsy done and the instructions were to place this pink, floral ice pack inside your bra.
Even the materials that we have are gender specific. I think those things all together can certainly contribute to a man feeling like a fish out of water.
Dr. Cardoso: Actually, I fought in my institution because they wanted to call the Breast and Gynecology Unit the Women’s Unit. I said that there is no way you can call it the Women’s Unit because we have male patients. There are small things that we can do in our institutions to try to decrease the stigma and to make it less awkward for a man to be in a waiting room that says Women’s Clinic or something similar to that.
The importance of a support system
Dr. Cardoso: I wanted Oliver, perhaps, to mention experiences that you may have heard from other men. Some men do not feel that comfortable speaking about the disease. Also, some of them do not feel comfortable after treatment to go to the beach, to show the scar, and to show what happens after you have radiation.
Some men actually take it quite heavily, psychologically speaking. Have you encountered some of these men?
Dr. Bogler: Definitely. I think it leads to men not accessing the support opportunities – their family, their friends, or the support groups – and staying away from those because of this feeling of not wanting to share about it. That can be damaging. Cancer treatment is usually a tough road for most people, and the long-term consequences of hormone therapy – most men have hormone-driven disease – can be significant. I agree with you.
I participated in the male breast cancer SCAR Project by David Jay, a famous photographer. One of the high points of my life has been appearing in The New York Times topless, right after my radiation treatment, showing my scar. There are quite a few of us out there who’ve done that.
I’ll just mention in passing the Male Breast Cancer Global Alliance, which is a patient support supergroup, if you will. We’ve got a symposium coming up in November. That’s a great place for men who are early in the stage of their disease, or at any stage, to connect to others who are facing this issue.
Dr. Cardoso: They can also find specific information. This is a really good website where you can find information. One of the most important topics that I’ve heard from my patients is, “I never thought that I could have this disease. I never heard that men could have breast cancer as well.” Information is very crucial.
I believe that if you are well informed, you will also be less scared of the disease. Sources of reliable information are really crucial for patients. Since you mentioned the SCAR Project, we have a similar project here in Portugal that really called attention to the disease. It was very visual and really interesting.
Discussions during and after treatment
Dr. Cardoso: I wanted to say something, and I don’t know if both of you would agree. I think only recently surgeons have started to pay attention to the way they operate on men with breast cancer, and even in considering techniques of breast conservation and oncoplastic surgery. I had the feeling, looking at those photos, that some years ago, it wouldn’t have mattered how they do with the mastectomy scar just because it was a man. This was biased, right?
Just because it was a man, there was no need to pay attention to the aesthetic outcome. That is wrong, in my perspective. I’m very happy to see that now there are surgeons considering other types of breast surgery to conserve as much as possible the aesthetic outcome.
Dr. Bogler: I have to say that I was offered reconstruction at MD Anderson. I declined it. It wasn’t that big a part of my body image. When I raised this issue at home, my kids, who were quite young at the time, just suggested, “Well, Dad, why don’t you just wear a swim shirt?” They came up with a very practical solution for this issue.
I agree with you that it should be an option. I was also offered a nipple tattoo. I have yet to take that up, but maybe one day.
Dr. Cardoso: I’m not sure that we need to go into reconstruction. It also depends on whether a man has gynecomastia, if it’s going to be very asymmetric. There are other techniques to do, and depending on the size of the tumor, we can also do breast conservation, which we have done here in a couple of patients.
It’s quite an interesting approach where, for example, a skin-sparing mastectomy would be less aggressive, let’s say. Sharon?
Dr. Giordano: I completely agree. I’ve noticed increasing attention to the issue over the years that I’ve been in practice. I do think that it’s more front-and-center when the surgeons are having discussions with the patients now.
Also, although it’s still a minority, some do choose to have reconstructive surgery; some have more extensive surgeries, and some maybe have nipple reconstruction or a nipple tattoo. In a few men, like you mentioned, who are somewhat asymmetric, it actually can make a difference even when they’re dressed.
For many men, it’s more that they want to take off their shirt to play basketball or go swimming, and to decrease the feeling of awkwardness or like they have to make an explanation for why they have a nipple missing and a scar across their chest.
Biological aspects of male patients
Dr. Cardoso: Let’s switch gears now to the management, and before that, the biology. Oliver, with your other hat of biology, speak a little bit on what we know so far – whether it is exactly the same disease or there are biological specific characteristics of breast cancer in men.
Dr. Bogler: I should preface this by saying that I spent my career studying brain tumors. That was clearly a mistake.
Dr. Cardoso: It starts with a B. ...
Dr. Bogler: It starts with a B, but it’s the wrong part of the body. The reality is that we don’t really know that much fundamental biology yet, though the picture is changing and it has changed in recent years. Part of the reason is we don’t have many of the tools that we’ve had for the female disease for many years, particularly laboratory models.
On the genetic and transcriptomics front, there has been some really good activity. There was a comprehensive systematic review by Professor Val Speirs from the University of Aberdeen earlier this year that summarized much of the recent data. It showed that there are a handful of molecular hallmarks of the male disease, compared with the female disease, that are worth exploring.
Interestingly enough, one of them is the androgen receptor. It does beg the question of whether hormone-driven disease might not show up quite differently in males and females, where the hormone picture is a little different. I think there’s increasing evidence that there’s information out there to go after.
I will say that I was treated by Dr. Giordano and her colleagues very much like a woman would have been with my disease, and actually, very similarly to my wife. I’ve done well with it, so I would say, in most cases, the current standard of care is very effective but it falls a little short of personalized medicine, particularly when it comes to the hormone component.
Dr. Cardoso: Sharon?
Dr. Giordano: I would add that when I think about it as a clinician, although there’s a large amount of overlap and many similarities, when we’re treating men with breast cancer, almost all of the men have hormone receptor–positive disease, which I think Oliver mentioned earlier. We’re really thinking about endocrine therapy as one of the mainstays of treatment.
Obviously, as he also mentioned, it’s a different biologic background of hormones in a male vs. a female patient. There’s reason to think that some of those treatments could differ. In general, the subtypes are a little bit different. We see very, very few cases of triple-negative breast cancer in men. I think I’ve seen only one or two in my career. The ones I remember were probably radiation induced. They were cancer survivors who’d had chest-wall radiation for previous diseases. Those patients are very uncommon.
We also tend to see that the histology patterns are a little bit different. We tend to see more ductal cancers in men than we do in women as a relative proportion.
One thing that I always try to remember is that the risk for BRCA mutations or underlying germline genetic mutations is higher in men than in women. Just having a diagnosis of male breast cancer is an indication to consider genetic testing or meet with a genetic counselor to look for a BRCA1 or BRCA2 mutation.
Now, most men will not have that. Only roughly 10% of male patients, or maybe a little less, will have a BRCA2 mutation; for BRCA1, it’s more like only 1% or 2%. They’re not that common. Certainly, male breast cancer is recognized as being associated with the BRCA mutations.
Dr. Cardoso: If I have to give a take-home message in terms of biology, it would be that if there is a diagnosis of hormone receptor–negative or HER2-positive disease in a male patient, I would ask for a confirmation of the diagnosis. It’s not that it cannot exist, but it’s so rare that it’s worthwhile to confirm.
You mentioned that triple-negative disease is less than 1%, at about 0.5%, and HER2-positive disease is about 9%-10%. I think it will be very important to keep this in mind and confirm the biology if you have a different diagnosis than ER-positive, HER2-negative. Unfortunately, I received some cases where this was not done, and in fact, it ended up being a technical problem. People can receive the wrong treatment based on that.
Dr. Giordano: I’ve also seen that happen when it’s a metastasis to the breast rather than a primary breast cancer. I completely agree. That’s an excellent point.
Management approaches
Dr. Cardoso: Let’s go now to management and focus on early breast cancer first. Sharon, what are your main take-home messages for a professional who doesn’t see this very often? What does someone need to remember when they manage a male patient who has early breast cancer?
Dr. Giordano: In general, in terms of chemotherapy, we essentially use the same guidelines as we do for women. Most of the male patients will have tumors that are hormone receptor positive. For endocrine therapy, we typically rely on tamoxifen as the standard of care for adjuvant endocrine treatment for breast cancer.
There are some data suggesting that there can be some efficacy of aromatase inhibitors as single agents. In general, and extrapolated from some population-based registry data, the outcomes for men treated with single-agent aromatase inhibitors don’t tend to be as good as for those treated with tamoxifen.
I know that these are not randomized data so there are all the caveats of that, but the best information we have suggests that tamoxifen appears to likely be more effective. Typically, we stay with tamoxifen. If, for some reason, a man cannot tolerate tamoxifen or has a contraindication, then we could use a GnRH agonist along with an aromatase inhibitor.
Dr. Cardoso: I would like to mention that, because it’s ER-positive, HER2-negative disease most of the time, there will be the question as to whether we can use genomic tests. I think it is important that people know that we have much less data regarding the use of Oncotype DX, MammaPrint, or any of the genomic tests in male patients.
We have some data on the distribution of, for example, Oncotype DX or MammaPrint scores. Whether we can use these tests for the decision of chemotherapy, we don’t have much data on that. I’ve seen many people making exactly the same decisions as with female patients, but that’s not really based on very strong evidence.
Dr. Giordano: It’s hard to know what to do with that. There are prognostic data on Oncotype, so the higher-risk tumors do seem to have a worse outcome than the lower-score tumors. You’re right, though; I don’t think we have any predictive information to really show that the Oncotype DX score predicts benefit to chemotherapy.
Having said that, I will sometimes order the test in my practice. If somebody comes back with a score of 5 or a very low-risk score, I will use that in my decision-making.
Dr. Cardoso: There is something we didn’t exactly mention in the diagnosis that may be important. We discussed most men not knowing that they can have breast cancer, and Oliver, you mentioned that sometimes the first-line physicians can think that very often. Usually, we have late diagnosis and that means a higher tumor burden.
Sometimes we have to go to chemotherapy because of locally advanced or very positive axillas and not really because of the biology. That’s one of the reasons to go for chemotherapy in this setting, right?
Dr. Bogler: Yes. I remember that conversation with you, Dr. Giordano. I asked you whether I should do one of these tests. You said, “Don’t worry about it. At stage III, you’re going to have chemo anyway.”
Dr. Cardoso: The problem of these rare diagnoses is the not thinking about it, even from the health professional side, and then having the diagnosis quite late that will demand chemotherapy use.
To clarify to everybody, in terms of distinguishing luminal A–like, luminal B–like, and what that implies in a male patient, we really don’t know if it’s the same as in a female. There have been some very interesting studies from our Nordic country colleagues showing that maybe the subtyping is different. There is likely a male-specific subtype that does not exist in female breast cancer and that probably behaves differently. We still have a large amount of research to do to understand that.
Is there anything else you would like to mention about early breast cancer management?
Dr. Bogler: One of the things that’s probably underexplored is adherence to tamoxifen therapy in men. I do know anecdotally that this is the discussion among men because of the impact on quality of life. I do worry that sometimes men perhaps make the wrong choice, and I think that’s an opportunity for more research. Again, if there were alternative therapies that were perhaps a little less impactful on things like libido, that might be an advance in the field.
Dr. Cardoso: We have been seeing more studies on the issue of quality of life. Noncompliance is also an issue in female patients. We have to acknowledge that. Not everybody is able to keep taking the treatments. Interestingly, when there is a relapse and people had stopped taking the tamoxifen, most of them say, “I stopped because I had not understood exactly how important it is.”
We come back to the importance of explaining that it is the most crucial treatment for this subtype of breast cancer. Again, information is really key.
Sometimes I also use the argument with my patients that the alternative is even worse because if you use an aromatase inhibitor, and you have to use an LHRH agonist, then the implications for your sexual life are even worse. That’s how I try to convince them to stay on tamoxifen.
Let’s finalize with a couple of words on metastatic breast cancer in male patients. Sharon, I’ll start with you again. Is there any difference in the management if you have a patient with metastatic, ER-positive, HER2-negative disease? How do you treat? How do you sequence the available therapies? Is it different from the female patient?
Dr. Giordano: I’d say that, big picture, it’s quite similar. Again, most of the men have hormone receptor–positive disease, so really, the mainstay of treatment and the first treatments are going to be endocrine therapies. We’ll sequence through the endocrine therapies like we do in women. When using aromatase inhibitors, I typically would add a GnRH agonist to that, and I have had that be a very successful therapy, along now with the CDK inhibitors that are also approved.
I don’t think the studies of CDK inhibitors included male patients, but at least palbociclib actually was approved in the United States, based on some real-world evidence of its efficacy. Anecdotally, again, in my clinical practice, that tends to be a really powerful combination of leuprolide, an aromatase inhibitor, and a CDK inhibitor.
I think there’s less information about drugs like fulvestrant, whether that would benefit from combination with a GnRH agonist or whether those should be given as single agents. We just don’t really know. We have a few case series out there.
Similar to the early breast cancer setting, I think it’s really important to remember to check for BRCA1 and BRCA2 mutations. PARP inhibitors could be a part of the treatment plan if those underlying germline mutations are found. Generally, we’re following a similar sequence of endocrine therapies and then, eventually, chemotherapy.
Dr. Cardoso: Maybe, Oliver, you’re also seeing that one consistent finding in the biology study is the importance of the AKT/PI3K/mTOR pathway in male patients with breast cancer, because we now have at least two classes of agents to tackle this pathway. Again, anecdotally – we’re not talking about trials – I’ve been seeing quite interesting responses, for example, to everolimus combined with endocrine therapy.
We have a little less experience with the PI3K inhibitor, but that’s just because of accessibility to the drug. I think this combination is also something to keep in mind that can be quite effective in these patients.
Dr. Bogler: I agree. Those findings are exciting in the context of dealing with something as difficult as metastatic breast cancer. It’s good to know that there’s some information coming and opportunities and options, hopefully, down the road for men facing that problem.
Dr. Cardoso: Sharon, although small numbers, in these cases where there is HER2-positive disease, you would also use the new anti-HER2 agents and more or less the same sequence, right?
Dr. Giordano: Absolutely. It’s not particularly data driven, but yes, I would. If it’s a HER2-positive tumor, I would use the same HER2-targeted therapies that are used for women with breast cancer.
Working toward a balance in patient care
Dr. Cardoso: I would like to add something for all of us to be united in the fight. I don’t know if it happens in the U.S., but in many countries, access to these new agents for male patients is very difficult because of the approval and the labeling. This is why I’m always fighting with those who are proposing that the labeling, again, says “women with breast cancer.”
It is really important that we keep on lobbying and pushing for the labeling to say “patients with breast cancer” so that nobody can withhold access to these new therapies because of gender. In the U.S., maybe you don’t have this problem. There are many European countries where men cannot access, for example, fulvestrant because it has been approved for women with breast cancer.
Dr. Giordano: Thankfully, I have not faced that issue very often. I’ve had occasional issues with getting GnRH agonists approved. Generally, in the U.S., if I provide, for example, the NCCN guideline recommendations, most insurers will cover it. I think it’s often just lack of knowledge.
Dr. Cardoso: It’s something to keep working hard on because for the old drugs that were approved with the wording that still said “women,” we have to keep fighting for accessibility.
I think we had a really nice discussion. I’m going to give you an opportunity for any last words that you want to say on this topic. Perhaps we’ll start with you, Sharon, and we’ll leave the very last word to Oliver.
Dr. Giordano: I would just emphasize the importance of doing research in this area. Hopefully, we will be able to get clinical trials. There are reasons to think that endocrine therapies may behave differently in men and women. We need to continue to work together as a community to collect the data so that we can ultimately improve the outcomes for our patients.
Dr. Bogler: I would echo what you just said, Dr. Giordano. I would like to express my gratitude to both of you. Dr. Giordano, you have a huge practice of men at MD Anderson. You took care of me and many other people I know.
Dr. Cardoso, you are a pioneer of a big registry trial that I am privileged to be working on, trying to gather data on men. You’re both pioneers in this field of working on behalf of people like me. I’m just very grateful for what you do.
Dr. Giordano: Thank you.
Dr. Cardoso: Thank you both for accepting this invitation. We hope that everybody takes more interest in this field. Who knows? Maybe we can find enough funds to run a specific trial for male patients with breast cancer.
Dr. Cardoso is director of the breast unit at Champalimaud Clinical Centre/Champalimaud Foundation, Lisbon. Dr. Giordano is professor of breast medical oncology and chair of health services research at the University of Texas MD Anderson Cancer Center, Houston. Dr. Bogler is a cancer biologist at the Randolph (Vt.) Center. Dr. Cardoso reported conflicts of interest with numerous pharmaceutical companies; Dr. Giordano and Dr. Bogler reported no conflicts of interest.
A version of this article first appeared on Medscape.com.
DMT discontinuation trial halted; MS returned in 17.8%
MILAN –
In the multicenter, randomized, controlled, noninferiority DOT-MS trial, inflammatory activity came back in 17.8% of 45 participants who discontinued DMT, researchers reported at the 9th Joint ECTRIMS-ACTRIMS Meeting.
“Because the number of participants with active disease – relapse or MRI activity – was higher in the discontinuation group, and this difference between the groups exceeded our predefined threshold, we prematurely terminated the trial in its current form,” said Eline Coerver, a graduate student with VU University Amsterdam, in an interview.
Previous studies have offered a mixed picture about whether stopping DMT is a good idea when patients with MS are doing well.
“Observational studies suggest that discontinuation of first-line DMTs, or platform therapies, might be safe in patients with MS who have been stable for a long period of time, meaning they did not have any clinical relapses or inflammatory MRI activity – new or contrast-enhancing lesions on MRI,” Ms. Coerver said. “These studies also suggest that patients with higher age have a lower risk of disease activity after DMT discontinuation.”
Discontinuation of DMTs can spare patients from side effects and the cost of the drugs. However, a phase 4 trial published earlier this year in The Lancet Neurology could not determine that stopping DMTs is noninferior to continuing treatment in patients with MS aged 55 and older.
“Six (4.7%) of 128 participants in the continue group and 16 (12.2%) of 131 in the discontinue group had a relapse or a new or expanding brain MRI lesion within 2 years,” the researchers reported.
For the new study, Ms. Coerver and colleagues recruited patients with relapse-onset MS aged 18 years or older who hadn’t had any relapses or substantial MRI activity in the last 5 years. The subjects were randomly assigned to discontinue DMT (interferon, glatiramer acetate, teriflunomide, or dimethyl fumarate) or continue taking the therapy for 2 years.
At pre-set interim analyses, the researchers would look for signs of inflammatory disease activity, which they defined as a confirmed relapse or three or more new T2-lesions or two or more contrast-enhancing lesions detected via MRI.
At the time of cessation in March 2023 (median follow-up = 12.0 months, interquartile range 7.0-20.0), the study had recruited 89 subjects: 67.4% female, mean age 53 (SD, 7.8). Just over half (50.6%) were randomized to discontinue treatment. Of the 45 in the discontinuation group, 8 (17.8%) developed inflammatory activity (7 significant MRI activity, 2 relapses) versus none of the 44 who continued therapy.
Interpreting the results
Two MS clinicians who are familiar with the study findings but weren’t involved with the research were reached for comment.
Katherine Knox, MD, a physiatrist and associate professor who specializes in MS care at the University of Saskatchewan, Saskatoon, said in an interview that the new study is useful “because it affirms that an appropriate stopping recommendation cannot be made primarily on the basis of a standard number of years without disease activity.”
In regard to the percentage of patients who had a recurrence of inflammatory activity (17.8%), Dr. Knox said “ideally patients can be triaged for stopping therapy appropriately with a much lower risk for return of disease activity based on their individual risk factors – i.e., under 2%.”
Michael J. Olek, DO, associate professor of neurology at Touro University Nevada, Henderson, took a different view. He said he does not discontinue medication in patients with MS even if they’re stable for 5 years.
“I am waiting for trials that show that discontinuing medication is OK for the patient. To date, there are no studies showing that stopping medication is a good idea,” he said. “The immune systems slows as people age, so there may be a point in a person’s lifetime when medication used to slow the immune system is no longer needed. But until then I will continue medication for all multiple sclerosis patients.”
Moving forward, study lead author Ms. Coerver said “there are large differences between patients, and there is still room for discussion regarding what percentage of disease activity can be accepted after DMT discontinuation. The most important point is to inform patients about the risks of discontinuation so that each individual patient can make a well-informed decision.”
The study was funded by the Netherlands Organization for Health Research and Development and Stichting MS Research. Ms. Coerver reports no disclosures; some other study authors report various disclosures. Dr. Olek reports no disclosures. Dr. Knox discloses research funding from the Saskatchewan Ministry of Health to evaluate and monitor long-term outcomes in MS.
MILAN –
In the multicenter, randomized, controlled, noninferiority DOT-MS trial, inflammatory activity came back in 17.8% of 45 participants who discontinued DMT, researchers reported at the 9th Joint ECTRIMS-ACTRIMS Meeting.
“Because the number of participants with active disease – relapse or MRI activity – was higher in the discontinuation group, and this difference between the groups exceeded our predefined threshold, we prematurely terminated the trial in its current form,” said Eline Coerver, a graduate student with VU University Amsterdam, in an interview.
