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AFib detection by smartwatch challenging in some patients
The ability of an Apple Watch to detect atrial fibrillation (AFib) is significantly affected by underlying ECG abnormalities such as sinus node dysfunction, atrioventricular (AV) block, or intraventricular conduction delay (IVCD), a single-center study suggests.
“We were surprised to find that in one in every five patients, the smartwatch ECG failed to produce an automatic diagnosis,” study author Marc Strik, MD, PhD, a clinician at Bordeaux University Hospital in Pessac, France, told this news organization. “This [failure] was mostly due to insufficient quality of the tracing [60%], but in a third of cases, [34%], it was due to bradycardia, and in some cases, tachycardia [6%].
“We were also surprised to find that the existence of ventricular conduction disease was associated with a higher likelihood of missing AFib,” he said.
The study was published in the Canadian Journal of Cardiology.
Abnormalities affected detection
The investigators tested the accuracy of the Apple Watch (Apple, Cupertino, California) in detecting AFib in patients with various ECG anomalies. All participants underwent 12-lead ECG, followed by a 30-second ECG tracing with an Apple Watch Series 5. The smartwatch’s automated AFib detection algorithm gave a result of “no signs of AFib,” “AFib,” or “not checked for AFib (unclassified).”
Unclassified recordings resulted from “low heart rate” (below 50 beats/min), “high heart rate” (above 150 beats/min), “poor recording,” or “inconclusive recording.”
The smartwatch recordings were reviewed by a blinded electrophysiologist who interpreted each tracing and assigned a diagnosis of “AFib,” “absence of AFib,” or “diagnosis unclear.” To assess interobserver agreement, a second blinded electrophysiologist interpreted 100 randomly selected tracings.
Among the 734 patients (mean age, 66; 58% men) enrolled, 539 (73%) were in normal sinus rhythm (SR), 154 (21%) in AFib, 33 in atrial flutter or atrial tachycardia, 3 in ventricular tachycardia, and 5 in junctional tachycardia.
Furthermore, 65 (8.9%) had sinus node dysfunction, 21 (2.9%) had second- or third-degree AV block, 39 (5.3%) had a ventricular paced rhythm, 54 (7.4%) had premature ventricular contractions (PVCs), and 132 (18%) had IVCD (right or left bundle branch block or nonspecific IVCD).
Of the 539 patients in normal SR, 437 recordings were correctly diagnosed by the smartwatch, 7 were diagnosed incorrectly as AFib, and 95 were not classified.
Of the 187 patients in AFib, 129 were correctly diagnosed, 17 were incorrectly diagnosed as SR, and 41 were not classified.
When unclassified ECGs were considered false results, the smartwatch had a sensitivity of 69% and specificity of 81% for AFib detection. When unclassified ECGs were excluded from the analysis, sensitivity was 88%, and specificity was 98%.
Compared with patients without the abnormality, the relative risk of having false positive tracings was higher for patients with premature atrial contractions (PACs) or PVCs (risk ratio, 2.9), sinus node dysfunction (RR, 3.71), and AV block (RR, 7.8).
Fifty-eight patients with AFib were classified as SR or inconclusive by the smartwatch. Among them, 21 (36%) had an IVCD, 7 (12%) had a ventricular paced rhythm, and 5 (9%) had PACs or PVCs.
The risk of having false negative tracings (missed AF) was higher for patients with IVCD (RR, 2.6) and pacing (RR, 2.47), compared with those without the abnormality.
‘A powerful tool’
Overall, cardiac electrophysiologists showed high agreement in differentiating between AFib and non-AFib, with high interobserver reproducibility. A manual diagnosis was not possible for 10% of tracings because of either poor ECG quality (3%) or unclear P-waves (7%).
Fifty-nine of the 580 patients in SR were misclassified as AFib by the experts, and 5 of the 154 patients in AFib were misclassified as SR.
“Our results show that the presence of sinus node dysfunction, second- or third-degree AV block, ventricular paced rhythm, PVCs, and IVCD were more frequently represented in smartwatch misdiagnoses,” wrote the authors. “Patients with PVCs were three times as likely to have false positive AFib diagnoses.”
Study limitations included the single-center nature of the study and the fact that patients were recruited in a cardiology office. The latter factor may have influenced the incidence of ECG abnormalities, which was much higher than for the average smartwatch user.
“Even with its limitations, the smartwatch remains a powerful tool that is able to detect AFib and multiple other abnormalities,” said Dr. Strik. “Missed diagnosis of AFib may be less important in real life because of repeated measurements, and algorithms will continue to improve.”
Technology improving
Richard C. Becker, MD, director and physician in chief of the University of Cincinnati Heart, Lung, and Vascular Institute, said, “This is exactly the kind of investigation required to improve upon existing detection algorithms that will someday facilitate routine use in patient care. An ability to detect AFib in a large proportion of those with the heart rhythm abnormality is encouraging.”
The findings should not detract from well-conducted studies in otherwise healthy individuals of varied age in whom AFib was accurately detected, he added. “Similarly, an automatic diagnosis algorithm for AF, pending optimization and validation in a large and diverse cohort, should be viewed as a communication tool between patients and health care providers.”
Patients at risk for developing AFib could benefit from continuous monitoring using a smartwatch, said Dr. Becker. “Pre-existing heart rhythm abnormalities must be taken into consideration. Optimal utilization of emerging technology to include wearables requires an understanding of performance and limitations. It is best undertaken in coordination with a health care provider.”
Andrés F. Miranda-Arboleda, MD, and Adrian Baranchuk, MD, of Kingston Health Sciences Center, Canada, conclude in an accompanying editorial, “In a certain manner, the smartwatch algorithms for the detection of AFib in patients with cardiovascular conditions are not yet smart enough ... but they may soon be.”
The study was supported by the French government. Dr. Strik, Dr. Miranda-Arboleda, Dr. Baranchuk, and Dr. Becker reported no conflicts of interest.
A version of this article first appeared on Medscape.com.
The ability of an Apple Watch to detect atrial fibrillation (AFib) is significantly affected by underlying ECG abnormalities such as sinus node dysfunction, atrioventricular (AV) block, or intraventricular conduction delay (IVCD), a single-center study suggests.
“We were surprised to find that in one in every five patients, the smartwatch ECG failed to produce an automatic diagnosis,” study author Marc Strik, MD, PhD, a clinician at Bordeaux University Hospital in Pessac, France, told this news organization. “This [failure] was mostly due to insufficient quality of the tracing [60%], but in a third of cases, [34%], it was due to bradycardia, and in some cases, tachycardia [6%].
“We were also surprised to find that the existence of ventricular conduction disease was