Previous studies have offered a mixed picture about whether stopping DMT is a good idea when patients with MS are doing well.
“Observational studies suggest that discontinuation of first-line DMTs, or platform therapies, might be safe in patients with MS who have been stable for a long period of time, meaning they did not have any clinical relapses or inflammatory MRI activity – new or contrast-enhancing lesions on MRI,” Ms. Coerver said. “These studies also suggest that patients with higher age have a lower risk of disease activity after DMT discontinuation.”
Discontinuation of DMTs can spare patients from side effects and the cost of the drugs. However, a phase 4 trial published earlier this year in The Lancet Neurology could not determine that stopping DMTs is noninferior to continuing treatment in patients with MS aged 55 and older.
“Six (4.7%) of 128 participants in the continue group and 16 (12.2%) of 131 in the discontinue group had a relapse or a new or expanding brain MRI lesion within 2 years,” the researchers reported.
For the new study, Ms. Coerver and colleagues recruited patients with relapse-onset MS aged 18 years or older who hadn’t had any relapses or substantial MRI activity in the last 5 years. The subjects were randomly assigned to discontinue DMT (interferon, glatiramer acetate, teriflunomide, or dimethyl fumarate) or continue taking the therapy for 2 years.
At pre-set interim analyses, the researchers would look for signs of inflammatory disease activity, which they defined as a confirmed relapse or three or more new T2-lesions or two or more contrast-enhancing lesions detected via MRI.
At the time of cessation in March 2023 (median follow-up = 12.0 months, interquartile range 7.0-20.0), the study had recruited 89 subjects: 67.4% female, mean age 53 (SD, 7.8). Just over half (50.6%) were randomized to discontinue treatment. Of the 45 in the discontinuation group, 8 (17.8%) developed inflammatory activity (7 significant MRI activity, 2 relapses) versus none of the 44 who continued therapy.
Interpreting the results
Two MS clinicians who are familiar with the study findings but weren’t involved with the research were reached for comment.
Katherine Knox, MD, a physiatrist and associate professor who specializes in MS care at the University of Saskatchewan, Saskatoon, said in an interview that the new study is useful “because it affirms that an appropriate stopping recommendation cannot be made primarily on the basis of a standard number of years without disease activity.”
In regard to the percentage of patients who had a recurrence of inflammatory activity (17.8%), Dr. Knox said “ideally patients can be triaged for stopping therapy appropriately with a much lower risk for return of disease activity based on their individual risk factors – i.e., under 2%.”
Michael J. Olek, DO, associate professor of neurology at Touro University Nevada, Henderson, took a different view. He said he does not discontinue medication in patients with MS even if they’re stable for 5 years.
“I am waiting for trials that show that discontinuing medication is OK for the patient. To date, there are no studies showing that stopping medication is a good idea,” he said. “The immune systems slows as people age, so there may be a point in a person’s lifetime when medication used to slow the immune system is no longer needed. But until then I will continue medication for all multiple sclerosis patients.”
Moving forward, study lead author Ms. Coerver said “there are large differences between patients, and there is still room for discussion regarding what percentage of disease activity can be accepted after DMT discontinuation. The most important point is to inform patients about the risks of discontinuation so that each individual patient can make a well-informed decision.”
The study was funded by the Netherlands Organization for Health Research and Development and Stichting MS Research. Ms. Coerver reports no disclosures; some other study authors report various disclosures. Dr. Olek reports no disclosures. Dr. Knox discloses research funding from the Saskatchewan Ministry of Health to evaluate and monitor long-term outcomes in MS.
MILAN –
In the multicenter, randomized, controlled, noninferiority DOT-MS trial, inflammatory activity came back in 17.8% of 45 participants who discontinued DMT, researchers reported at the 9th Joint ECTRIMS-ACTRIMS Meeting.
“Because the number of participants with active disease – relapse or MRI activity – was higher in the discontinuation group, and this difference between the groups exceeded our predefined threshold, we prematurely terminated the trial in its current form,” said Eline Coerver, a graduate student with VU University Amsterdam, in an interview.
Previous studies have offered a mixed picture about whether stopping DMT is a good idea when patients with MS are doing well.
“Observational studies suggest that discontinuation of first-line DMTs, or platform therapies, might be safe in patients with MS who have been stable for a long period of time, meaning they did not have any clinical relapses or inflammatory MRI activity – new or contrast-enhancing lesions on MRI,” Ms. Coerver said. “These studies also suggest that patients with higher age have a lower risk of disease activity after DMT discontinuation.”
Discontinuation of DMTs can spare patients from side effects and the cost of the drugs. However, a phase 4 trial published earlier this year in The Lancet Neurology could not determine that stopping DMTs is noninferior to continuing treatment in patients with MS aged 55 and older.
“Six (4.7%) of 128 participants in the continue group and 16 (12.2%) of 131 in the discontinue group had a relapse or a new or expanding brain MRI lesion within 2 years,” the researchers reported.
For the new study, Ms. Coerver and colleagues recruited patients with relapse-onset MS aged 18 years or older who hadn’t had any relapses or substantial MRI activity in the last 5 years. The subjects were randomly assigned to discontinue DMT (interferon, glatiramer acetate, teriflunomide, or dimethyl fumarate) or continue taking the therapy for 2 years.
At pre-set interim analyses, the researchers would look for signs of inflammatory disease activity, which they defined as a confirmed relapse or three or more new T2-lesions or two or more contrast-enhancing lesions detected via MRI.
At the time of cessation in March 2023 (median follow-up = 12.0 months, interquartile range 7.0-20.0), the study had recruited 89 subjects: 67.4% female, mean age 53 (SD, 7.8). Just over half (50.6%) were randomized to discontinue treatment. Of the 45 in the discontinuation group, 8 (17.8%) developed inflammatory activity (7 significant MRI activity, 2 relapses) versus none of the 44 who continued therapy.
Interpreting the results
Two MS clinicians who are familiar with the study findings but weren’t involved with the research were reached for comment.
Katherine Knox, MD, a physiatrist and associate professor who specializes in MS care at the University of Saskatchewan, Saskatoon, said in an interview that the new study is useful “because it affirms that an appropriate stopping recommendation cannot be made primarily on the basis of a standard number of years without disease activity.”
In regard to the percentage of patients who had a recurrence of inflammatory activity (17.8%), Dr. Knox said “ideally patients can be triaged for stopping therapy appropriately with a much lower risk for return of disease activity based on their individual risk factors – i.e., under 2%.”
Michael J. Olek, DO, associate professor of neurology at Touro University Nevada, Henderson, took a different view. He said he does not discontinue medication in patients with MS even if they’re stable for 5 years.
“I am waiting for trials that show that discontinuing medication is OK for the patient. To date, there are no studies showing that stopping medication is a good idea,” he said. “The immune systems slows as people age, so there may be a point in a person’s lifetime when medication used to slow the immune system is no longer needed. But until then I will continue medication for all multiple sclerosis patients.”
Moving forward, study lead author Ms. Coerver said “there are large differences between patients, and there is still room for discussion regarding what percentage of disease activity can be accepted after DMT discontinuation. The most important point is to inform patients about the risks of discontinuation so that each individual patient can make a well-informed decision.”
The study was funded by the Netherlands Organization for Health Research and Development and Stichting MS Research. Ms. Coerver reports no disclosures; some other study authors report various disclosures. Dr. Olek reports no disclosures. Dr. Knox discloses research funding from the Saskatchewan Ministry of Health to evaluate and monitor long-term outcomes in MS.
FROM ECTRIMS 2023
Updated pleural disease guidelines from the British Thoracic Society
Thoracic Oncology & Chest Imaging Network
Pleural Disease Section
After more than a decade, the British Thoracic Society (BTS) released updated guidelines for pleural disease (Roberts ME , et al. Thorax 2023; 78, s1-s42). Their focus includes spontaneous pneumothorax, undiagnosed unilateral pleural effusion, pleural infections, and malignant pleural effusion (MPE). Separate statements for pleural procedures (Asciak R et al. Thorax. 2023;78:s43-s68) and pleural mesothelioma (Woolhouse I et al. Thorax. 2018;73:i1-i30) are available.
Major highlights of the recommendations are as follows:
- Conservative management can be considered for minimally symptomatic primary spontaneous pneumothorax regardless of size. A multi-disciplinary approach and shared decision-making is vital, especially when deciding between needle aspiration, intercostal drainage or ambulatory devices. Special recommendations were for pregnancy, cystic fibrosis, catamenial, iatrogenic and familial.
- Undiagnosed unilateral pleural effusion. Besides pleural fluid studies, in those with unclear etiology, thoracoscopic or image-guided pleural biopsy is recommended.
- Pleural infection. Use of renal, age, purulence, infection source, dietary factors (RAPID) scoring may be considered for risk stratification. Drainage of the pleural space with catheter and intrapleural therapy with combination tissue plasminogen activator (TPA) and DNAse in residual pleural fluid should be considered. Medical thoracoscopy not supported due to lack of evidence.
- MPE. Definitive pleural intervention based on symptoms and shared decision making was supported. Modality may include talc slurry via chest tube, talc poudrage via thoracoscopy or talc instillation via indwelling pleural catheter. Intrapleural chemotherapy should not be routinely used for treatment of MPE.
These guidelines provide a comprehensive consensus to the literature and reinforce prior recommendations of other professional societies (Gilbert CR et al. Chest. 2020;158:2221-8. Miller RJ et al.; J Bronchology Interv Pulmonol. 2020;27[4]:229-45. Feller-Kopman DJ et al.; Am J Respir Crit Care Med. 2018;198:839-49).
Munish Sharma, MD
Hiren Mehta, MD, Section Member-at-Large
Philip Ong, MD, Section Member-at-Large
Thoracic Oncology & Chest Imaging Network
Pleural Disease Section
After more than a decade, the British Thoracic Society (BTS) released updated guidelines for pleural disease (Roberts ME , et al. Thorax 2023; 78, s1-s42). Their focus includes spontaneous pneumothorax, undiagnosed unilateral pleural effusion, pleural infections, and malignant pleural effusion (MPE). Separate statements for pleural procedures (Asciak R et al. Thorax. 2023;78:s43-s68) and pleural mesothelioma (Woolhouse I et al. Thorax. 2018;73:i1-i30) are available.
Major highlights of the recommendations are as follows:
- Conservative management can be considered for minimally symptomatic primary spontaneous pneumothorax regardless of size. A multi-disciplinary approach and shared decision-making is vital, especially when deciding between needle aspiration, intercostal drainage or ambulatory devices. Special recommendations were for pregnancy, cystic fibrosis, catamenial, iatrogenic and familial.
- Undiagnosed unilateral pleural effusion. Besides pleural fluid studies, in those with unclear etiology, thoracoscopic or image-guided pleural biopsy is recommended.
- Pleural infection. Use of renal, age, purulence, infection source, dietary factors (RAPID) scoring may be considered for risk stratification. Drainage of the pleural space with catheter and intrapleural therapy with combination tissue plasminogen activator (TPA) and DNAse in residual pleural fluid should be considered. Medical thoracoscopy not supported due to lack of evidence.
- MPE. Definitive pleural intervention based on symptoms and shared decision making was supported. Modality may include talc slurry via chest tube, talc poudrage via thoracoscopy or talc instillation via indwelling pleural catheter. Intrapleural chemotherapy should not be routinely used for treatment of MPE.
These guidelines provide a comprehensive consensus to the literature and reinforce prior recommendations of other professional societies (Gilbert CR et al. Chest. 2020;158:2221-8. Miller RJ et al.; J Bronchology Interv Pulmonol. 2020;27[4]:229-45. Feller-Kopman DJ et al.; Am J Respir Crit Care Med. 2018;198:839-49).
Munish Sharma, MD
Hiren Mehta, MD, Section Member-at-Large
Philip Ong, MD, Section Member-at-Large
Thoracic Oncology & Chest Imaging Network
Pleural Disease Section
After more than a decade, the British Thoracic Society (BTS) released updated guidelines for pleural disease (Roberts ME , et al. Thorax 2023; 78, s1-s42). Their focus includes spontaneous pneumothorax, undiagnosed unilateral pleural effusion, pleural infections, and malignant pleural effusion (MPE). Separate statements for pleural procedures (Asciak R et al. Thorax. 2023;78:s43-s68) and pleural mesothelioma (Woolhouse I et al. Thorax. 2018;73:i1-i30) are available.
Major highlights of the recommendations are as follows:
- Conservative management can be considered for minimally symptomatic primary spontaneous pneumothorax regardless of size. A multi-disciplinary approach and shared decision-making is vital, especially when deciding between needle aspiration, intercostal drainage or ambulatory devices. Special recommendations were for pregnancy, cystic fibrosis, catamenial, iatrogenic and familial.
- Undiagnosed unilateral pleural effusion. Besides pleural fluid studies, in those with unclear etiology, thoracoscopic or image-guided pleural biopsy is recommended.
- Pleural infection. Use of renal, age, purulence, infection source, dietary factors (RAPID) scoring may be considered for risk stratification. Drainage of the pleural space with catheter and intrapleural therapy with combination tissue plasminogen activator (TPA) and DNAse in residual pleural fluid should be considered. Medical thoracoscopy not supported due to lack of evidence.
- MPE. Definitive pleural intervention based on symptoms and shared decision making was supported. Modality may include talc slurry via chest tube, talc poudrage via thoracoscopy or talc instillation via indwelling pleural catheter. Intrapleural chemotherapy should not be routinely used for treatment of MPE.
These guidelines provide a comprehensive consensus to the literature and reinforce prior recommendations of other professional societies (Gilbert CR et al. Chest. 2020;158:2221-8. Miller RJ et al.; J Bronchology Interv Pulmonol. 2020;27[4]:229-45. Feller-Kopman DJ et al.; Am J Respir Crit Care Med. 2018;198:839-49).
Munish Sharma, MD
Hiren Mehta, MD, Section Member-at-Large
Philip Ong, MD, Section Member-at-Large
Guillain-Barré syndrome: Honing treatment strategies
Recent insights into the pathophysiology of Guillain-Barré syndrome (GBS) – which affects 1 or 2 persons for every 100,000 people annually, usually post infection – indicate that classic subtypes represent varying manifestations of a shared disease process. This knowledge is yielding new treatment strategies aimed at halting the illness in its tracks. Promising therapies include inhibitors of complement and, perhaps one day, the calcium-activated protease calpain.
Meanwhile, an association between COVID-19 and GBS has been debunked, whereas a small risk of GBS following adenovirus-vectored COVID vaccination is now accepted and quantified. Regardless of cause, the potential severity of GBS and variability in its presentation demand constant vigilance.
Shutting down the disease process
When patients present to an emergency department with sensory symptoms and increasing muscle weakness, “most of the damage has been or is being done,” said Michael P. Lunn, MBBS, MRCP, PhD, professor of clinical neurology, consultant neurologist, and clinical lead in neuroimmunology at University College London Queen Square Institute of Neurology, who spoke at length about GBS with Neurology Reviews 2023 Rare Neurological Disease Special Report. “The crucial reason that GBS treatment has not advanced significantly – and why we’re still slightly stuck where we are in terms of helping people get better more quickly – is that we need something that absolutely turns the disease off as patients come through the door.”
GBS is probably the best-understood autoimmune-mediated neurological disease, in some respects surpassing myasthenia gravis, Dr. Lunn said. “We know very frequently the organisms and stimuli that set off Guillain-Barré syndrome. We understand, to an extent, the immunology and how you break tolerance of the immune system so that an invading organism can provoke an immune response that damages peripheral nerves.”
Compared to what was known about GBS in decades past, neurologists now better understand how and where antibodies attack the nerve; how complement then damages the nodes of Ranvier and paranodes; and how an external attack results in sometimes irreparable internal nerve damage. “We’ve got a string, beginning to end, of understanding the disease,” declared Dr. Lunn.
Understanding of differences in the spectrum of pathology of GBS has led to additional diagnostic categories, said Dr. Lunn. Acute inflammatory demyelinating polyradiculoneuropathy, or typical GBS, represents the most common form in affluent Western nations. A motor variant was recognized in the 1980s; in the mid-1990s, Ho and colleagues described a cohort of patients in China who had acute motor axonal neuropathy and acute motor sensory axonal neuropathy1 – two forms that are particularly common throughout Asia and South America.
Shared mechanism
Based on the findings of electrophysiologic studies, Dr. Lunn said, experts traditionally believed that GBS attacked either axons themselves or their myelin sheaths. “That’s where the anti-ganglioside antibodies come in, providing targeting to nerve structures.” The dichotomous classification system, he added, was partially correct.
Then, through the 2010s and 2020s, neurophysiologist Antonio Uncini, MD, recognized, based partly on histologic studies by Ho and colleagues, that the myelin and axonal subtypes are both likely to stem from the same mechanism.2 When antibodies and complement damage the node of Ranvier, Dr. Lunn said, “the myelin gets stripped off and the conduction becomes slow. But then the myelin can return, and patients get better.” But if damage is severe, it severs the axon, resulting in unrecoverable motor axonal neuropathy. “It’s basically all the same spectrum of disease,” Dr. Lunn said. “Anti-ganglioside antibodies may account for different GBS ‘flavors,’ but the immunological attack all occurs at the node of Ranvier in one way or another.”
The foregoing insight has focused development efforts on the shared seminal pathway of all GBS subtypes and given rise to the concept of nodo-paranodopathy, which incorporates damage at either the node of Ranvier or nearby paranodes.3
Simultaneously, Spanish and French researchers began elucidating new antibodies responsible for neuropathology at the node of Ranvier.4 Anti-ganglioside antibodies have long been loosely associated with acute motor axonal neuropathy and poor outcomes, although, Dr. Lunn said, they fail to tell the full story. Anti-GQ1b antibodies are associated with the Miller-Fisher syndrome subtype, well recognized for its medical features: double vision, loss of tendon reflexes, and arm and leg weakness.
However, Dr. Lunn said, most GBS cases lack anti-ganglioside antibodies. In some GBS cases, antibodies attack neurofascin, contactins, and gliomedin, which are mainly adhesion proteins at nodes of Ranvier.
“Therefore,” Dr. Lunn said, “there must be an antibody-mediated attack of the node of Ranvier or the paranode. That’s an important series of discoveries, primarily because it helps us understand the immunological attack at the node of Ranvier, which goes along with what Dr. Uncini was saying. But it also divides off a group of chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) that present acutely and look initially, for all purposes, like GBS.”
Recognizing acute CIDP (A-CIDP) is critically important for clinicians, Dr. Lunn stressed, because it requires treatment with rituximab (the most commonly used option), steroids, or plasma exchange.
Key clues that distinguish A-CIDP from GBS include:
• A high level of cerebrospinal fluid protein.
• Very slow nerve conduction.
• Early muscle wasting (rare in GBS).
Recognizing CIDP and A-CIDP is crucial, said Dr. Lunn, because it begins to bring all the pathology back together to make sense of GBS. Neurologists have known for decades that, if one damages a nerve with antibodies, then binds complement to those antibodies, the complement punches holes in the affected cells, resulting in death. “But it wasn’t quite clear how those cells might die,” Dr. Lunn said.
After complement-induced injury, calcium-activated calpain permanently damages the entire internal axonal structure.5 Perhaps more important, a 2022 mouse study showed that complement-mediated damage could be directed to myelin or axons using the genetically programmed presence or absence of gangliosides to understand subsequent calpain-induced destruction in either axons or myelin.6
Some of the engineered mouse cells included ganglioside; others did not. “So you can have anti-ganglioside antibodies directed at one cell type or the other, which would, or would not, have calpain within them,” Dr. Lunn said. Investigators also showed that a calpain inhibitor (AK295) or overproduction of an endogenous inhibitor, calpastatin, prevented damage to both cell types.6All existing calpain inhibitors are unsuitable for clinical use because they are highly toxic. “But if you could inhibit calpain and stop it from being activated by calcium,” Dr. Lunn explained, “you would have a mechanism for stopping cell degradation during GBS. That would be an important future target for pharmacotherapy. That whole story – from the beginning to the end of GBS – has opened up options for treatment.”
Because complement bound to antibodies, set up by infection, plays a pivotal role, complement inhibitors have become an exciting area of research over the past decade. The 36-patient Japanese Eculizumab Trial for GBS (JET-GBS) trial showed that, after 6 months, significantly more eculizumab-treated patients could run, compared with placebo-treated patients.7
“No other trials of complement inhibitors have yet been completed,” Dr. Lunn said. “But several different complement inhibitors work at different places, in a very complicated immune process. One of the complement inhibitors will become transformative in treating GBS – preventing disability and improving recovery – in the not-very-distant future.”
Additional investigational treatments that have demonstrated early promise in eliminating problem antibodies faster include imlifidase (Idefirix [Hansa Biopharma]), which destroys antibodies, and Fc receptor inhibitors such as efgartigimod alfa-fcab (Vyvgart [argenx]), which push antibodies into the natural catabolic pathway.
“We’ve been stuck with plasma exchange and intravenous immunoglobulin (IVIg) for three or four decades,” Dr. Lunn said. “We now have a series of strategies by which we can completely turn off complement and resulting nerve damage. If we can find a calpain inhibitor that turns off the end of that pathway, we will make dramatic improvements. Our understanding of the immunopathology has changed enormously and influences pharmacotherapy going forward.”
Recap of diagnosis and treatment
For decades, the diagnosis of GBS has relied on the presence of symptoms, including progressive weakness and loss of reflexes and sensations. Nerve-conduction studies and cerebrospinal fluid evaluation can help confirm the diagnosis.
IVIg shortens recovery, said Dr. Lunn, although nothing cures GBS. “And that’s a common problem: Clinicians think that they’re going to give somebody IVIg, and the patient’s going to get better immediately.” When that doesn’t happen, he said, physicians are tempted to give a second immunoglobulin dose.
However, a study published in 2021 shows that a second IVIg dose does not result in faster or better improvement – only in a significant risk of cardiovascular, cerebrovascular, and other thrombotic events 3 weeks later.8 Dr. Lunn noted that, although adverse-event data were “buried” in the supplemental materials of that study, the high cost of IVIg (approximately $12,500 per dose) means that the study has changed practice for the benefit of patients, providers, and health care systems.
COVID-19 and GBS triggers
Campylobacter jejuni infection still accounts for 30% to 40% of GBS cases, followed by other bacteria, including Mycoplasma pneumoniae and Haemophilus influenzae, and then by viruses, including cytomegalovirus and, rarely, human immunodeficiency virus. In recent years, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection – COVID-19 – and vaccines against the viral infection have captured headlines for purportedly being a cause of GBS.
The Zika virus epidemic of 2015-2016 has been linked to GBS-like illness. The 2003 severe acute respiratory syndrome (SARS) pandemic and the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic were associated with GBS – although, taken together, SARS and MERS-CoV produced fewer than 10 cases of GBS, Dr. Lunn noted. Nevertheless, heightened awareness of these viruses fueled hypervigilance regarding the prospect that COVID-19 could cause GBS. Following reports of a single such case in Wuhan and hundreds in Italy, worry over pandemic GBS grew worldwide.
Dr. Lunn and colleagues addressed the COVID-19–GBS question in a 2023 publication.9 “Because GBS is largely treated only with IVIg, and IVIg costs a lot of money, and the U.K. government insists on every dose of IVIg being logged in a government database, we were able to identify virtually every case of GBS,” he said.
GBS diagnoses were reliable, he added, because each case was confirmed by physicians outside the emergency department. Analysis revealed that, in 2020, U.K. GBS cases actually declined by around one-third. “And even when there was a second wave of COVID-19 at the end of 2020, partly caused by better counting,” Dr. Lunn said, “there was no further increase in GBS cases. We concluded that there was no link between GBS and COVID-19, as the cases simply didn’t appear.”
The foregoing findings have since been corroborated by studies in Singapore, the United States, and South America, he pointed out. Earlier case series suggesting a link between COVID-19 and GBS were selective, Dr. Lunn added, with numbers too small to support robust conclusions.
The lack of a causal link between COVID-19 and GBS suggested to Dr. Lunn that there was no reason COVID-19 vaccination should cause GBS. All COVID-19 vaccines were designed to provoke an immune response either (1) by producing the SARS-CoV-2 spike protein on the surface of virus (through a replication-incompetent adenoviral vector) or (2) through DNA or mRNA transcription, he explained. “The spike protein is only a small part of COVID-19.”
GBS: ‘Adverse event of interest’
A link between modern vaccines and GBS first appeared in the 1970s with the hastily developed swine flu vaccine. “In late 1976,” Dr. Lunn explained, “it was identified that patients who were given that vaccine seemed to be developing illnesses consistent with GBS.” By 1980, Dr. Lunn said, the risk level was determined to be only five or six cases for every 1 million doses of vaccine administered. “But the vaccine program was aborted, and swine flu never really happened.” Every year since, “there has been a surveillance program looking at the occurrence of an association of GBS with influenza vaccine.”
Minor fluctuations aside, he said, the overall incidence of GBS with influenza vaccination – 1 GBS case for every 1 million vaccine doses given – has remained consistent over several decades. “Nevertheless, GBS became an adverse event of special interest for any vaccination campaign.”
COVID-19 vaccination. Dr. Lunn and colleagues used the United Kingdom National Health Service (NHS) National Immunoglobulin Database, and other databases, to pinpoint the risk of GBS presented by the first dose of the AstraZeneca ChAdOx1 nCoV-19 adenoviral vaccine.10 As with U.K. GBS cases, every COVID-19 vaccination is linked to an NHS number. “We identified all the cases of GBS, found their NHS numbers, and went back and found the exact dates they’d been vaccinated, and with which vaccine.” Only the adenoviral-vector vaccine carried an excess risk of GBS – 5.8 cases for every 1 million doses, associated only with the first dose and peaking at approximately 25 days post vaccination – compared with other vaccines used in the United Kingdom.
Researchers looked at data from the Vaccine Adverse Event Reporting System (VAERS), a program of the Centers for Disease Control and Prevention and the Food and Drug Administration, encompassing nearly 500 million COVID-19 vaccine doses given between December 2020 and January 2022. They found that patients who received the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) had a rate of GBS (within 21 and 41 days post vaccination) that was 9 and 12 times higher, respectively, than corresponding rates for the mRNA-1273 (Moderna) and BNT162b2 (Pfizer BioNTech) COVID-19 vaccines.11 Risk was distributed relatively evenly by gender and age. Also at day 21 and day 41, observed event ratios with the adenoviral-vector vaccine (use of which has been suspended in the United States) were 3.79 and 2.34, respectively. Observed-event ratios with the other vaccines mirrored expected background rates.
The VAERS analysis confirms earlier data from the CDC’s Vaccine Safety Datalink, which showed that, among approximately 15 million U.S. vaccine doses given between mid-December 2020 and mid-November 2021, the unadjusted GBS incidence rate for every 100,000 person-years for the adenoviral vaccine, 21 days post exposure, was 32.4, compared with 1.3 for the mRNA vaccine. The adjusted relative risk with the adenoviral vaccine in the first 3 weeks post vaccination, compared to the 3- to 6-week interval post vaccination, was 6.03.12 In addition, a head-to-head comparison of adenoviral versus mRNA vaccines at 21 days revealed an adjusted rate ratio of 20.56. Mechanistically, some experts theorize that antibodies induced by the Janssen vaccine might cross-react with glycoproteins on the myelin sheath of peripheral nerve axons to cause GBS, but this remains unproven.11
The AstraZeneca vaccine uses a chimpanzee adenovirus; the Janssen vaccine uses a human adenoviral carrier. “The only commonality between the Janssen/Johnson & Johnson and AstraZeneca vaccines, and the only thing that’s different from the other vaccines, is the adenoviral vector packaging,” Dr. Lunn emphasized. “I believe it’s what generates GBS after COVID-19 vaccination. It has nothing to do with the COVID-19 vaccination, the spike protein, the nucleic acid, the DNA, or anything else.”
The adenoviral vector probably also explains why GBS peaks during winter, said Dr. Lunn. “That’s when adenovirus is circulating.” When people contract the common cold, he explained, they don’t visit their family physician and request a swab to isolate the adenovirus. “By the time you get GBS, the adenovirus has been cleared. We’ve all got antibodies to adenovirus all over the place, anyway, because we get it so often.”
It would be difficult to prove conclusively that adenovirus belongs on the list of GBS causes, Dr. Lunn allowed. “But I have a strong suspicion that it does. COVID-19 and COVID-19 vaccination have given us some new avenues into identifying GBS causation potentially in the near future.” More research is needed in this area, he said.
Dr. Lunn has been a principal investigator for argenx (efgartigimod) and an adviser to AstraZeneca (ChAdOx1 nCoV-19). He has received travel grants from CSL Behring.
References
1. Ho TW et al. Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies. Brain. 1995;118(Pt 3):597-605. doi: 10.1093/brain/118.3.597.
2. Uncini A. A common mechanism and a new categorization for anti-ganglioside antibody-mediated neuropathies. Exp Neurol. 2012;235(2):513-6. doi: 10.1016/j.expneurol.2012.03.023.
3. Uncini A and Kuwabara S. The electrodiagnosis of Guillain-Barré syndrome subtypes: where do we stand? Clin Neurophysiol. 2018;129(12):2586-93. doi: 10.1016/j.clinph.2018.09.025.
4. Delmont E et al. Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy. Brain. 2017;140(7):1851-8. doi: 10.1093/brain/awx124.
5. McGonigal R et al. Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain. 2010;133(Pt 7):1944-60. doi: 10.1093/brain/awq119.
6. Cunningham ME et al. Real time imaging of intra-axonal calcium flux in an explant mouse model of axonal Guillain-Barré syndrome. Exp Neurol. 2022 Sep;355:114127. doi: 10.1016/j.expneurol.2022.114127.
7. Misawa S et al; Japanese Eculizumab Trial for GBS (JET-GBS) Study Group. Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial. Lancet Neurol. 2018;17(6):519-29. doi: 10.1016/S1474-4422(18)30114-5.
8. Walgaard C et al; Dutch GBS Study Group. Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2021;20(4):275-83. doi: 10.1016/S1474-4422(20)30494-4.
9. Keddie S et al. Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome. Brain. 2021;144(2):682-93. doi: 10.1093/brain/awaa433.
10. Keh RYS et al; BPNS/ABN COVID-19 Vaccine GBS Study Group. COVID-19 vaccination and Guillain-Barré syndrome: Analyses using the National Immunoglobulin Database. Brain. 2023;146(2):739-48. doi: 10.1093/brain/awac067.
11. Abara WE et al. Reports of Guillain-Barré syndrome after COVID-19 vaccination in the United States. JAMA Netw Open. 2023;6(2):e2253845. doi: 10.1001/jamanetworkopen.2022.53845.
12. Hanson KE et al. Incidence of Guillain-Barré syndrome after COVID-19 vaccination in the Vaccine Safety Datalink. JAMA Netw Open. 2022;5(4):e228879. doi: 10.1001/jamanetworkopen.2022.8879.
Recent insights into the pathophysiology of Guillain-Barré syndrome (GBS) – which affects 1 or 2 persons for every 100,000 people annually, usually post infection – indicate that classic subtypes represent varying manifestations of a shared disease process. This knowledge is yielding new treatment strategies aimed at halting the illness in its tracks. Promising therapies include inhibitors of complement and, perhaps one day, the calcium-activated protease calpain.
Meanwhile, an association between COVID-19 and GBS has been debunked, whereas a small risk of GBS following adenovirus-vectored COVID vaccination is now accepted and quantified. Regardless of cause, the potential severity of GBS and variability in its presentation demand constant vigilance.
Shutting down the disease process
When patients present to an emergency department with sensory symptoms and increasing muscle weakness, “most of the damage has been or is being done,” said Michael P. Lunn, MBBS, MRCP, PhD, professor of clinical neurology, consultant neurologist, and clinical lead in neuroimmunology at University College London Queen Square Institute of Neurology, who spoke at length about GBS with Neurology Reviews 2023 Rare Neurological Disease Special Report. “The crucial reason that GBS treatment has not advanced significantly – and why we’re still slightly stuck where we are in terms of helping people get better more quickly – is that we need something that absolutely turns the disease off as patients come through the door.”
GBS is probably the best-understood autoimmune-mediated neurological disease, in some respects surpassing myasthenia gravis, Dr. Lunn said. “We know very frequently the organisms and stimuli that set off Guillain-Barré syndrome. We understand, to an extent, the immunology and how you break tolerance of the immune system so that an invading organism can provoke an immune response that damages peripheral nerves.”
Compared to what was known about GBS in decades past, neurologists now better understand how and where antibodies attack the nerve; how complement then damages the nodes of Ranvier and paranodes; and how an external attack results in sometimes irreparable internal nerve damage. “We’ve got a string, beginning to end, of understanding the disease,” declared Dr. Lunn.
Understanding of differences in the spectrum of pathology of GBS has led to additional diagnostic categories, said Dr. Lunn. Acute inflammatory demyelinating polyradiculoneuropathy, or typical GBS, represents the most common form in affluent Western nations. A motor variant was recognized in the 1980s; in the mid-1990s, Ho and colleagues described a cohort of patients in China who had acute motor axonal neuropathy and acute motor sensory axonal neuropathy1 – two forms that are particularly common throughout Asia and South America.
Shared mechanism
Based on the findings of electrophysiologic studies, Dr. Lunn said, experts traditionally believed that GBS attacked either axons themselves or their myelin sheaths. “That’s where the anti-ganglioside antibodies come in, providing targeting to nerve structures.” The dichotomous classification system, he added, was partially correct.
Then, through the 2010s and 2020s, neurophysiologist Antonio Uncini, MD, recognized, based partly on histologic studies by Ho and colleagues, that the myelin and axonal subtypes are both likely to stem from the same mechanism.2 When antibodies and complement damage the node of Ranvier, Dr. Lunn said, “the myelin gets stripped off and the conduction becomes slow. But then the myelin can return, and patients get better.” But if damage is severe, it severs the axon, resulting in unrecoverable motor axonal neuropathy. “It’s basically all the same spectrum of disease,” Dr. Lunn said. “Anti-ganglioside antibodies may account for different GBS ‘flavors,’ but the immunological attack all occurs at the node of Ranvier in one way or another.”
The foregoing insight has focused development efforts on the shared seminal pathway of all GBS subtypes and given rise to the concept of nodo-paranodopathy, which incorporates damage at either the node of Ranvier or nearby paranodes.3
Simultaneously, Spanish and French researchers began elucidating new antibodies responsible for neuropathology at the node of Ranvier.4 Anti-ganglioside antibodies have long been loosely associated with acute motor axonal neuropathy and poor outcomes, although, Dr. Lunn said, they fail to tell the full story. Anti-GQ1b antibodies are associated with the Miller-Fisher syndrome subtype, well recognized for its medical features: double vision, loss of tendon reflexes, and arm and leg weakness.
However, Dr. Lunn said, most GBS cases lack anti-ganglioside antibodies. In some GBS cases, antibodies attack neurofascin, contactins, and gliomedin, which are mainly adhesion proteins at nodes of Ranvier.
“Therefore,” Dr. Lunn said, “there must be an antibody-mediated attack of the node of Ranvier or the paranode. That’s an important series of discoveries, primarily because it helps us understand the immunological attack at the node of Ranvier, which goes along with what Dr. Uncini was saying. But it also divides off a group of chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) that present acutely and look initially, for all purposes, like GBS.”
Recognizing acute CIDP (A-CIDP) is critically important for clinicians, Dr. Lunn stressed, because it requires treatment with rituximab (the most commonly used option), steroids, or plasma exchange.
Key clues that distinguish A-CIDP from GBS include:
• A high level of cerebrospinal fluid protein.
• Very slow nerve conduction.
• Early muscle wasting (rare in GBS).
Recognizing CIDP and A-CIDP is crucial, said Dr. Lunn, because it begins to bring all the pathology back together to make sense of GBS. Neurologists have known for decades that, if one damages a nerve with antibodies, then binds complement to those antibodies, the complement punches holes in the affected cells, resulting in death. “But it wasn’t quite clear how those cells might die,” Dr. Lunn said.
After complement-induced injury, calcium-activated calpain permanently damages the entire internal axonal structure.5 Perhaps more important, a 2022 mouse study showed that complement-mediated damage could be directed to myelin or axons using the genetically programmed presence or absence of gangliosides to understand subsequent calpain-induced destruction in either axons or myelin.6
Some of the engineered mouse cells included ganglioside; others did not. “So you can have anti-ganglioside antibodies directed at one cell type or the other, which would, or would not, have calpain within them,” Dr. Lunn said. Investigators also showed that a calpain inhibitor (AK295) or overproduction of an endogenous inhibitor, calpastatin, prevented damage to both cell types.6All existing calpain inhibitors are unsuitable for clinical use because they are highly toxic. “But if you could inhibit calpain and stop it from being activated by calcium,” Dr. Lunn explained, “you would have a mechanism for stopping cell degradation during GBS. That would be an important future target for pharmacotherapy. That whole story – from the beginning to the end of GBS – has opened up options for treatment.”
Because complement bound to antibodies, set up by infection, plays a pivotal role, complement inhibitors have become an exciting area of research over the past decade. The 36-patient Japanese Eculizumab Trial for GBS (JET-GBS) trial showed that, after 6 months, significantly more eculizumab-treated patients could run, compared with placebo-treated patients.7
“No other trials of complement inhibitors have yet been completed,” Dr. Lunn said. “But several different complement inhibitors work at different places, in a very complicated immune process. One of the complement inhibitors will become transformative in treating GBS – preventing disability and improving recovery – in the not-very-distant future.”
Additional investigational treatments that have demonstrated early promise in eliminating problem antibodies faster include imlifidase (Idefirix [Hansa Biopharma]), which destroys antibodies, and Fc receptor inhibitors such as efgartigimod alfa-fcab (Vyvgart [argenx]), which push antibodies into the natural catabolic pathway.
“We’ve been stuck with plasma exchange and intravenous immunoglobulin (IVIg) for three or four decades,” Dr. Lunn said. “We now have a series of strategies by which we can completely turn off complement and resulting nerve damage. If we can find a calpain inhibitor that turns off the end of that pathway, we will make dramatic improvements. Our understanding of the immunopathology has changed enormously and influences pharmacotherapy going forward.”
Recap of diagnosis and treatment
For decades, the diagnosis of GBS has relied on the presence of symptoms, including progressive weakness and loss of reflexes and sensations. Nerve-conduction studies and cerebrospinal fluid evaluation can help confirm the diagnosis.
IVIg shortens recovery, said Dr. Lunn, although nothing cures GBS. “And that’s a common problem: Clinicians think that they’re going to give somebody IVIg, and the patient’s going to get better immediately.” When that doesn’t happen, he said, physicians are tempted to give a second immunoglobulin dose.
However, a study published in 2021 shows that a second IVIg dose does not result in faster or better improvement – only in a significant risk of cardiovascular, cerebrovascular, and other thrombotic events 3 weeks later.8 Dr. Lunn noted that, although adverse-event data were “buried” in the supplemental materials of that study, the high cost of IVIg (approximately $12,500 per dose) means that the study has changed practice for the benefit of patients, providers, and health care systems.
COVID-19 and GBS triggers
Campylobacter jejuni infection still accounts for 30% to 40% of GBS cases, followed by other bacteria, including Mycoplasma pneumoniae and Haemophilus influenzae, and then by viruses, including cytomegalovirus and, rarely, human immunodeficiency virus. In recent years, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection – COVID-19 – and vaccines against the viral infection have captured headlines for purportedly being a cause of GBS.
The Zika virus epidemic of 2015-2016 has been linked to GBS-like illness. The 2003 severe acute respiratory syndrome (SARS) pandemic and the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic were associated with GBS – although, taken together, SARS and MERS-CoV produced fewer than 10 cases of GBS, Dr. Lunn noted. Nevertheless, heightened awareness of these viruses fueled hypervigilance regarding the prospect that COVID-19 could cause GBS. Following reports of a single such case in Wuhan and hundreds in Italy, worry over pandemic GBS grew worldwide.
Dr. Lunn and colleagues addressed the COVID-19–GBS question in a 2023 publication.9 “Because GBS is largely treated only with IVIg, and IVIg costs a lot of money, and the U.K. government insists on every dose of IVIg being logged in a government database, we were able to identify virtually every case of GBS,” he said.
GBS diagnoses were reliable, he added, because each case was confirmed by physicians outside the emergency department. Analysis revealed that, in 2020, U.K. GBS cases actually declined by around one-third. “And even when there was a second wave of COVID-19 at the end of 2020, partly caused by better counting,” Dr. Lunn said, “there was no further increase in GBS cases. We concluded that there was no link between GBS and COVID-19, as the cases simply didn’t appear.”
The foregoing findings have since been corroborated by studies in Singapore, the United States, and South America, he pointed out. Earlier case series suggesting a link between COVID-19 and GBS were selective, Dr. Lunn added, with numbers too small to support robust conclusions.
The lack of a causal link between COVID-19 and GBS suggested to Dr. Lunn that there was no reason COVID-19 vaccination should cause GBS. All COVID-19 vaccines were designed to provoke an immune response either (1) by producing the SARS-CoV-2 spike protein on the surface of virus (through a replication-incompetent adenoviral vector) or (2) through DNA or mRNA transcription, he explained. “The spike protein is only a small part of COVID-19.”
GBS: ‘Adverse event of interest’
A link between modern vaccines and GBS first appeared in the 1970s with the hastily developed swine flu vaccine. “In late 1976,” Dr. Lunn explained, “it was identified that patients who were given that vaccine seemed to be developing illnesses consistent with GBS.” By 1980, Dr. Lunn said, the risk level was determined to be only five or six cases for every 1 million doses of vaccine administered. “But the vaccine program was aborted, and swine flu never really happened.” Every year since, “there has been a surveillance program looking at the occurrence of an association of GBS with influenza vaccine.”
Minor fluctuations aside, he said, the overall incidence of GBS with influenza vaccination – 1 GBS case for every 1 million vaccine doses given – has remained consistent over several decades. “Nevertheless, GBS became an adverse event of special interest for any vaccination campaign.”
COVID-19 vaccination. Dr. Lunn and colleagues used the United Kingdom National Health Service (NHS) National Immunoglobulin Database, and other databases, to pinpoint the risk of GBS presented by the first dose of the AstraZeneca ChAdOx1 nCoV-19 adenoviral vaccine.10 As with U.K. GBS cases, every COVID-19 vaccination is linked to an NHS number. “We identified all the cases of GBS, found their NHS numbers, and went back and found the exact dates they’d been vaccinated, and with which vaccine.” Only the adenoviral-vector vaccine carried an excess risk of GBS – 5.8 cases for every 1 million doses, associated only with the first dose and peaking at approximately 25 days post vaccination – compared with other vaccines used in the United Kingdom.
Researchers looked at data from the Vaccine Adverse Event Reporting System (VAERS), a program of the Centers for Disease Control and Prevention and the Food and Drug Administration, encompassing nearly 500 million COVID-19 vaccine doses given between December 2020 and January 2022. They found that patients who received the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) had a rate of GBS (within 21 and 41 days post vaccination) that was 9 and 12 times higher, respectively, than corresponding rates for the mRNA-1273 (Moderna) and BNT162b2 (Pfizer BioNTech) COVID-19 vaccines.11 Risk was distributed relatively evenly by gender and age. Also at day 21 and day 41, observed event ratios with the adenoviral-vector vaccine (use of which has been suspended in the United States) were 3.79 and 2.34, respectively. Observed-event ratios with the other vaccines mirrored expected background rates.
The VAERS analysis confirms earlier data from the CDC’s Vaccine Safety Datalink, which showed that, among approximately 15 million U.S. vaccine doses given between mid-December 2020 and mid-November 2021, the unadjusted GBS incidence rate for every 100,000 person-years for the adenoviral vaccine, 21 days post exposure, was 32.4, compared with 1.3 for the mRNA vaccine. The adjusted relative risk with the adenoviral vaccine in the first 3 weeks post vaccination, compared to the 3- to 6-week interval post vaccination, was 6.03.12 In addition, a head-to-head comparison of adenoviral versus mRNA vaccines at 21 days revealed an adjusted rate ratio of 20.56. Mechanistically, some experts theorize that antibodies induced by the Janssen vaccine might cross-react with glycoproteins on the myelin sheath of peripheral nerve axons to cause GBS, but this remains unproven.11
The AstraZeneca vaccine uses a chimpanzee adenovirus; the Janssen vaccine uses a human adenoviral carrier. “The only commonality between the Janssen/Johnson & Johnson and AstraZeneca vaccines, and the only thing that’s different from the other vaccines, is the adenoviral vector packaging,” Dr. Lunn emphasized. “I believe it’s what generates GBS after COVID-19 vaccination. It has nothing to do with the COVID-19 vaccination, the spike protein, the nucleic acid, the DNA, or anything else.”
The adenoviral vector probably also explains why GBS peaks during winter, said Dr. Lunn. “That’s when adenovirus is circulating.” When people contract the common cold, he explained, they don’t visit their family physician and request a swab to isolate the adenovirus. “By the time you get GBS, the adenovirus has been cleared. We’ve all got antibodies to adenovirus all over the place, anyway, because we get it so often.”
It would be difficult to prove conclusively that adenovirus belongs on the list of GBS causes, Dr. Lunn allowed. “But I have a strong suspicion that it does. COVID-19 and COVID-19 vaccination have given us some new avenues into identifying GBS causation potentially in the near future.” More research is needed in this area, he said.
Dr. Lunn has been a principal investigator for argenx (efgartigimod) and an adviser to AstraZeneca (ChAdOx1 nCoV-19). He has received travel grants from CSL Behring.
References
1. Ho TW et al. Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies. Brain. 1995;118(Pt 3):597-605. doi: 10.1093/brain/118.3.597.
2. Uncini A. A common mechanism and a new categorization for anti-ganglioside antibody-mediated neuropathies. Exp Neurol. 2012;235(2):513-6. doi: 10.1016/j.expneurol.2012.03.023.
3. Uncini A and Kuwabara S. The electrodiagnosis of Guillain-Barré syndrome subtypes: where do we stand? Clin Neurophysiol. 2018;129(12):2586-93. doi: 10.1016/j.clinph.2018.09.025.
4. Delmont E et al. Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy. Brain. 2017;140(7):1851-8. doi: 10.1093/brain/awx124.
5. McGonigal R et al. Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain. 2010;133(Pt 7):1944-60. doi: 10.1093/brain/awq119.
6. Cunningham ME et al. Real time imaging of intra-axonal calcium flux in an explant mouse model of axonal Guillain-Barré syndrome. Exp Neurol. 2022 Sep;355:114127. doi: 10.1016/j.expneurol.2022.114127.
7. Misawa S et al; Japanese Eculizumab Trial for GBS (JET-GBS) Study Group. Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial. Lancet Neurol. 2018;17(6):519-29. doi: 10.1016/S1474-4422(18)30114-5.
8. Walgaard C et al; Dutch GBS Study Group. Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2021;20(4):275-83. doi: 10.1016/S1474-4422(20)30494-4.
9. Keddie S et al. Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome. Brain. 2021;144(2):682-93. doi: 10.1093/brain/awaa433.
10. Keh RYS et al; BPNS/ABN COVID-19 Vaccine GBS Study Group. COVID-19 vaccination and Guillain-Barré syndrome: Analyses using the National Immunoglobulin Database. Brain. 2023;146(2):739-48. doi: 10.1093/brain/awac067.
11. Abara WE et al. Reports of Guillain-Barré syndrome after COVID-19 vaccination in the United States. JAMA Netw Open. 2023;6(2):e2253845. doi: 10.1001/jamanetworkopen.2022.53845.
12. Hanson KE et al. Incidence of Guillain-Barré syndrome after COVID-19 vaccination in the Vaccine Safety Datalink. JAMA Netw Open. 2022;5(4):e228879. doi: 10.1001/jamanetworkopen.2022.8879.
Recent insights into the pathophysiology of Guillain-Barré syndrome (GBS) – which affects 1 or 2 persons for every 100,000 people annually, usually post infection – indicate that classic subtypes represent varying manifestations of a shared disease process. This knowledge is yielding new treatment strategies aimed at halting the illness in its tracks. Promising therapies include inhibitors of complement and, perhaps one day, the calcium-activated protease calpain.
Meanwhile, an association between COVID-19 and GBS has been debunked, whereas a small risk of GBS following adenovirus-vectored COVID vaccination is now accepted and quantified. Regardless of cause, the potential severity of GBS and variability in its presentation demand constant vigilance.
Shutting down the disease process
When patients present to an emergency department with sensory symptoms and increasing muscle weakness, “most of the damage has been or is being done,” said Michael P. Lunn, MBBS, MRCP, PhD, professor of clinical neurology, consultant neurologist, and clinical lead in neuroimmunology at University College London Queen Square Institute of Neurology, who spoke at length about GBS with Neurology Reviews 2023 Rare Neurological Disease Special Report. “The crucial reason that GBS treatment has not advanced significantly – and why we’re still slightly stuck where we are in terms of helping people get better more quickly – is that we need something that absolutely turns the disease off as patients come through the door.”
GBS is probably the best-understood autoimmune-mediated neurological disease, in some respects surpassing myasthenia gravis, Dr. Lunn said. “We know very frequently the organisms and stimuli that set off Guillain-Barré syndrome. We understand, to an extent, the immunology and how you break tolerance of the immune system so that an invading organism can provoke an immune response that damages peripheral nerves.”
Compared to what was known about GBS in decades past, neurologists now better understand how and where antibodies attack the nerve; how complement then damages the nodes of Ranvier and paranodes; and how an external attack results in sometimes irreparable internal nerve damage. “We’ve got a string, beginning to end, of understanding the disease,” declared Dr. Lunn.
Understanding of differences in the spectrum of pathology of GBS has led to additional diagnostic categories, said Dr. Lunn. Acute inflammatory demyelinating polyradiculoneuropathy, or typical GBS, represents the most common form in affluent Western nations. A motor variant was recognized in the 1980s; in the mid-1990s, Ho and colleagues described a cohort of patients in China who had acute motor axonal neuropathy and acute motor sensory axonal neuropathy1 – two forms that are particularly common throughout Asia and South America.
Shared mechanism
Based on the findings of electrophysiologic studies, Dr. Lunn said, experts traditionally believed that GBS attacked either axons themselves or their myelin sheaths. “That’s where the anti-ganglioside antibodies come in, providing targeting to nerve structures.” The dichotomous classification system, he added, was partially correct.
Then, through the 2010s and 2020s, neurophysiologist Antonio Uncini, MD, recognized, based partly on histologic studies by Ho and colleagues, that the myelin and axonal subtypes are both likely to stem from the same mechanism.2 When antibodies and complement damage the node of Ranvier, Dr. Lunn said, “the myelin gets stripped off and the conduction becomes slow. But then the myelin can return, and patients get better.” But if damage is severe, it severs the axon, resulting in unrecoverable motor axonal neuropathy. “It’s basically all the same spectrum of disease,” Dr. Lunn said. “Anti-ganglioside antibodies may account for different GBS ‘flavors,’ but the immunological attack all occurs at the node of Ranvier in one way or another.”
The foregoing insight has focused development efforts on the shared seminal pathway of all GBS subtypes and given rise to the concept of nodo-paranodopathy, which incorporates damage at either the node of Ranvier or nearby paranodes.3
Simultaneously, Spanish and French researchers began elucidating new antibodies responsible for neuropathology at the node of Ranvier.4 Anti-ganglioside antibodies have long been loosely associated with acute motor axonal neuropathy and poor outcomes, although, Dr. Lunn said, they fail to tell the full story. Anti-GQ1b antibodies are associated with the Miller-Fisher syndrome subtype, well recognized for its medical features: double vision, loss of tendon reflexes, and arm and leg weakness.
However, Dr. Lunn said, most GBS cases lack anti-ganglioside antibodies. In some GBS cases, antibodies attack neurofascin, contactins, and gliomedin, which are mainly adhesion proteins at nodes of Ranvier.
“Therefore,” Dr. Lunn said, “there must be an antibody-mediated attack of the node of Ranvier or the paranode. That’s an important series of discoveries, primarily because it helps us understand the immunological attack at the node of Ranvier, which goes along with what Dr. Uncini was saying. But it also divides off a group of chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) that present acutely and look initially, for all purposes, like GBS.”
Recognizing acute CIDP (A-CIDP) is critically important for clinicians, Dr. Lunn stressed, because it requires treatment with rituximab (the most commonly used option), steroids, or plasma exchange.
Key clues that distinguish A-CIDP from GBS include:
• A high level of cerebrospinal fluid protein.
• Very slow nerve conduction.
• Early muscle wasting (rare in GBS).
Recognizing CIDP and A-CIDP is crucial, said Dr. Lunn, because it begins to bring all the pathology back together to make sense of GBS. Neurologists have known for decades that, if one damages a nerve with antibodies, then binds complement to those antibodies, the complement punches holes in the affected cells, resulting in death. “But it wasn’t quite clear how those cells might die,” Dr. Lunn said.
After complement-induced injury, calcium-activated calpain permanently damages the entire internal axonal structure.5 Perhaps more important, a 2022 mouse study showed that complement-mediated damage could be directed to myelin or axons using the genetically programmed presence or absence of gangliosides to understand subsequent calpain-induced destruction in either axons or myelin.6
Some of the engineered mouse cells included ganglioside; others did not. “So you can have anti-ganglioside antibodies directed at one cell type or the other, which would, or would not, have calpain within them,” Dr. Lunn said. Investigators also showed that a calpain inhibitor (AK295) or overproduction of an endogenous inhibitor, calpastatin, prevented damage to both cell types.6All existing calpain inhibitors are unsuitable for clinical use because they are highly toxic. “But if you could inhibit calpain and stop it from being activated by calcium,” Dr. Lunn explained, “you would have a mechanism for stopping cell degradation during GBS. That would be an important future target for pharmacotherapy. That whole story – from the beginning to the end of GBS – has opened up options for treatment.”
Because complement bound to antibodies, set up by infection, plays a pivotal role, complement inhibitors have become an exciting area of research over the past decade. The 36-patient Japanese Eculizumab Trial for GBS (JET-GBS) trial showed that, after 6 months, significantly more eculizumab-treated patients could run, compared with placebo-treated patients.7
“No other trials of complement inhibitors have yet been completed,” Dr. Lunn said. “But several different complement inhibitors work at different places, in a very complicated immune process. One of the complement inhibitors will become transformative in treating GBS – preventing disability and improving recovery – in the not-very-distant future.”
Additional investigational treatments that have demonstrated early promise in eliminating problem antibodies faster include imlifidase (Idefirix [Hansa Biopharma]), which destroys antibodies, and Fc receptor inhibitors such as efgartigimod alfa-fcab (Vyvgart [argenx]), which push antibodies into the natural catabolic pathway.
“We’ve been stuck with plasma exchange and intravenous immunoglobulin (IVIg) for three or four decades,” Dr. Lunn said. “We now have a series of strategies by which we can completely turn off complement and resulting nerve damage. If we can find a calpain inhibitor that turns off the end of that pathway, we will make dramatic improvements. Our understanding of the immunopathology has changed enormously and influences pharmacotherapy going forward.”
Recap of diagnosis and treatment
For decades, the diagnosis of GBS has relied on the presence of symptoms, including progressive weakness and loss of reflexes and sensations. Nerve-conduction studies and cerebrospinal fluid evaluation can help confirm the diagnosis.
IVIg shortens recovery, said Dr. Lunn, although nothing cures GBS. “And that’s a common problem: Clinicians think that they’re going to give somebody IVIg, and the patient’s going to get better immediately.” When that doesn’t happen, he said, physicians are tempted to give a second immunoglobulin dose.
However, a study published in 2021 shows that a second IVIg dose does not result in faster or better improvement – only in a significant risk of cardiovascular, cerebrovascular, and other thrombotic events 3 weeks later.8 Dr. Lunn noted that, although adverse-event data were “buried” in the supplemental materials of that study, the high cost of IVIg (approximately $12,500 per dose) means that the study has changed practice for the benefit of patients, providers, and health care systems.
COVID-19 and GBS triggers
Campylobacter jejuni infection still accounts for 30% to 40% of GBS cases, followed by other bacteria, including Mycoplasma pneumoniae and Haemophilus influenzae, and then by viruses, including cytomegalovirus and, rarely, human immunodeficiency virus. In recent years, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection – COVID-19 – and vaccines against the viral infection have captured headlines for purportedly being a cause of GBS.
The Zika virus epidemic of 2015-2016 has been linked to GBS-like illness. The 2003 severe acute respiratory syndrome (SARS) pandemic and the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic were associated with GBS – although, taken together, SARS and MERS-CoV produced fewer than 10 cases of GBS, Dr. Lunn noted. Nevertheless, heightened awareness of these viruses fueled hypervigilance regarding the prospect that COVID-19 could cause GBS. Following reports of a single such case in Wuhan and hundreds in Italy, worry over pandemic GBS grew worldwide.
Dr. Lunn and colleagues addressed the COVID-19–GBS question in a 2023 publication.9 “Because GBS is largely treated only with IVIg, and IVIg costs a lot of money, and the U.K. government insists on every dose of IVIg being logged in a government database, we were able to identify virtually every case of GBS,” he said.
GBS diagnoses were reliable, he added, because each case was confirmed by physicians outside the emergency department. Analysis revealed that, in 2020, U.K. GBS cases actually declined by around one-third. “And even when there was a second wave of COVID-19 at the end of 2020, partly caused by better counting,” Dr. Lunn said, “there was no further increase in GBS cases. We concluded that there was no link between GBS and COVID-19, as the cases simply didn’t appear.”
The foregoing findings have since been corroborated by studies in Singapore, the United States, and South America, he pointed out. Earlier case series suggesting a link between COVID-19 and GBS were selective, Dr. Lunn added, with numbers too small to support robust conclusions.
The lack of a causal link between COVID-19 and GBS suggested to Dr. Lunn that there was no reason COVID-19 vaccination should cause GBS. All COVID-19 vaccines were designed to provoke an immune response either (1) by producing the SARS-CoV-2 spike protein on the surface of virus (through a replication-incompetent adenoviral vector) or (2) through DNA or mRNA transcription, he explained. “The spike protein is only a small part of COVID-19.”
GBS: ‘Adverse event of interest’
A link between modern vaccines and GBS first appeared in the 1970s with the hastily developed swine flu vaccine. “In late 1976,” Dr. Lunn explained, “it was identified that patients who were given that vaccine seemed to be developing illnesses consistent with GBS.” By 1980, Dr. Lunn said, the risk level was determined to be only five or six cases for every 1 million doses of vaccine administered. “But the vaccine program was aborted, and swine flu never really happened.” Every year since, “there has been a surveillance program looking at the occurrence of an association of GBS with influenza vaccine.”
Minor fluctuations aside, he said, the overall incidence of GBS with influenza vaccination – 1 GBS case for every 1 million vaccine doses given – has remained consistent over several decades. “Nevertheless, GBS became an adverse event of special interest for any vaccination campaign.”
COVID-19 vaccination. Dr. Lunn and colleagues used the United Kingdom National Health Service (NHS) National Immunoglobulin Database, and other databases, to pinpoint the risk of GBS presented by the first dose of the AstraZeneca ChAdOx1 nCoV-19 adenoviral vaccine.10 As with U.K. GBS cases, every COVID-19 vaccination is linked to an NHS number. “We identified all the cases of GBS, found their NHS numbers, and went back and found the exact dates they’d been vaccinated, and with which vaccine.” Only the adenoviral-vector vaccine carried an excess risk of GBS – 5.8 cases for every 1 million doses, associated only with the first dose and peaking at approximately 25 days post vaccination – compared with other vaccines used in the United Kingdom.
Researchers looked at data from the Vaccine Adverse Event Reporting System (VAERS), a program of the Centers for Disease Control and Prevention and the Food and Drug Administration, encompassing nearly 500 million COVID-19 vaccine doses given between December 2020 and January 2022. They found that patients who received the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) had a rate of GBS (within 21 and 41 days post vaccination) that was 9 and 12 times higher, respectively, than corresponding rates for the mRNA-1273 (Moderna) and BNT162b2 (Pfizer BioNTech) COVID-19 vaccines.11 Risk was distributed relatively evenly by gender and age. Also at day 21 and day 41, observed event ratios with the adenoviral-vector vaccine (use of which has been suspended in the United States) were 3.79 and 2.34, respectively. Observed-event ratios with the other vaccines mirrored expected background rates.
The VAERS analysis confirms earlier data from the CDC’s Vaccine Safety Datalink, which showed that, among approximately 15 million U.S. vaccine doses given between mid-December 2020 and mid-November 2021, the unadjusted GBS incidence rate for every 100,000 person-years for the adenoviral vaccine, 21 days post exposure, was 32.4, compared with 1.3 for the mRNA vaccine. The adjusted relative risk with the adenoviral vaccine in the first 3 weeks post vaccination, compared to the 3- to 6-week interval post vaccination, was 6.03.12 In addition, a head-to-head comparison of adenoviral versus mRNA vaccines at 21 days revealed an adjusted rate ratio of 20.56. Mechanistically, some experts theorize that antibodies induced by the Janssen vaccine might cross-react with glycoproteins on the myelin sheath of peripheral nerve axons to cause GBS, but this remains unproven.11
The AstraZeneca vaccine uses a chimpanzee adenovirus; the Janssen vaccine uses a human adenoviral carrier. “The only commonality between the Janssen/Johnson & Johnson and AstraZeneca vaccines, and the only thing that’s different from the other vaccines, is the adenoviral vector packaging,” Dr. Lunn emphasized. “I believe it’s what generates GBS after COVID-19 vaccination. It has nothing to do with the COVID-19 vaccination, the spike protein, the nucleic acid, the DNA, or anything else.”
The adenoviral vector probably also explains why GBS peaks during winter, said Dr. Lunn. “That’s when adenovirus is circulating.” When people contract the common cold, he explained, they don’t visit their family physician and request a swab to isolate the adenovirus. “By the time you get GBS, the adenovirus has been cleared. We’ve all got antibodies to adenovirus all over the place, anyway, because we get it so often.”
It would be difficult to prove conclusively that adenovirus belongs on the list of GBS causes, Dr. Lunn allowed. “But I have a strong suspicion that it does. COVID-19 and COVID-19 vaccination have given us some new avenues into identifying GBS causation potentially in the near future.” More research is needed in this area, he said.
Dr. Lunn has been a principal investigator for argenx (efgartigimod) and an adviser to AstraZeneca (ChAdOx1 nCoV-19). He has received travel grants from CSL Behring.
References
1. Ho TW et al. Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies. Brain. 1995;118(Pt 3):597-605. doi: 10.1093/brain/118.3.597.
2. Uncini A. A common mechanism and a new categorization for anti-ganglioside antibody-mediated neuropathies. Exp Neurol. 2012;235(2):513-6. doi: 10.1016/j.expneurol.2012.03.023.
3. Uncini A and Kuwabara S. The electrodiagnosis of Guillain-Barré syndrome subtypes: where do we stand? Clin Neurophysiol. 2018;129(12):2586-93. doi: 10.1016/j.clinph.2018.09.025.
4. Delmont E et al. Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy. Brain. 2017;140(7):1851-8. doi: 10.1093/brain/awx124.
5. McGonigal R et al. Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain. 2010;133(Pt 7):1944-60. doi: 10.1093/brain/awq119.
6. Cunningham ME et al. Real time imaging of intra-axonal calcium flux in an explant mouse model of axonal Guillain-Barré syndrome. Exp Neurol. 2022 Sep;355:114127. doi: 10.1016/j.expneurol.2022.114127.
7. Misawa S et al; Japanese Eculizumab Trial for GBS (JET-GBS) Study Group. Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial. Lancet Neurol. 2018;17(6):519-29. doi: 10.1016/S1474-4422(18)30114-5.
8. Walgaard C et al; Dutch GBS Study Group. Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2021;20(4):275-83. doi: 10.1016/S1474-4422(20)30494-4.
9. Keddie S et al. Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome. Brain. 2021;144(2):682-93. doi: 10.1093/brain/awaa433.
10. Keh RYS et al; BPNS/ABN COVID-19 Vaccine GBS Study Group. COVID-19 vaccination and Guillain-Barré syndrome: Analyses using the National Immunoglobulin Database. Brain. 2023;146(2):739-48. doi: 10.1093/brain/awac067.
11. Abara WE et al. Reports of Guillain-Barré syndrome after COVID-19 vaccination in the United States. JAMA Netw Open. 2023;6(2):e2253845. doi: 10.1001/jamanetworkopen.2022.53845.
12. Hanson KE et al. Incidence of Guillain-Barré syndrome after COVID-19 vaccination in the Vaccine Safety Datalink. JAMA Netw Open. 2022;5(4):e228879. doi: 10.1001/jamanetworkopen.2022.8879.
Advances in testing and therapeutics are improving the lives of patients with Fabry disease
Earlier diagnostic screening, routine and emerging therapies, and increased awareness are helping people with the lysosomal storage disorder Fabry disease lead longer, healthier lives. Because Fabry disease is rare, however, it can be misdiagnosed and treated incorrectly – for years and by various providers – while the patient’s health declines.
Four Fabry disease experts shared their perspectives, and recommendations, with Neurology Reviews 2023 Rare Neurological Disease Special Report.
What is Fabry disease?
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene that causes reduced or absent alpha-galactosidase A (alpha-Gal A) enzyme activity. As a result, globotriaosylceramide (Gb3) accumulates, leading to cell, tissue, and organ damage in a range of systems. People with Fabry disease can develop progressive renal and cardiovascular dysfunction, neuropathy, and psychiatric disorders. They can experience cerebrovascular events; have eye, skin, gastrointestinal, and neuro-otologic involvement; and die prematurely.
Estimates of Fabry disease prevalence in the general population range from approximately 1 in 40,000 to 1 in 117,000 people. As an X-linked disorder, Fabry disease has been considered a disease mainly of males; however, affected females who are heterozygous for GLA mutations can remain asymptomatic through a normal lifespan or be as severely affected as a male would be.
Generally speaking, for every Fabry patient whose disease is diagnosed, there are five undiagnosed family members. Fabry disease affects future generations: Many patients are in their reproductive years; they want to have children and are therefore concerned about passing down the disease.
Symptoms of classic Fabry disease tend to appear during childhood or adolescence, often, and as early as 2 years of age, as acroparesthesias that intensify over time. In late-onset Fabry disease, symptoms might begin with renal failure or heart disease in the patient’s 30s, or later.
“Patients with classic Fabry disease commonly complain of acroparesthesias or whole-body pain,” said Anjay Rastogi, MD, PhD, professor of clinical medicine, clinical chief of nephrology, and director of the Fabry Disease Program at UCLA Health, Los Angeles. “With neuropathic pain, drugs like nonsteroidal anti-inflammatory drugs will probably not lessen the pain and might cause further cardiovascular, kidney, and other problems. So much of this pain is controlled by medications that are specific for nerves, including phenytoin, carbamazepine, and gabapentin.”
How do patients with Fabry disease typically present?
“Typically, with classic Fabry, young men visit the neurologist in their teenage years or later due to acroparesthesias – burning and tingling of the hands and feet,” further explained Gerald Vincent Raymond, MD, professor of genetic medicine and neurology and director of the Lysosomal Storage Disease Center at Johns Hopkins Medicine in Baltimore. “Sometimes they come to the attention of neurologists as 20- to 30-year-old men with strokes.
“These patients often undergo a long diagnostic odyssey of being misdiagnosed and treated incorrectly,” Dr. Raymond said. “Only years later, when they develop renal disease, cardiomyopathy, throw emboli, or have large- and small-vessel strokes, does a provider connect the dots.
“Neurologists should consider Fabry disease with any young patient with stroke, history of cardiomyopathy, renal disease, small-fiber peripheral neuropathy, tinnitus, hearing loss, unusual corneal whorls, or gastrointestinal issues. Because Fabry is an X-linked disease, women are usually less affected, but women can have the full manifestations of this disease.”
Who oversees the care of patients with Fabry disease?
“As a multisystem disease, Fabry disease must be managed by a multidisciplinary team, including genetics, neurology, nephrology, cardiology, psychiatry, ophthalmology, and otolaryngology,” explained Lizbeth Mellin, MD, assistant professor of pediatrics and clinical geneticist at University of Florida Health Jacksonville.
At what point does a neurologist encounter patients with Fabry disease? “Patients with Fabry disease are usually treated by rheumatologists and other specialists before they find a neurologist,” Dr. Mellin said. “Or they may see the neurologist for transient ischemic attacks or stroke, or for treatment of headaches, vascular dementia, dizziness or vertigo, hearing loss, seizures, hemiplegia, or aphasia.
“Almost 80% of adults with Fabry disease have distal neuropathic pain characterized by acroparesthesias and sensory loss starting in the palms of the hands or the soles of the feet, spreading to the entire body, and lasting for hours or days.
Dr. Mellin continued: “Neurologists play a critical role in treating manifestations such as neuropathic pain, stroke, and seizure. Without a current curative treatment for Fabry disease, the goals of its management are focused on treating manifestations and maintaining organ function, optimizing quality of life, and preserving life expectancy.”
What role does the neurologist play in ongoing management of Fabry disease? “Neurologists are involved in primary and secondary stroke prevention and pain management,” Dr. Rastogi explained, “and in diagnosing possible Fabry disease when they find cryptogenic stroke, especially in younger patients; when screening family members; and when reaching out to other appropriate Fabry providers.
“Primary care providers, geneticists, and, sometimes, nephrologists may manage the patient’s overall care. We send our patients to neurologists to evaluate and manage neuropathic pain, stroke, white-matter lesions, and cerebrovascular disease. After a stroke, a support team cares for the patient and manages the rehab.
“Neurologists tend to have organ-specific involvement, and they may treat pain. They may have their first encounter with the patient when they do nerve testing, brain scans, or other tests, or when they diagnose nervous system problems that they may continue to treat.”
How does the role of the neurologist complement others on the interdisciplinary care team? “Fabry requires management by specialists familiar with the multiple aspects of the disorder,” Dr. Raymond said. “As a geneticist and neurologist, I care for a broad portfolio of lysosomal storage diseases. Usually, a metabolic genetics center or a Fabry center will handle the therapy. Fabry requires a multidisciplinary approach, and someone needs to be quarterbacking the patient’s overall management.”
“Teamwork is about patient well-being and empowerment,” Dr. Mellin pointed out. “Patients with Fabry disease require multidisciplinary care to reduce their morbidity and improve their health-related quality of life. Early diagnosis and treatment are critical to preventing irreversible organ damage and failure. Patients with stroke are usually evaluated in a hospital setting. To protect major organs from progressive damage, the differential diagnosis must include Fabry disease.”
“It’s important to provide coordinated care to the entire patient, not only the affected organ,” Dr. Rastogi pointed out. “Taking care of patients with Fabry disease is difficult, complicated, and time-consuming. Academic programs have various specialties under the same umbrella, so it’s easier to coordinate care than in private practice. In private practice, the neurologist needs to reach out to other specialists to coordinate care. “An interdisciplinary team approach, with integrative care in which the team members communicate with each other, is very important. The team may include geneticists, pediatricians, nephrologists, cardiologists, neurologists, gastroenterologists, and a pain management team that may use biofeedback and other non-opioid approaches. The interdisciplinary UCLA Fabry Disease Program addresses almost every aspect of Fabry. As a nephrologist, I oversee the entire care of the patient, not just the kidneys.
“Some medical practices may have only three to five patients, with a geneticist leading the care team. In others, the primary care physician oversees and coordinates care with a neurologist, nephrologist, cardiologist, pain specialist, and other specialists. Patients are often anxious and depressed, so a psychologist and psychiatrist should also be involved.
“A neurologist who diagnoses a patient with Fabry disease should contact their local Fabry disease experts. If none are available, they should refer their patients to geneticists to oversee their care. At-risk family members also need to be screened.”
Monroe Carell Jr. Children’s Hospital at Vanderbilt, in Nashville, Tenn., has a multidisciplinary Fabry Disease Clinic with specialists in genetics, neurology, and cardiology. Chelsea J. Lauderdale, DNP, MPH, APRN, CPNP-PC, in the division of medical genetics and genomic medicine, helps screen and diagnose patients with Fabry disease.
“A nurse practitioner in this setting may work closely with newborn screening and be involved in infant and adult diagnosis,” Ms. Lauderdale said. “They may identify the onset of new symptoms and aid specialists in their evaluations. Nurse practitioners may be involved throughout Fabry disease patients’ care, monitoring labs, ensuring they are treated by the appropriate specialists, and initiating treatment when indicated.”
What recent research and advances should neurologists be aware of?
Diagnostics. Tests for Fabry disease now include an enzyme assay to measure alpha-galactosidase activity in the blood of males and genetic testing in males and females to identify GLA mutations. Several states now test newborns for Fabry disease, enabling earlier diagnosis and treatment, Dr. Raymond said. Identifying Fabry disease in a boy by enzyme assay sometimes leads to identifying an uncle, a grandfather, or others in the family who have Fabry. Fabry is sometimes discovered from genetic panels to help diagnose peripheral neuropathy and from prenatal genetic testing.
“Genetic screening of at-risk family members, of any degree, in various generations, is important,” Dr. Rastogi emphasized, “so we construct a family tree to find everyone at risk. Genetic testing is much easier and more widespread than it was even 5 years ago. It’s more accessible and you don’t need to go through a geneticist to diagnose Fabry disease.
“Some patients first come to us for dialysis in their 40s or 50s, but people are being tested and treated at younger ages now, and we also have newborn screening. Genetic testing for Fabry is not common, but in several states, every newborn is tested for Fabry. And, if parents have Fabry, we test their children.”
Therapeutics. “Available and emerging therapies make the field exciting,” Dr. Raymond said. “Some current gene therapy trials look promising, and preliminary evidence suggests that gene therapy may stabilize kidney and heart function.”
“Although Fabry disease does not have a cure,” Dr. Rastogi pointed out, “two treatments for Fabry disease appear to help prevent life-threatening complications: enzyme replacement therapy (ERT) and chaperone therapy.”
Replacing enzymes. “In Fabry disease, the enzyme alpha-galactosidase A is deficient,” Dr. Rastogi explained, “causing build-up of sphingolipids in blood vessels and tissues. ERT, a great advance that we’ve had for over 20 years, replenishes that deficiency. ERT has some challenges: It’s an infusion every 2 weeks for life, and it can have infusion reactions and other complications.
“Newer, second-generation, versions of ERT are being developed, including pegunigalsidase alfa (Elfabrio, Chiesi Global Rare Diseases, Protalix Biotherapeutics), recently approved by the U.S. Food and Drug Administration to treat adults with Fabry disease.”
Chaperone therapy. “The oral drug migalastat (Galafold, Fabrazyme) is a small-molecule chaperone therapy that stabilizes the faulty alpha-galactosidase A enzyme,” Dr. Rastogi explained. “It is easier to take, every other day for life, than [undergoing] infusion. Limitations include that it is available only to patients who have the amenable mutations, and whose estimated glomerular filtration rate is greater than 30 [mL/min/1.73 m2], and they may have some adverse events including nausea or vomiting.”
On the horizon: substrate reduction, gene therapy. “[These] are also exciting avenues of research,” said Dr. Rastogi. “Substrate reduction therapy aims to reduce glycosphingolipid accumulation, and lucerastat [Idorsia Pharmaceutical]1,2 and venglustat [Sanofi Genzyme]3,4 are in active clinical trials or trials that have been completed.
Gene therapy “delivers a healthy gene that helps the body produce a previously deficient enzyme,” Dr. Rastogi explained. “This is an early, very promising field in need of more research, with many challenges involving the vector and complications.
“While it is still too early to predict how effective gene therapy will be, research is encouraging. Another promising therapy is modulation of gene expression, which changes the activity of a gene.”
“Gene therapy may potentially offer an alternative to typical ERT, which some patients find burdensome,” Ms. Lauderdale added. “If a neurologist has a patient who may be a good candidate for a gene therapy clinical trial that is recruiting participants, I encourage them to learn more about the study and its requirements.”
Dr. Mellin concurred: “Several gene therapy clinical trials show promise, but further information and evidence are required.”
How might these advances affect the trajectory of Fabry disease?
“Untreated Fabry compromises quality of life and may shorten the lifespan,” Dr. Raymond said. “I’m aware of individuals and their family members who died in their 60s. In the past, individuals would develop renal failure, stroke, or cardiomyopathy before being diagnosed and treated, but now we can begin treating them earlier and head off those outcomes.
“We have many options, and their number is increasing. We now diagnose patients when they are younger and maybe presymptomatic, when therapies have much greater potential to ameliorate their lives.”
Dr. Raymond spoke hopefully: “With gene therapy, people with Fabry disease will no longer need enzyme replacement or chaperone therapy. Ultimately, if gene therapy proves to be as efficacious as we hope, without big downsides, we will, essentially, be curing Fabry.”
Concluding remarks
In summing up, the four experts quoted in this article offered the following observations and advice for neurologists:
Dr. Mellin. “Pain has a significant impact on quality of life for patients with Fabry disease. Identifying and adequately treating neuropathic pain can be life-changing.”
Ms. Lauderdale. “Reach out to geneticists and other appropriate specialists. We all need to communicate the needs of our patients to ensure they receive the best possible patient-centered care.”
Dr. Rastogi. “Fabry disease is an area of active research that can be a prototype for, and affect the outcomes of, other genetic disorders. I expect to see more centers of excellence for the study and treatment of Fabry disease.”
Dr. Raymond. “With therapies rapidly evolving, neurologists need to consider rare diseases and think about how to build them into their diagnostic schemes.”
Dr. Raymond, Dr. Mellin, and Ms. Lauderdale, have nothing to disclose. Dr. Rastogi discloses a financial relationship with several pharmaceutical and biopharmaceutical companies involved in Fabry disease therapeutics research and development, including Amicus Therapeutics, Chiesi Global Rare Diseases, Genzyme Sanofi, Sanofi S.A., Idorsia Pharmaceuticals Ltd., and Protalix Biotherapeutics.
Additional recommended reading
Beck M et al. Twenty years of the Fabry Outcome Survey (FOS): Insights, achievements, and lessons learned from a global patient registry. Orphanet J Rare Dis. 2022;17(1):238. doi: 10.1186/s13023-022-02392-9.
Beraza-Millor M et al. Novel golden lipid nanoparticles with small interference ribonucleic acid for substrate reduction therapy in Fabry disease. Pharmaceutics. 2023;15(7):1936. doi: 10.3390/pharmaceutics15071936.
Ezgu F et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: A multidisciplinary Turkey perspective. Orphanet J Rare Dis. 2022;17(1):90. doi: 10.1186/s13023-022-02215-x.
Fabry disease registry & pregnancy sub-registry. ClinicalTrials.gov Identifier: NCT00196742. Updated July 13, 2023. Accessed Sept. 13, 2023. https://www.clinicaltrials.gov/study/NCT00196742?term=Fabry%20Disease%20Registry%20%26%20Pregnancy%20Sub-registry&rank=1.
Umer M and Kalra DK. Treatment of Fabry disease: established and emerging therapies. Pharmaceuticals. 2023;16(2):320. doi: 10.3390/ph16020320.
Weidemann F et al. Chaperone therapy in Fabry disease. Int J Mol Sci. 2022;23(3):1887. doi: 10.3390/ijms23031887.
References
1. Efficacy and safety of lucerastat oral monotherapy in adult subjects with Fabry disease (MODIFY). ClinicalTrials.gov Identifier: NCT03425539. Updated Aug. 9, 2022. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03425539?term=NCT03425539&rank=1.
2. A study to evaluate the long-term safety and tolerability of lucerastat in adult subjects with Fabry disease. ClinicalTrials.gov Identifier: NCT03737214. Updated Aug. 16, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03737214?term=NCT03737214&rank=1.
3. Evaluate the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02228460. Updated Dec. 17, 2019. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02228460?term=NCT02228460&rank=1.
4. Evaluation of the long-term safety, pharmacodynamics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02489344. Updated March 23, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02489344?term=NC
Earlier diagnostic screening, routine and emerging therapies, and increased awareness are helping people with the lysosomal storage disorder Fabry disease lead longer, healthier lives. Because Fabry disease is rare, however, it can be misdiagnosed and treated incorrectly – for years and by various providers – while the patient’s health declines.
Four Fabry disease experts shared their perspectives, and recommendations, with Neurology Reviews 2023 Rare Neurological Disease Special Report.
What is Fabry disease?
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene that causes reduced or absent alpha-galactosidase A (alpha-Gal A) enzyme activity. As a result, globotriaosylceramide (Gb3) accumulates, leading to cell, tissue, and organ damage in a range of systems. People with Fabry disease can develop progressive renal and cardiovascular dysfunction, neuropathy, and psychiatric disorders. They can experience cerebrovascular events; have eye, skin, gastrointestinal, and neuro-otologic involvement; and die prematurely.
Estimates of Fabry disease prevalence in the general population range from approximately 1 in 40,000 to 1 in 117,000 people. As an X-linked disorder, Fabry disease has been considered a disease mainly of males; however, affected females who are heterozygous for GLA mutations can remain asymptomatic through a normal lifespan or be as severely affected as a male would be.
Generally speaking, for every Fabry patient whose disease is diagnosed, there are five undiagnosed family members. Fabry disease affects future generations: Many patients are in their reproductive years; they want to have children and are therefore concerned about passing down the disease.
Symptoms of classic Fabry disease tend to appear during childhood or adolescence, often, and as early as 2 years of age, as acroparesthesias that intensify over time. In late-onset Fabry disease, symptoms might begin with renal failure or heart disease in the patient’s 30s, or later.
“Patients with classic Fabry disease commonly complain of acroparesthesias or whole-body pain,” said Anjay Rastogi, MD, PhD, professor of clinical medicine, clinical chief of nephrology, and director of the Fabry Disease Program at UCLA Health, Los Angeles. “With neuropathic pain, drugs like nonsteroidal anti-inflammatory drugs will probably not lessen the pain and might cause further cardiovascular, kidney, and other problems. So much of this pain is controlled by medications that are specific for nerves, including phenytoin, carbamazepine, and gabapentin.”
How do patients with Fabry disease typically present?
“Typically, with classic Fabry, young men visit the neurologist in their teenage years or later due to acroparesthesias – burning and tingling of the hands and feet,” further explained Gerald Vincent Raymond, MD, professor of genetic medicine and neurology and director of the Lysosomal Storage Disease Center at Johns Hopkins Medicine in Baltimore. “Sometimes they come to the attention of neurologists as 20- to 30-year-old men with strokes.
“These patients often undergo a long diagnostic odyssey of being misdiagnosed and treated incorrectly,” Dr. Raymond said. “Only years later, when they develop renal disease, cardiomyopathy, throw emboli, or have large- and small-vessel strokes, does a provider connect the dots.
“Neurologists should consider Fabry disease with any young patient with stroke, history of cardiomyopathy, renal disease, small-fiber peripheral neuropathy, tinnitus, hearing loss, unusual corneal whorls, or gastrointestinal issues. Because Fabry is an X-linked disease, women are usually less affected, but women can have the full manifestations of this disease.”
Who oversees the care of patients with Fabry disease?
“As a multisystem disease, Fabry disease must be managed by a multidisciplinary team, including genetics, neurology, nephrology, cardiology, psychiatry, ophthalmology, and otolaryngology,” explained Lizbeth Mellin, MD, assistant professor of pediatrics and clinical geneticist at University of Florida Health Jacksonville.
At what point does a neurologist encounter patients with Fabry disease? “Patients with Fabry disease are usually treated by rheumatologists and other specialists before they find a neurologist,” Dr. Mellin said. “Or they may see the neurologist for transient ischemic attacks or stroke, or for treatment of headaches, vascular dementia, dizziness or vertigo, hearing loss, seizures, hemiplegia, or aphasia.
“Almost 80% of adults with Fabry disease have distal neuropathic pain characterized by acroparesthesias and sensory loss starting in the palms of the hands or the soles of the feet, spreading to the entire body, and lasting for hours or days.
Dr. Mellin continued: “Neurologists play a critical role in treating manifestations such as neuropathic pain, stroke, and seizure. Without a current curative treatment for Fabry disease, the goals of its management are focused on treating manifestations and maintaining organ function, optimizing quality of life, and preserving life expectancy.”
What role does the neurologist play in ongoing management of Fabry disease? “Neurologists are involved in primary and secondary stroke prevention and pain management,” Dr. Rastogi explained, “and in diagnosing possible Fabry disease when they find cryptogenic stroke, especially in younger patients; when screening family members; and when reaching out to other appropriate Fabry providers.
“Primary care providers, geneticists, and, sometimes, nephrologists may manage the patient’s overall care. We send our patients to neurologists to evaluate and manage neuropathic pain, stroke, white-matter lesions, and cerebrovascular disease. After a stroke, a support team cares for the patient and manages the rehab.
“Neurologists tend to have organ-specific involvement, and they may treat pain. They may have their first encounter with the patient when they do nerve testing, brain scans, or other tests, or when they diagnose nervous system problems that they may continue to treat.”
How does the role of the neurologist complement others on the interdisciplinary care team? “Fabry requires management by specialists familiar with the multiple aspects of the disorder,” Dr. Raymond said. “As a geneticist and neurologist, I care for a broad portfolio of lysosomal storage diseases. Usually, a metabolic genetics center or a Fabry center will handle the therapy. Fabry requires a multidisciplinary approach, and someone needs to be quarterbacking the patient’s overall management.”
“Teamwork is about patient well-being and empowerment,” Dr. Mellin pointed out. “Patients with Fabry disease require multidisciplinary care to reduce their morbidity and improve their health-related quality of life. Early diagnosis and treatment are critical to preventing irreversible organ damage and failure. Patients with stroke are usually evaluated in a hospital setting. To protect major organs from progressive damage, the differential diagnosis must include Fabry disease.”
“It’s important to provide coordinated care to the entire patient, not only the affected organ,” Dr. Rastogi pointed out. “Taking care of patients with Fabry disease is difficult, complicated, and time-consuming. Academic programs have various specialties under the same umbrella, so it’s easier to coordinate care than in private practice. In private practice, the neurologist needs to reach out to other specialists to coordinate care. “An interdisciplinary team approach, with integrative care in which the team members communicate with each other, is very important. The team may include geneticists, pediatricians, nephrologists, cardiologists, neurologists, gastroenterologists, and a pain management team that may use biofeedback and other non-opioid approaches. The interdisciplinary UCLA Fabry Disease Program addresses almost every aspect of Fabry. As a nephrologist, I oversee the entire care of the patient, not just the kidneys.
“Some medical practices may have only three to five patients, with a geneticist leading the care team. In others, the primary care physician oversees and coordinates care with a neurologist, nephrologist, cardiologist, pain specialist, and other specialists. Patients are often anxious and depressed, so a psychologist and psychiatrist should also be involved.
“A neurologist who diagnoses a patient with Fabry disease should contact their local Fabry disease experts. If none are available, they should refer their patients to geneticists to oversee their care. At-risk family members also need to be screened.”
Monroe Carell Jr. Children’s Hospital at Vanderbilt, in Nashville, Tenn., has a multidisciplinary Fabry Disease Clinic with specialists in genetics, neurology, and cardiology. Chelsea J. Lauderdale, DNP, MPH, APRN, CPNP-PC, in the division of medical genetics and genomic medicine, helps screen and diagnose patients with Fabry disease.
“A nurse practitioner in this setting may work closely with newborn screening and be involved in infant and adult diagnosis,” Ms. Lauderdale said. “They may identify the onset of new symptoms and aid specialists in their evaluations. Nurse practitioners may be involved throughout Fabry disease patients’ care, monitoring labs, ensuring they are treated by the appropriate specialists, and initiating treatment when indicated.”
What recent research and advances should neurologists be aware of?
Diagnostics. Tests for Fabry disease now include an enzyme assay to measure alpha-galactosidase activity in the blood of males and genetic testing in males and females to identify GLA mutations. Several states now test newborns for Fabry disease, enabling earlier diagnosis and treatment, Dr. Raymond said. Identifying Fabry disease in a boy by enzyme assay sometimes leads to identifying an uncle, a grandfather, or others in the family who have Fabry. Fabry is sometimes discovered from genetic panels to help diagnose peripheral neuropathy and from prenatal genetic testing.
“Genetic screening of at-risk family members, of any degree, in various generations, is important,” Dr. Rastogi emphasized, “so we construct a family tree to find everyone at risk. Genetic testing is much easier and more widespread than it was even 5 years ago. It’s more accessible and you don’t need to go through a geneticist to diagnose Fabry disease.
“Some patients first come to us for dialysis in their 40s or 50s, but people are being tested and treated at younger ages now, and we also have newborn screening. Genetic testing for Fabry is not common, but in several states, every newborn is tested for Fabry. And, if parents have Fabry, we test their children.”
Therapeutics. “Available and emerging therapies make the field exciting,” Dr. Raymond said. “Some current gene therapy trials look promising, and preliminary evidence suggests that gene therapy may stabilize kidney and heart function.”
“Although Fabry disease does not have a cure,” Dr. Rastogi pointed out, “two treatments for Fabry disease appear to help prevent life-threatening complications: enzyme replacement therapy (ERT) and chaperone therapy.”
Replacing enzymes. “In Fabry disease, the enzyme alpha-galactosidase A is deficient,” Dr. Rastogi explained, “causing build-up of sphingolipids in blood vessels and tissues. ERT, a great advance that we’ve had for over 20 years, replenishes that deficiency. ERT has some challenges: It’s an infusion every 2 weeks for life, and it can have infusion reactions and other complications.
“Newer, second-generation, versions of ERT are being developed, including pegunigalsidase alfa (Elfabrio, Chiesi Global Rare Diseases, Protalix Biotherapeutics), recently approved by the U.S. Food and Drug Administration to treat adults with Fabry disease.”
Chaperone therapy. “The oral drug migalastat (Galafold, Fabrazyme) is a small-molecule chaperone therapy that stabilizes the faulty alpha-galactosidase A enzyme,” Dr. Rastogi explained. “It is easier to take, every other day for life, than [undergoing] infusion. Limitations include that it is available only to patients who have the amenable mutations, and whose estimated glomerular filtration rate is greater than 30 [mL/min/1.73 m2], and they may have some adverse events including nausea or vomiting.”
On the horizon: substrate reduction, gene therapy. “[These] are also exciting avenues of research,” said Dr. Rastogi. “Substrate reduction therapy aims to reduce glycosphingolipid accumulation, and lucerastat [Idorsia Pharmaceutical]1,2 and venglustat [Sanofi Genzyme]3,4 are in active clinical trials or trials that have been completed.
Gene therapy “delivers a healthy gene that helps the body produce a previously deficient enzyme,” Dr. Rastogi explained. “This is an early, very promising field in need of more research, with many challenges involving the vector and complications.
“While it is still too early to predict how effective gene therapy will be, research is encouraging. Another promising therapy is modulation of gene expression, which changes the activity of a gene.”
“Gene therapy may potentially offer an alternative to typical ERT, which some patients find burdensome,” Ms. Lauderdale added. “If a neurologist has a patient who may be a good candidate for a gene therapy clinical trial that is recruiting participants, I encourage them to learn more about the study and its requirements.”
Dr. Mellin concurred: “Several gene therapy clinical trials show promise, but further information and evidence are required.”
How might these advances affect the trajectory of Fabry disease?
“Untreated Fabry compromises quality of life and may shorten the lifespan,” Dr. Raymond said. “I’m aware of individuals and their family members who died in their 60s. In the past, individuals would develop renal failure, stroke, or cardiomyopathy before being diagnosed and treated, but now we can begin treating them earlier and head off those outcomes.
“We have many options, and their number is increasing. We now diagnose patients when they are younger and maybe presymptomatic, when therapies have much greater potential to ameliorate their lives.”
Dr. Raymond spoke hopefully: “With gene therapy, people with Fabry disease will no longer need enzyme replacement or chaperone therapy. Ultimately, if gene therapy proves to be as efficacious as we hope, without big downsides, we will, essentially, be curing Fabry.”
Concluding remarks
In summing up, the four experts quoted in this article offered the following observations and advice for neurologists:
Dr. Mellin. “Pain has a significant impact on quality of life for patients with Fabry disease. Identifying and adequately treating neuropathic pain can be life-changing.”
Ms. Lauderdale. “Reach out to geneticists and other appropriate specialists. We all need to communicate the needs of our patients to ensure they receive the best possible patient-centered care.”
Dr. Rastogi. “Fabry disease is an area of active research that can be a prototype for, and affect the outcomes of, other genetic disorders. I expect to see more centers of excellence for the study and treatment of Fabry disease.”
Dr. Raymond. “With therapies rapidly evolving, neurologists need to consider rare diseases and think about how to build them into their diagnostic schemes.”
Dr. Raymond, Dr. Mellin, and Ms. Lauderdale, have nothing to disclose. Dr. Rastogi discloses a financial relationship with several pharmaceutical and biopharmaceutical companies involved in Fabry disease therapeutics research and development, including Amicus Therapeutics, Chiesi Global Rare Diseases, Genzyme Sanofi, Sanofi S.A., Idorsia Pharmaceuticals Ltd., and Protalix Biotherapeutics.
Additional recommended reading
Beck M et al. Twenty years of the Fabry Outcome Survey (FOS): Insights, achievements, and lessons learned from a global patient registry. Orphanet J Rare Dis. 2022;17(1):238. doi: 10.1186/s13023-022-02392-9.
Beraza-Millor M et al. Novel golden lipid nanoparticles with small interference ribonucleic acid for substrate reduction therapy in Fabry disease. Pharmaceutics. 2023;15(7):1936. doi: 10.3390/pharmaceutics15071936.
Ezgu F et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: A multidisciplinary Turkey perspective. Orphanet J Rare Dis. 2022;17(1):90. doi: 10.1186/s13023-022-02215-x.
Fabry disease registry & pregnancy sub-registry. ClinicalTrials.gov Identifier: NCT00196742. Updated July 13, 2023. Accessed Sept. 13, 2023. https://www.clinicaltrials.gov/study/NCT00196742?term=Fabry%20Disease%20Registry%20%26%20Pregnancy%20Sub-registry&rank=1.
Umer M and Kalra DK. Treatment of Fabry disease: established and emerging therapies. Pharmaceuticals. 2023;16(2):320. doi: 10.3390/ph16020320.
Weidemann F et al. Chaperone therapy in Fabry disease. Int J Mol Sci. 2022;23(3):1887. doi: 10.3390/ijms23031887.
References
1. Efficacy and safety of lucerastat oral monotherapy in adult subjects with Fabry disease (MODIFY). ClinicalTrials.gov Identifier: NCT03425539. Updated Aug. 9, 2022. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03425539?term=NCT03425539&rank=1.
2. A study to evaluate the long-term safety and tolerability of lucerastat in adult subjects with Fabry disease. ClinicalTrials.gov Identifier: NCT03737214. Updated Aug. 16, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03737214?term=NCT03737214&rank=1.
3. Evaluate the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02228460. Updated Dec. 17, 2019. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02228460?term=NCT02228460&rank=1.
4. Evaluation of the long-term safety, pharmacodynamics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02489344. Updated March 23, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02489344?term=NC
Earlier diagnostic screening, routine and emerging therapies, and increased awareness are helping people with the lysosomal storage disorder Fabry disease lead longer, healthier lives. Because Fabry disease is rare, however, it can be misdiagnosed and treated incorrectly – for years and by various providers – while the patient’s health declines.
Four Fabry disease experts shared their perspectives, and recommendations, with Neurology Reviews 2023 Rare Neurological Disease Special Report.
What is Fabry disease?
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene that causes reduced or absent alpha-galactosidase A (alpha-Gal A) enzyme activity. As a result, globotriaosylceramide (Gb3) accumulates, leading to cell, tissue, and organ damage in a range of systems. People with Fabry disease can develop progressive renal and cardiovascular dysfunction, neuropathy, and psychiatric disorders. They can experience cerebrovascular events; have eye, skin, gastrointestinal, and neuro-otologic involvement; and die prematurely.
Estimates of Fabry disease prevalence in the general population range from approximately 1 in 40,000 to 1 in 117,000 people. As an X-linked disorder, Fabry disease has been considered a disease mainly of males; however, affected females who are heterozygous for GLA mutations can remain asymptomatic through a normal lifespan or be as severely affected as a male would be.
Generally speaking, for every Fabry patient whose disease is diagnosed, there are five undiagnosed family members. Fabry disease affects future generations: Many patients are in their reproductive years; they want to have children and are therefore concerned about passing down the disease.
Symptoms of classic Fabry disease tend to appear during childhood or adolescence, often, and as early as 2 years of age, as acroparesthesias that intensify over time. In late-onset Fabry disease, symptoms might begin with renal failure or heart disease in the patient’s 30s, or later.
“Patients with classic Fabry disease commonly complain of acroparesthesias or whole-body pain,” said Anjay Rastogi, MD, PhD, professor of clinical medicine, clinical chief of nephrology, and director of the Fabry Disease Program at UCLA Health, Los Angeles. “With neuropathic pain, drugs like nonsteroidal anti-inflammatory drugs will probably not lessen the pain and might cause further cardiovascular, kidney, and other problems. So much of this pain is controlled by medications that are specific for nerves, including phenytoin, carbamazepine, and gabapentin.”
How do patients with Fabry disease typically present?
“Typically, with classic Fabry, young men visit the neurologist in their teenage years or later due to acroparesthesias – burning and tingling of the hands and feet,” further explained Gerald Vincent Raymond, MD, professor of genetic medicine and neurology and director of the Lysosomal Storage Disease Center at Johns Hopkins Medicine in Baltimore. “Sometimes they come to the attention of neurologists as 20- to 30-year-old men with strokes.
“These patients often undergo a long diagnostic odyssey of being misdiagnosed and treated incorrectly,” Dr. Raymond said. “Only years later, when they develop renal disease, cardiomyopathy, throw emboli, or have large- and small-vessel strokes, does a provider connect the dots.
“Neurologists should consider Fabry disease with any young patient with stroke, history of cardiomyopathy, renal disease, small-fiber peripheral neuropathy, tinnitus, hearing loss, unusual corneal whorls, or gastrointestinal issues. Because Fabry is an X-linked disease, women are usually less affected, but women can have the full manifestations of this disease.”
Who oversees the care of patients with Fabry disease?
“As a multisystem disease, Fabry disease must be managed by a multidisciplinary team, including genetics, neurology, nephrology, cardiology, psychiatry, ophthalmology, and otolaryngology,” explained Lizbeth Mellin, MD, assistant professor of pediatrics and clinical geneticist at University of Florida Health Jacksonville.
At what point does a neurologist encounter patients with Fabry disease? “Patients with Fabry disease are usually treated by rheumatologists and other specialists before they find a neurologist,” Dr. Mellin said. “Or they may see the neurologist for transient ischemic attacks or stroke, or for treatment of headaches, vascular dementia, dizziness or vertigo, hearing loss, seizures, hemiplegia, or aphasia.
“Almost 80% of adults with Fabry disease have distal neuropathic pain characterized by acroparesthesias and sensory loss starting in the palms of the hands or the soles of the feet, spreading to the entire body, and lasting for hours or days.
Dr. Mellin continued: “Neurologists play a critical role in treating manifestations such as neuropathic pain, stroke, and seizure. Without a current curative treatment for Fabry disease, the goals of its management are focused on treating manifestations and maintaining organ function, optimizing quality of life, and preserving life expectancy.”
What role does the neurologist play in ongoing management of Fabry disease? “Neurologists are involved in primary and secondary stroke prevention and pain management,” Dr. Rastogi explained, “and in diagnosing possible Fabry disease when they find cryptogenic stroke, especially in younger patients; when screening family members; and when reaching out to other appropriate Fabry providers.
“Primary care providers, geneticists, and, sometimes, nephrologists may manage the patient’s overall care. We send our patients to neurologists to evaluate and manage neuropathic pain, stroke, white-matter lesions, and cerebrovascular disease. After a stroke, a support team cares for the patient and manages the rehab.
“Neurologists tend to have organ-specific involvement, and they may treat pain. They may have their first encounter with the patient when they do nerve testing, brain scans, or other tests, or when they diagnose nervous system problems that they may continue to treat.”
How does the role of the neurologist complement others on the interdisciplinary care team? “Fabry requires management by specialists familiar with the multiple aspects of the disorder,” Dr. Raymond said. “As a geneticist and neurologist, I care for a broad portfolio of lysosomal storage diseases. Usually, a metabolic genetics center or a Fabry center will handle the therapy. Fabry requires a multidisciplinary approach, and someone needs to be quarterbacking the patient’s overall management.”
“Teamwork is about patient well-being and empowerment,” Dr. Mellin pointed out. “Patients with Fabry disease require multidisciplinary care to reduce their morbidity and improve their health-related quality of life. Early diagnosis and treatment are critical to preventing irreversible organ damage and failure. Patients with stroke are usually evaluated in a hospital setting. To protect major organs from progressive damage, the differential diagnosis must include Fabry disease.”
“It’s important to provide coordinated care to the entire patient, not only the affected organ,” Dr. Rastogi pointed out. “Taking care of patients with Fabry disease is difficult, complicated, and time-consuming. Academic programs have various specialties under the same umbrella, so it’s easier to coordinate care than in private practice. In private practice, the neurologist needs to reach out to other specialists to coordinate care. “An interdisciplinary team approach, with integrative care in which the team members communicate with each other, is very important. The team may include geneticists, pediatricians, nephrologists, cardiologists, neurologists, gastroenterologists, and a pain management team that may use biofeedback and other non-opioid approaches. The interdisciplinary UCLA Fabry Disease Program addresses almost every aspect of Fabry. As a nephrologist, I oversee the entire care of the patient, not just the kidneys.
“Some medical practices may have only three to five patients, with a geneticist leading the care team. In others, the primary care physician oversees and coordinates care with a neurologist, nephrologist, cardiologist, pain specialist, and other specialists. Patients are often anxious and depressed, so a psychologist and psychiatrist should also be involved.
“A neurologist who diagnoses a patient with Fabry disease should contact their local Fabry disease experts. If none are available, they should refer their patients to geneticists to oversee their care. At-risk family members also need to be screened.”
Monroe Carell Jr. Children’s Hospital at Vanderbilt, in Nashville, Tenn., has a multidisciplinary Fabry Disease Clinic with specialists in genetics, neurology, and cardiology. Chelsea J. Lauderdale, DNP, MPH, APRN, CPNP-PC, in the division of medical genetics and genomic medicine, helps screen and diagnose patients with Fabry disease.
“A nurse practitioner in this setting may work closely with newborn screening and be involved in infant and adult diagnosis,” Ms. Lauderdale said. “They may identify the onset of new symptoms and aid specialists in their evaluations. Nurse practitioners may be involved throughout Fabry disease patients’ care, monitoring labs, ensuring they are treated by the appropriate specialists, and initiating treatment when indicated.”
What recent research and advances should neurologists be aware of?
Diagnostics. Tests for Fabry disease now include an enzyme assay to measure alpha-galactosidase activity in the blood of males and genetic testing in males and females to identify GLA mutations. Several states now test newborns for Fabry disease, enabling earlier diagnosis and treatment, Dr. Raymond said. Identifying Fabry disease in a boy by enzyme assay sometimes leads to identifying an uncle, a grandfather, or others in the family who have Fabry. Fabry is sometimes discovered from genetic panels to help diagnose peripheral neuropathy and from prenatal genetic testing.
“Genetic screening of at-risk family members, of any degree, in various generations, is important,” Dr. Rastogi emphasized, “so we construct a family tree to find everyone at risk. Genetic testing is much easier and more widespread than it was even 5 years ago. It’s more accessible and you don’t need to go through a geneticist to diagnose Fabry disease.
“Some patients first come to us for dialysis in their 40s or 50s, but people are being tested and treated at younger ages now, and we also have newborn screening. Genetic testing for Fabry is not common, but in several states, every newborn is tested for Fabry. And, if parents have Fabry, we test their children.”
Therapeutics. “Available and emerging therapies make the field exciting,” Dr. Raymond said. “Some current gene therapy trials look promising, and preliminary evidence suggests that gene therapy may stabilize kidney and heart function.”
“Although Fabry disease does not have a cure,” Dr. Rastogi pointed out, “two treatments for Fabry disease appear to help prevent life-threatening complications: enzyme replacement therapy (ERT) and chaperone therapy.”
Replacing enzymes. “In Fabry disease, the enzyme alpha-galactosidase A is deficient,” Dr. Rastogi explained, “causing build-up of sphingolipids in blood vessels and tissues. ERT, a great advance that we’ve had for over 20 years, replenishes that deficiency. ERT has some challenges: It’s an infusion every 2 weeks for life, and it can have infusion reactions and other complications.
“Newer, second-generation, versions of ERT are being developed, including pegunigalsidase alfa (Elfabrio, Chiesi Global Rare Diseases, Protalix Biotherapeutics), recently approved by the U.S. Food and Drug Administration to treat adults with Fabry disease.”
Chaperone therapy. “The oral drug migalastat (Galafold, Fabrazyme) is a small-molecule chaperone therapy that stabilizes the faulty alpha-galactosidase A enzyme,” Dr. Rastogi explained. “It is easier to take, every other day for life, than [undergoing] infusion. Limitations include that it is available only to patients who have the amenable mutations, and whose estimated glomerular filtration rate is greater than 30 [mL/min/1.73 m2], and they may have some adverse events including nausea or vomiting.”
On the horizon: substrate reduction, gene therapy. “[These] are also exciting avenues of research,” said Dr. Rastogi. “Substrate reduction therapy aims to reduce glycosphingolipid accumulation, and lucerastat [Idorsia Pharmaceutical]1,2 and venglustat [Sanofi Genzyme]3,4 are in active clinical trials or trials that have been completed.
Gene therapy “delivers a healthy gene that helps the body produce a previously deficient enzyme,” Dr. Rastogi explained. “This is an early, very promising field in need of more research, with many challenges involving the vector and complications.
“While it is still too early to predict how effective gene therapy will be, research is encouraging. Another promising therapy is modulation of gene expression, which changes the activity of a gene.”
“Gene therapy may potentially offer an alternative to typical ERT, which some patients find burdensome,” Ms. Lauderdale added. “If a neurologist has a patient who may be a good candidate for a gene therapy clinical trial that is recruiting participants, I encourage them to learn more about the study and its requirements.”
Dr. Mellin concurred: “Several gene therapy clinical trials show promise, but further information and evidence are required.”
How might these advances affect the trajectory of Fabry disease?
“Untreated Fabry compromises quality of life and may shorten the lifespan,” Dr. Raymond said. “I’m aware of individuals and their family members who died in their 60s. In the past, individuals would develop renal failure, stroke, or cardiomyopathy before being diagnosed and treated, but now we can begin treating them earlier and head off those outcomes.
“We have many options, and their number is increasing. We now diagnose patients when they are younger and maybe presymptomatic, when therapies have much greater potential to ameliorate their lives.”
Dr. Raymond spoke hopefully: “With gene therapy, people with Fabry disease will no longer need enzyme replacement or chaperone therapy. Ultimately, if gene therapy proves to be as efficacious as we hope, without big downsides, we will, essentially, be curing Fabry.”
Concluding remarks
In summing up, the four experts quoted in this article offered the following observations and advice for neurologists:
Dr. Mellin. “Pain has a significant impact on quality of life for patients with Fabry disease. Identifying and adequately treating neuropathic pain can be life-changing.”
Ms. Lauderdale. “Reach out to geneticists and other appropriate specialists. We all need to communicate the needs of our patients to ensure they receive the best possible patient-centered care.”
Dr. Rastogi. “Fabry disease is an area of active research that can be a prototype for, and affect the outcomes of, other genetic disorders. I expect to see more centers of excellence for the study and treatment of Fabry disease.”
Dr. Raymond. “With therapies rapidly evolving, neurologists need to consider rare diseases and think about how to build them into their diagnostic schemes.”
Dr. Raymond, Dr. Mellin, and Ms. Lauderdale, have nothing to disclose. Dr. Rastogi discloses a financial relationship with several pharmaceutical and biopharmaceutical companies involved in Fabry disease therapeutics research and development, including Amicus Therapeutics, Chiesi Global Rare Diseases, Genzyme Sanofi, Sanofi S.A., Idorsia Pharmaceuticals Ltd., and Protalix Biotherapeutics.
Additional recommended reading
Beck M et al. Twenty years of the Fabry Outcome Survey (FOS): Insights, achievements, and lessons learned from a global patient registry. Orphanet J Rare Dis. 2022;17(1):238. doi: 10.1186/s13023-022-02392-9.
Beraza-Millor M et al. Novel golden lipid nanoparticles with small interference ribonucleic acid for substrate reduction therapy in Fabry disease. Pharmaceutics. 2023;15(7):1936. doi: 10.3390/pharmaceutics15071936.
Ezgu F et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: A multidisciplinary Turkey perspective. Orphanet J Rare Dis. 2022;17(1):90. doi: 10.1186/s13023-022-02215-x.
Fabry disease registry & pregnancy sub-registry. ClinicalTrials.gov Identifier: NCT00196742. Updated July 13, 2023. Accessed Sept. 13, 2023. https://www.clinicaltrials.gov/study/NCT00196742?term=Fabry%20Disease%20Registry%20%26%20Pregnancy%20Sub-registry&rank=1.
Umer M and Kalra DK. Treatment of Fabry disease: established and emerging therapies. Pharmaceuticals. 2023;16(2):320. doi: 10.3390/ph16020320.
Weidemann F et al. Chaperone therapy in Fabry disease. Int J Mol Sci. 2022;23(3):1887. doi: 10.3390/ijms23031887.
References
1. Efficacy and safety of lucerastat oral monotherapy in adult subjects with Fabry disease (MODIFY). ClinicalTrials.gov Identifier: NCT03425539. Updated Aug. 9, 2022. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03425539?term=NCT03425539&rank=1.
2. A study to evaluate the long-term safety and tolerability of lucerastat in adult subjects with Fabry disease. ClinicalTrials.gov Identifier: NCT03737214. Updated Aug. 16, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT03737214?term=NCT03737214&rank=1.
3. Evaluate the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02228460. Updated Dec. 17, 2019. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02228460?term=NCT02228460&rank=1.
4. Evaluation of the long-term safety, pharmacodynamics, and exploratory efficacy of GZ/SAR402671 in treatment-naive adult male patients with Fabry disease. ClinicalTrials.gov Identifier: NCT02489344. Updated March 23, 2023. Accessed Sept. 18, 2023. https://www.clinicaltrials.gov/study/NCT02489344?term=NC
Stiff person syndrome: When a rare disorder hits the headlines
When, in 2022, singer and international celebrity Celine Dion announced what she called her “one-in-a-million diagnosis” of stiff person syndrome, clinicians and medical scientists who specialize in the disorder took a deep breath. Scott D. Newsome, DO, professor of neurology and director of the Johns Hopkins Stiff Person Syndrome Center, Baltimore – a glass-half-full kind of person – saw in Ms. Dion’s worrying announcement a huge opportunity nonetheless: To raise awareness about the rare cluster of disorders known collectively as stiff person spectrum disorders (SPSD).
“Even at the clinician level, if you don’t know the hallmark signs and symptoms, you could possibly misdiagnose it,” Dr. Newsome said in an interview.
But misdiagnosis can go either way; increased awareness of SPSD can have a downside. Thirty years ago, when Marinos C. Dalakas, MD, first began studying SPSD, the diagnosis was frequently missed – “because people were not aware of it,” he said. But now, Dr. Dalakas, professor of neurology and director of the division of neuromuscular diseases in the department of neurology at Thomas Jefferson University and the Jefferson Hospital for Neuroscience, both in Philadelphia, said overdiagnosis is also a concern, particularly with increased public awareness.
“Just this last month I saw two patients who told me: ‘I read about it, and I believe I have symptoms of stiff person,’ ” he said.
These days, most patients in whom SPSD is suspected end up with an alternate diagnosis. In a recent retrospective study that Dr. Dalakas coauthored, of 173 patients who had been referred to the Mayo Clinic in Rochester, Minn., with suspected SPSD,1 Dr. Dalakas and colleagues determined that only 48 (27.7%) actually had the disorder – meaning that the rest might have been unnecessarily exposed to immunosuppressive SPSD therapies and that treatment for their actual disorder (most often, a functional neurologic disorder or nonneurologic condition) was delayed.
At the root of both underdiagnosis and overdiagnosis of SPSD is the heterogeneity of the condition and a lack of definitive diagnostic markers.
SPSD has been considered an autoimmune disorder for a long time, and observations by Dr. Dalakas and others have shown that as many as 35% of cases co-occur with another autoimmune disease, such as vitiligo, celiac disease, rheumatologic disease, type 1 diabetes mellitus, and thyroid disease (Grave’s disease and Hashimoto’s thyroiditis).2 A more recent study by his group observed an even higher rate (42%) of comorbid autoimmunity, with autoimmune thyroid disease being most common. However, although most cases of SPDS are characterized by an elevated level of glutamic acid decarboxylase (GAD)65-IgG, these autoantibodies are not specific to SPSD (low levels are also seen in diabetes, thyroid disease, healthy controls, etc.). Some SPSD patients have less common autoantibodies and a minority has no autoantibodies. Dr. Newsome said seronegative cases and the antibody presence and titers not being associated with disease severity or treatment response are clues that “SPSD does not appear to be a primary antibody-mediated condition and that there must be other immune factors at play.”
Autoimmune process drives SPSD
Autoimmunity, even if not detected by serologic studies, is believed to inhibit expression of gamma aminobutyric acid (GABA) receptors, which, in turn, results in stiffness and spasms. Although what are known as “Dalakas criteria,” proposed in 2009,2 describe the “classic” SPSD phenotype, encompassing roughly three-quarters of SPSD patients, there have now been other phenotypes proposed under SPSD, including isolated forms (stiff limb or trunk syndrome) and “nonclassic” phenotypes like SPS-plus (classic features plus brain stem and/or cerebellar involvement),3 overlap syndromes (for example, classic features with refractory epilepsy/limbic encephalitis), and probably the most severe phenotype, progressive encephalomyelitis with rigidity and myoclonus.
Early and aggressive therapy with benzodiazepines and other GABA-ergic agonists, as well as immune-based treatments, is considered critical to slowing progression of SPSD. However, the insidious onset of what is often a cluster of vague, nonspecific symptoms is a challenge for clinicians to recognize.
“When a patient comes in with muscular spasms, with stiffness in the back, in the legs, and it’s unexplained and it’s not due to spinal cord disease, or multiple sclerosis ... think SPSD,” said Dr. Dalakas. “Check antibodies – that’s the first thing to do.”
Antibody positivity is most helpful at high levels, he added; low titers can be present in autoimmune diabetes and other conditions, as previously mentioned. The real challenge? When a patient is seronegative.
Embarking on a diagnostic odyssey
Patients “bounce from one clinician to the next looking for answers,” said Dr. Newsome. “Patients will often start with their general practitioner and be referred to physical therapy, rheumatology, or orthopedics, and other specialists, which could include neurology and/or psychiatry, among others. SPSD is often not considered as a possible diagnosis until the patient develops more concrete symptoms and/or objective signs on exam. Of course, considering this diagnosis starts at knowing that it exists.”
Task-specific phobias and exaggerated acoustic startle or sensory reflex are specific symptoms that can red-flag some SPSD patients, said Dr. Dalakas. “Impaired GABA is also important for fears and anxiety. So, when you have a reduction of GABA you have more phobic neuroses – fear of crossing the street, fear of speaking in public, and they get very tense and they cannot perform.
“If the GABA-ergic pathways are dysfunctional, then there’s a relative hyper-excitability within the nervous system,” said Dr. Newsome. “This can be evaluated with electromyography. “The muscles are unhinged and going crazy: Agonists and antagonists are contracting together, which is abnormal. We will also assess for continuous motor unit potential activity within individual muscles – angry muscles just continuously firing. In our experience, this finding appears to be a pretty specific sign of SPS, especially in the torso.” Importantly, the sudden contraction of muscles along with stiffness can lead to traumatic falls, causing major orthopedic and brain injury.
In early stages of SPSD, a careful history and clinical exam is critical to try to shorten what Dr. Newsome calls the patient’s “diagnostic odyssey.”
“It behooves the clinician to put their hands on the patient. Check their back, their abdomen – try to feel for rigidity, paraspinal muscle spasms, and tightness. These regions of the body often have a ropey feel to them, which is due to chronic muscle spasms and tightness. Most [SPSD] patients will have this present in the thoracolumbar area,” he explained. “Check for hyperlordosis, as this is a hallmark sign on exam in SPSD. Additionally, patients can have rigidity and spasticity in their legs or arms. Also, patients with nonclassical phenotypes can present with a variety of other symptoms and findings on exam, including ataxia, nystagmus, ophthalmoparesis, and dysarthria.”
Lumbar puncture can sometimes reveal signs of inflammation, such as an elevated white blood cell count and oligoclonal bands in spinal fluid.
“The classic teaching was that you can only see such findings in conditions like multiple sclerosis, but that’s not the case,” said Dr. Newsome. “You can see these findings in other autoimmune conditions, including SPSD. Hence, as part of the workup, we will have patients undergo lumbar punctures to assess for these markers of autoimmunity.”
Other mimics of SPSD, including multiple sclerosis, tumors, and spinal stenosis, should be ruled out with MRI of the brain and spine.
Treatment options
Because of wide variability in signs and symptoms of the disorder, treatment of SPSD is a highly individualized cocktail of interventions, which might include immunotherapy and GABA-ergic agonists, as well as nonmedication treatments. The response to these agents can be difficult to quantify.
Benzodiazepines (diazepam, clonazepam, baclofen) along with other oral symptomatic treatments are often recommended as first-line therapy because of their ability to enhance GABA.4
First-line immunotherapy is usually intravenous immunoglobulin, steroids, or plasmapheresis. Second- and third-line agents include rituximab, mycophenolate mofetil, azathioprine, cyclophosphamide, and combination immune treatments.
Dr. Newsome and Dr. Dalakas have independently published a step-by-step therapeutic approach to SPSD.3,5 But in patients with paraneoplastic stiff person syndrome, eradication of their cancer is critical, although, per Dr. Newsome, “this does not always cure SPS and most of these patients still have residual disability.”
But immune-based therapies are only part of what should be a multipronged treatment approach, said Dr. Newsome. He also strongly advocates for non-pharmacological interventions, such as selective physical therapy (stretching, ultrasound, and gait and balance training), heat therapy, aquatherapy, deep-tissue massage or myofascial techniques, osteopathic or chiropractic manipulation, acupuncture, and acupressure.3
Because SPSD is considered a progressive disorder for some, a reasonable goal of treatment is to prevent worsening, said Dr. Newsome. This can take time: “We don’t expect the treatments to work overnight. It involves consecutive months and, sometimes, a couple of years of immune treatment before you start to see it impact the person’s life favorably.”
Patients who are not well informed about the long-term goal of treatments might be tempted to abandon the treatments prematurely because they don’t see immediate results, Dr. Newsome added. Encouraging realistic expectations is also important, without dashing hopes.
“I have patients who were marathon runners, and they want to get back to doing marathons. I would love nothing more than for people to get back to their pre-SPSD levels of function. But this may not be a realistic goal. However, this does not mean that quality of life can’t be helped.”
Nevertheless, Dr. Newsome encourages clinicians to reassess regularly, especially because lack of disease biomarkers makes it hard to objectively monitor the impact of therapy.
“It’s always a good rule of thumb, especially in the rare disease space, to step back and ask: ‘Are we on the right treatment path or not?’ If we’re not, then it is important to make sure you have the correct diagnosis. Even when you have a patient who fits the textbook and you, yourself, diagnosed them, it is important to continue to re-evaluate the diagnosis over time, especially if there is consideration of changing treatments. It is also important to make sure there is not something else on top of the stiff person syndrome that is working in parallel to worsen their condition.”
Be alert for comorbidity
Undiagnosed comorbid conditions that can complicate SPSD include Parkinson’s disease or myasthenia gravis, to name a couple, which Dr. Newsome has seen more than once. “We’ve seen a few people over the years who have both SPSD and another autoimmune or degenerative neurological condition.”
Diabetes also co-occurs in approximately 30% of people with SPSD, said Dr. Dalakas. “Endocrinologists should also be aware of this connection.”
Paraneoplastic stiff person syndrome is thought to be triggered by cancer, which might not have been diagnosed, making it important to work up patients for malignancy – particularly breast cancer, small cell lung cancer, lymphoma, and thymoma, Dr. Newsome advised.
Although most cases of SPSD are diagnosed in mid-life, the disorder can occur in teenagers and the elderly.
“It’s not the first thing you think of when a 70-year-old patient comes with neck pain, so it’s missed more often, and the prognosis is worse,” Dr. Dalakas warned.
What does the future hold?
Like Dr. Newsome, Dr. Dalakas is encouraged when SPSD hits the headlines because, generally, awareness facilitates diagnosis and research. (Both clinicians serve on the medical advisory board of The Stiff Person Syndrome Research Foundation.)
“We are looking for better therapies that target immune factors,” said Dr. Dalakas. “There are several of those that are relevant, so we need to select the best immune marker that we think plays a role in the antibody production,” he said.
“There’s a lot of hope – at least I have a lot of hope for what the future holds with SPSD,” added Dr. Newsome. “More research is needed and it starts with awareness of SPSD.”
Dr. Newsome discloses that he has received consulting fees for serving on scientific advisory boards of Biogen, Genentech, Bristol Myers Squibb, EMD Serono, Jazz Pharmaceuticals, Novartis, Horizon Therapeutics, TG Therapeutics; is the study lead principal investigator for a Roche clinical trial; and has received research funding (paid directly to his employing institution) from Biogen, Roche, Lundbeck, Genentech, The Stiff Person Syndrome Research Foundation, National Multiple Sclerosis Society, U.S. Department of Defense, and Patient-Centered Outcomes Research Institute. Dr. Dalakas reports nothing relevant to disclose.
References
1. Chia NH et al. Ann Clin Transl Neurol. 2023;10(7):1083-94. doi: 10.1002/acn3.51791.
2. Dalakas MC.. Curr Treat Options Neurol. 2009;11(2):102-10. doi: 10.1007/s11940-009-0013-9.
3. Newsome SD and Johnson T. J Neuroimmunol. 2022;369:577915. doi: 10.1016/j.jneuroim.2022.577915.
4. Ortiz JF et al. Cureus. 2020;12(12):e11995. doi: 10.7759/cureus.11995.
5. Dalakas CD. Neurol Neuroimmunol Neuroinflamm. 2023;10(3):e200109. doi: 10.1212/NXI.0000000000200109.
When, in 2022, singer and international celebrity Celine Dion announced what she called her “one-in-a-million diagnosis” of stiff person syndrome, clinicians and medical scientists who specialize in the disorder took a deep breath. Scott D. Newsome, DO, professor of neurology and director of the Johns Hopkins Stiff Person Syndrome Center, Baltimore – a glass-half-full kind of person – saw in Ms. Dion’s worrying announcement a huge opportunity nonetheless: To raise awareness about the rare cluster of disorders known collectively as stiff person spectrum disorders (SPSD).
“Even at the clinician level, if you don’t know the hallmark signs and symptoms, you could possibly misdiagnose it,” Dr. Newsome said in an interview.
But misdiagnosis can go either way; increased awareness of SPSD can have a downside. Thirty years ago, when Marinos C. Dalakas, MD, first began studying SPSD, the diagnosis was frequently missed – “because people were not aware of it,” he said. But now, Dr. Dalakas, professor of neurology and director of the division of neuromuscular diseases in the department of neurology at Thomas Jefferson University and the Jefferson Hospital for Neuroscience, both in Philadelphia, said overdiagnosis is also a concern, particularly with increased public awareness.
“Just this last month I saw two patients who told me: ‘I read about it, and I believe I have symptoms of stiff person,’ ” he said.
These days, most patients in whom SPSD is suspected end up with an alternate diagnosis. In a recent retrospective study that Dr. Dalakas coauthored, of 173 patients who had been referred to the Mayo Clinic in Rochester, Minn., with suspected SPSD,1 Dr. Dalakas and colleagues determined that only 48 (27.7%) actually had the disorder – meaning that the rest might have been unnecessarily exposed to immunosuppressive SPSD therapies and that treatment for their actual disorder (most often, a functional neurologic disorder or nonneurologic condition) was delayed.
At the root of both underdiagnosis and overdiagnosis of SPSD is the heterogeneity of the condition and a lack of definitive diagnostic markers.
SPSD has been considered an autoimmune disorder for a long time, and observations by Dr. Dalakas and others have shown that as many as 35% of cases co-occur with another autoimmune disease, such as vitiligo, celiac disease, rheumatologic disease, type 1 diabetes mellitus, and thyroid disease (Grave’s disease and Hashimoto’s thyroiditis).2 A more recent study by his group observed an even higher rate (42%) of comorbid autoimmunity, with autoimmune thyroid disease being most common. However, although most cases of SPDS are characterized by an elevated level of glutamic acid decarboxylase (GAD)65-IgG, these autoantibodies are not specific to SPSD (low levels are also seen in diabetes, thyroid disease, healthy controls, etc.). Some SPSD patients have less common autoantibodies and a minority has no autoantibodies. Dr. Newsome said seronegative cases and the antibody presence and titers not being associated with disease severity or treatment response are clues that “SPSD does not appear to be a primary antibody-mediated condition and that there must be other immune factors at play.”
Autoimmune process drives SPSD
Autoimmunity, even if not detected by serologic studies, is believed to inhibit expression of gamma aminobutyric acid (GABA) receptors, which, in turn, results in stiffness and spasms. Although what are known as “Dalakas criteria,” proposed in 2009,2 describe the “classic” SPSD phenotype, encompassing roughly three-quarters of SPSD patients, there have now been other phenotypes proposed under SPSD, including isolated forms (stiff limb or trunk syndrome) and “nonclassic” phenotypes like SPS-plus (classic features plus brain stem and/or cerebellar involvement),3 overlap syndromes (for example, classic features with refractory epilepsy/limbic encephalitis), and probably the most severe phenotype, progressive encephalomyelitis with rigidity and myoclonus.
Early and aggressive therapy with benzodiazepines and other GABA-ergic agonists, as well as immune-based treatments, is considered critical to slowing progression of SPSD. However, the insidious onset of what is often a cluster of vague, nonspecific symptoms is a challenge for clinicians to recognize.
“When a patient comes in with muscular spasms, with stiffness in the back, in the legs, and it’s unexplained and it’s not due to spinal cord disease, or multiple sclerosis ... think SPSD,” said Dr. Dalakas. “Check antibodies – that’s the first thing to do.”
Antibody positivity is most helpful at high levels, he added; low titers can be present in autoimmune diabetes and other conditions, as previously mentioned. The real challenge? When a patient is seronegative.
Embarking on a diagnostic odyssey
Patients “bounce from one clinician to the next looking for answers,” said Dr. Newsome. “Patients will often start with their general practitioner and be referred to physical therapy, rheumatology, or orthopedics, and other specialists, which could include neurology and/or psychiatry, among others. SPSD is often not considered as a possible diagnosis until the patient develops more concrete symptoms and/or objective signs on exam. Of course, considering this diagnosis starts at knowing that it exists.”
Task-specific phobias and exaggerated acoustic startle or sensory reflex are specific symptoms that can red-flag some SPSD patients, said Dr. Dalakas. “Impaired GABA is also important for fears and anxiety. So, when you have a reduction of GABA you have more phobic neuroses – fear of crossing the street, fear of speaking in public, and they get very tense and they cannot perform.
“If the GABA-ergic pathways are dysfunctional, then there’s a relative hyper-excitability within the nervous system,” said Dr. Newsome. “This can be evaluated with electromyography. “The muscles are unhinged and going crazy: Agonists and antagonists are contracting together, which is abnormal. We will also assess for continuous motor unit potential activity within individual muscles – angry muscles just continuously firing. In our experience, this finding appears to be a pretty specific sign of SPS, especially in the torso.” Importantly, the sudden contraction of muscles along with stiffness can lead to traumatic falls, causing major orthopedic and brain injury.
In early stages of SPSD, a careful history and clinical exam is critical to try to shorten what Dr. Newsome calls the patient’s “diagnostic odyssey.”
“It behooves the clinician to put their hands on the patient. Check their back, their abdomen – try to feel for rigidity, paraspinal muscle spasms, and tightness. These regions of the body often have a ropey feel to them, which is due to chronic muscle spasms and tightness. Most [SPSD] patients will have this present in the thoracolumbar area,” he explained. “Check for hyperlordosis, as this is a hallmark sign on exam in SPSD. Additionally, patients can have rigidity and spasticity in their legs or arms. Also, patients with nonclassical phenotypes can present with a variety of other symptoms and findings on exam, including ataxia, nystagmus, ophthalmoparesis, and dysarthria.”
Lumbar puncture can sometimes reveal signs of inflammation, such as an elevated white blood cell count and oligoclonal bands in spinal fluid.
“The classic teaching was that you can only see such findings in conditions like multiple sclerosis, but that’s not the case,” said Dr. Newsome. “You can see these findings in other autoimmune conditions, including SPSD. Hence, as part of the workup, we will have patients undergo lumbar punctures to assess for these markers of autoimmunity.”
Other mimics of SPSD, including multiple sclerosis, tumors, and spinal stenosis, should be ruled out with MRI of the brain and spine.
Treatment options
Because of wide variability in signs and symptoms of the disorder, treatment of SPSD is a highly individualized cocktail of interventions, which might include immunotherapy and GABA-ergic agonists, as well as nonmedication treatments. The response to these agents can be difficult to quantify.
Benzodiazepines (diazepam, clonazepam, baclofen) along with other oral symptomatic treatments are often recommended as first-line therapy because of their ability to enhance GABA.4
First-line immunotherapy is usually intravenous immunoglobulin, steroids, or plasmapheresis. Second- and third-line agents include rituximab, mycophenolate mofetil, azathioprine, cyclophosphamide, and combination immune treatments.
Dr. Newsome and Dr. Dalakas have independently published a step-by-step therapeutic approach to SPSD.3,5 But in patients with paraneoplastic stiff person syndrome, eradication of their cancer is critical, although, per Dr. Newsome, “this does not always cure SPS and most of these patients still have residual disability.”
But immune-based therapies are only part of what should be a multipronged treatment approach, said Dr. Newsome. He also strongly advocates for non-pharmacological interventions, such as selective physical therapy (stretching, ultrasound, and gait and balance training), heat therapy, aquatherapy, deep-tissue massage or myofascial techniques, osteopathic or chiropractic manipulation, acupuncture, and acupressure.3
Because SPSD is considered a progressive disorder for some, a reasonable goal of treatment is to prevent worsening, said Dr. Newsome. This can take time: “We don’t expect the treatments to work overnight. It involves consecutive months and, sometimes, a couple of years of immune treatment before you start to see it impact the person’s life favorably.”
Patients who are not well informed about the long-term goal of treatments might be tempted to abandon the treatments prematurely because they don’t see immediate results, Dr. Newsome added. Encouraging realistic expectations is also important, without dashing hopes.
“I have patients who were marathon runners, and they want to get back to doing marathons. I would love nothing more than for people to get back to their pre-SPSD levels of function. But this may not be a realistic goal. However, this does not mean that quality of life can’t be helped.”
Nevertheless, Dr. Newsome encourages clinicians to reassess regularly, especially because lack of disease biomarkers makes it hard to objectively monitor the impact of therapy.
“It’s always a good rule of thumb, especially in the rare disease space, to step back and ask: ‘Are we on the right treatment path or not?’ If we’re not, then it is important to make sure you have the correct diagnosis. Even when you have a patient who fits the textbook and you, yourself, diagnosed them, it is important to continue to re-evaluate the diagnosis over time, especially if there is consideration of changing treatments. It is also important to make sure there is not something else on top of the stiff person syndrome that is working in parallel to worsen their condition.”
Be alert for comorbidity
Undiagnosed comorbid conditions that can complicate SPSD include Parkinson’s disease or myasthenia gravis, to name a couple, which Dr. Newsome has seen more than once. “We’ve seen a few people over the years who have both SPSD and another autoimmune or degenerative neurological condition.”
Diabetes also co-occurs in approximately 30% of people with SPSD, said Dr. Dalakas. “Endocrinologists should also be aware of this connection.”
Paraneoplastic stiff person syndrome is thought to be triggered by cancer, which might not have been diagnosed, making it important to work up patients for malignancy – particularly breast cancer, small cell lung cancer, lymphoma, and thymoma, Dr. Newsome advised.
Although most cases of SPSD are diagnosed in mid-life, the disorder can occur in teenagers and the elderly.
“It’s not the first thing you think of when a 70-year-old patient comes with neck pain, so it’s missed more often, and the prognosis is worse,” Dr. Dalakas warned.
What does the future hold?
Like Dr. Newsome, Dr. Dalakas is encouraged when SPSD hits the headlines because, generally, awareness facilitates diagnosis and research. (Both clinicians serve on the medical advisory board of The Stiff Person Syndrome Research Foundation.)
“We are looking for better therapies that target immune factors,” said Dr. Dalakas. “There are several of those that are relevant, so we need to select the best immune marker that we think plays a role in the antibody production,” he said.
“There’s a lot of hope – at least I have a lot of hope for what the future holds with SPSD,” added Dr. Newsome. “More research is needed and it starts with awareness of SPSD.”
Dr. Newsome discloses that he has received consulting fees for serving on scientific advisory boards of Biogen, Genentech, Bristol Myers Squibb, EMD Serono, Jazz Pharmaceuticals, Novartis, Horizon Therapeutics, TG Therapeutics; is the study lead principal investigator for a Roche clinical trial; and has received research funding (paid directly to his employing institution) from Biogen, Roche, Lundbeck, Genentech, The Stiff Person Syndrome Research Foundation, National Multiple Sclerosis Society, U.S. Department of Defense, and Patient-Centered Outcomes Research Institute. Dr. Dalakas reports nothing relevant to disclose.
References
1. Chia NH et al. Ann Clin Transl Neurol. 2023;10(7):1083-94. doi: 10.1002/acn3.51791.
2. Dalakas MC.. Curr Treat Options Neurol. 2009;11(2):102-10. doi: 10.1007/s11940-009-0013-9.
3. Newsome SD and Johnson T. J Neuroimmunol. 2022;369:577915. doi: 10.1016/j.jneuroim.2022.577915.
4. Ortiz JF et al. Cureus. 2020;12(12):e11995. doi: 10.7759/cureus.11995.
5. Dalakas CD. Neurol Neuroimmunol Neuroinflamm. 2023;10(3):e200109. doi: 10.1212/NXI.0000000000200109.
When, in 2022, singer and international celebrity Celine Dion announced what she called her “one-in-a-million diagnosis” of stiff person syndrome, clinicians and medical scientists who specialize in the disorder took a deep breath. Scott D. Newsome, DO, professor of neurology and director of the Johns Hopkins Stiff Person Syndrome Center, Baltimore – a glass-half-full kind of person – saw in Ms. Dion’s worrying announcement a huge opportunity nonetheless: To raise awareness about the rare cluster of disorders known collectively as stiff person spectrum disorders (SPSD).
“Even at the clinician level, if you don’t know the hallmark signs and symptoms, you could possibly misdiagnose it,” Dr. Newsome said in an interview.
But misdiagnosis can go either way; increased awareness of SPSD can have a downside. Thirty years ago, when Marinos C. Dalakas, MD, first began studying SPSD, the diagnosis was frequently missed – “because people were not aware of it,” he said. But now, Dr. Dalakas, professor of neurology and director of the division of neuromuscular diseases in the department of neurology at Thomas Jefferson University and the Jefferson Hospital for Neuroscience, both in Philadelphia, said overdiagnosis is also a concern, particularly with increased public awareness.
“Just this last month I saw two patients who told me: ‘I read about it, and I believe I have symptoms of stiff person,’ ” he said.
These days, most patients in whom SPSD is suspected end up with an alternate diagnosis. In a recent retrospective study that Dr. Dalakas coauthored, of 173 patients who had been referred to the Mayo Clinic in Rochester, Minn., with suspected SPSD,1 Dr. Dalakas and colleagues determined that only 48 (27.7%) actually had the disorder – meaning that the rest might have been unnecessarily exposed to immunosuppressive SPSD therapies and that treatment for their actual disorder (most often, a functional neurologic disorder or nonneurologic condition) was delayed.
At the root of both underdiagnosis and overdiagnosis of SPSD is the heterogeneity of the condition and a lack of definitive diagnostic markers.
SPSD has been considered an autoimmune disorder for a long time, and observations by Dr. Dalakas and others have shown that as many as 35% of cases co-occur with another autoimmune disease, such as vitiligo, celiac disease, rheumatologic disease, type 1 diabetes mellitus, and thyroid disease (Grave’s disease and Hashimoto’s thyroiditis).2 A more recent study by his group observed an even higher rate (42%) of comorbid autoimmunity, with autoimmune thyroid disease being most common. However, although most cases of SPDS are characterized by an elevated level of glutamic acid decarboxylase (GAD)65-IgG, these autoantibodies are not specific to SPSD (low levels are also seen in diabetes, thyroid disease, healthy controls, etc.). Some SPSD patients have less common autoantibodies and a minority has no autoantibodies. Dr. Newsome said seronegative cases and the antibody presence and titers not being associated with disease severity or treatment response are clues that “SPSD does not appear to be a primary antibody-mediated condition and that there must be other immune factors at play.”
Autoimmune process drives SPSD
Autoimmunity, even if not detected by serologic studies, is believed to inhibit expression of gamma aminobutyric acid (GABA) receptors, which, in turn, results in stiffness and spasms. Although what are known as “Dalakas criteria,” proposed in 2009,2 describe the “classic” SPSD phenotype, encompassing roughly three-quarters of SPSD patients, there have now been other phenotypes proposed under SPSD, including isolated forms (stiff limb or trunk syndrome) and “nonclassic” phenotypes like SPS-plus (classic features plus brain stem and/or cerebellar involvement),3 overlap syndromes (for example, classic features with refractory epilepsy/limbic encephalitis), and probably the most severe phenotype, progressive encephalomyelitis with rigidity and myoclonus.
Early and aggressive therapy with benzodiazepines and other GABA-ergic agonists, as well as immune-based treatments, is considered critical to slowing progression of SPSD. However, the insidious onset of what is often a cluster of vague, nonspecific symptoms is a challenge for clinicians to recognize.
“When a patient comes in with muscular spasms, with stiffness in the back, in the legs, and it’s unexplained and it’s not due to spinal cord disease, or multiple sclerosis ... think SPSD,” said Dr. Dalakas. “Check antibodies – that’s the first thing to do.”
Antibody positivity is most helpful at high levels, he added; low titers can be present in autoimmune diabetes and other conditions, as previously mentioned. The real challenge? When a patient is seronegative.
Embarking on a diagnostic odyssey
Patients “bounce from one clinician to the next looking for answers,” said Dr. Newsome. “Patients will often start with their general practitioner and be referred to physical therapy, rheumatology, or orthopedics, and other specialists, which could include neurology and/or psychiatry, among others. SPSD is often not considered as a possible diagnosis until the patient develops more concrete symptoms and/or objective signs on exam. Of course, considering this diagnosis starts at knowing that it exists.”
Task-specific phobias and exaggerated acoustic startle or sensory reflex are specific symptoms that can red-flag some SPSD patients, said Dr. Dalakas. “Impaired GABA is also important for fears and anxiety. So, when you have a reduction of GABA you have more phobic neuroses – fear of crossing the street, fear of speaking in public, and they get very tense and they cannot perform.
“If the GABA-ergic pathways are dysfunctional, then there’s a relative hyper-excitability within the nervous system,” said Dr. Newsome. “This can be evaluated with electromyography. “The muscles are unhinged and going crazy: Agonists and antagonists are contracting together, which is abnormal. We will also assess for continuous motor unit potential activity within individual muscles – angry muscles just continuously firing. In our experience, this finding appears to be a pretty specific sign of SPS, especially in the torso.” Importantly, the sudden contraction of muscles along with stiffness can lead to traumatic falls, causing major orthopedic and brain injury.
In early stages of SPSD, a careful history and clinical exam is critical to try to shorten what Dr. Newsome calls the patient’s “diagnostic odyssey.”
“It behooves the clinician to put their hands on the patient. Check their back, their abdomen – try to feel for rigidity, paraspinal muscle spasms, and tightness. These regions of the body often have a ropey feel to them, which is due to chronic muscle spasms and tightness. Most [SPSD] patients will have this present in the thoracolumbar area,” he explained. “Check for hyperlordosis, as this is a hallmark sign on exam in SPSD. Additionally, patients can have rigidity and spasticity in their legs or arms. Also, patients with nonclassical phenotypes can present with a variety of other symptoms and findings on exam, including ataxia, nystagmus, ophthalmoparesis, and dysarthria.”
Lumbar puncture can sometimes reveal signs of inflammation, such as an elevated white blood cell count and oligoclonal bands in spinal fluid.
“The classic teaching was that you can only see such findings in conditions like multiple sclerosis, but that’s not the case,” said Dr. Newsome. “You can see these findings in other autoimmune conditions, including SPSD. Hence, as part of the workup, we will have patients undergo lumbar punctures to assess for these markers of autoimmunity.”
Other mimics of SPSD, including multiple sclerosis, tumors, and spinal stenosis, should be ruled out with MRI of the brain and spine.
Treatment options
Because of wide variability in signs and symptoms of the disorder, treatment of SPSD is a highly individualized cocktail of interventions, which might include immunotherapy and GABA-ergic agonists, as well as nonmedication treatments. The response to these agents can be difficult to quantify.
Benzodiazepines (diazepam, clonazepam, baclofen) along with other oral symptomatic treatments are often recommended as first-line therapy because of their ability to enhance GABA.4
First-line immunotherapy is usually intravenous immunoglobulin, steroids, or plasmapheresis. Second- and third-line agents include rituximab, mycophenolate mofetil, azathioprine, cyclophosphamide, and combination immune treatments.
Dr. Newsome and Dr. Dalakas have independently published a step-by-step therapeutic approach to SPSD.3,5 But in patients with paraneoplastic stiff person syndrome, eradication of their cancer is critical, although, per Dr. Newsome, “this does not always cure SPS and most of these patients still have residual disability.”
But immune-based therapies are only part of what should be a multipronged treatment approach, said Dr. Newsome. He also strongly advocates for non-pharmacological interventions, such as selective physical therapy (stretching, ultrasound, and gait and balance training), heat therapy, aquatherapy, deep-tissue massage or myofascial techniques, osteopathic or chiropractic manipulation, acupuncture, and acupressure.3
Because SPSD is considered a progressive disorder for some, a reasonable goal of treatment is to prevent worsening, said Dr. Newsome. This can take time: “We don’t expect the treatments to work overnight. It involves consecutive months and, sometimes, a couple of years of immune treatment before you start to see it impact the person’s life favorably.”
Patients who are not well informed about the long-term goal of treatments might be tempted to abandon the treatments prematurely because they don’t see immediate results, Dr. Newsome added. Encouraging realistic expectations is also important, without dashing hopes.
“I have patients who were marathon runners, and they want to get back to doing marathons. I would love nothing more than for people to get back to their pre-SPSD levels of function. But this may not be a realistic goal. However, this does not mean that quality of life can’t be helped.”
Nevertheless, Dr. Newsome encourages clinicians to reassess regularly, especially because lack of disease biomarkers makes it hard to objectively monitor the impact of therapy.
“It’s always a good rule of thumb, especially in the rare disease space, to step back and ask: ‘Are we on the right treatment path or not?’ If we’re not, then it is important to make sure you have the correct diagnosis. Even when you have a patient who fits the textbook and you, yourself, diagnosed them, it is important to continue to re-evaluate the diagnosis over time, especially if there is consideration of changing treatments. It is also important to make sure there is not something else on top of the stiff person syndrome that is working in parallel to worsen their condition.”
Be alert for comorbidity
Undiagnosed comorbid conditions that can complicate SPSD include Parkinson’s disease or myasthenia gravis, to name a couple, which Dr. Newsome has seen more than once. “We’ve seen a few people over the years who have both SPSD and another autoimmune or degenerative neurological condition.”
Diabetes also co-occurs in approximately 30% of people with SPSD, said Dr. Dalakas. “Endocrinologists should also be aware of this connection.”
Paraneoplastic stiff person syndrome is thought to be triggered by cancer, which might not have been diagnosed, making it important to work up patients for malignancy – particularly breast cancer, small cell lung cancer, lymphoma, and thymoma, Dr. Newsome advised.
Although most cases of SPSD are diagnosed in mid-life, the disorder can occur in teenagers and the elderly.
“It’s not the first thing you think of when a 70-year-old patient comes with neck pain, so it’s missed more often, and the prognosis is worse,” Dr. Dalakas warned.
What does the future hold?
Like Dr. Newsome, Dr. Dalakas is encouraged when SPSD hits the headlines because, generally, awareness facilitates diagnosis and research. (Both clinicians serve on the medical advisory board of The Stiff Person Syndrome Research Foundation.)
“We are looking for better therapies that target immune factors,” said Dr. Dalakas. “There are several of those that are relevant, so we need to select the best immune marker that we think plays a role in the antibody production,” he said.
“There’s a lot of hope – at least I have a lot of hope for what the future holds with SPSD,” added Dr. Newsome. “More research is needed and it starts with awareness of SPSD.”
Dr. Newsome discloses that he has received consulting fees for serving on scientific advisory boards of Biogen, Genentech, Bristol Myers Squibb, EMD Serono, Jazz Pharmaceuticals, Novartis, Horizon Therapeutics, TG Therapeutics; is the study lead principal investigator for a Roche clinical trial; and has received research funding (paid directly to his employing institution) from Biogen, Roche, Lundbeck, Genentech, The Stiff Person Syndrome Research Foundation, National Multiple Sclerosis Society, U.S. Department of Defense, and Patient-Centered Outcomes Research Institute. Dr. Dalakas reports nothing relevant to disclose.
References
1. Chia NH et al. Ann Clin Transl Neurol. 2023;10(7):1083-94. doi: 10.1002/acn3.51791.
2. Dalakas MC.. Curr Treat Options Neurol. 2009;11(2):102-10. doi: 10.1007/s11940-009-0013-9.
3. Newsome SD and Johnson T. J Neuroimmunol. 2022;369:577915. doi: 10.1016/j.jneuroim.2022.577915.
4. Ortiz JF et al. Cureus. 2020;12(12):e11995. doi: 10.7759/cureus.11995.
5. Dalakas CD. Neurol Neuroimmunol Neuroinflamm. 2023;10(3):e200109. doi: 10.1212/NXI.0000000000200109.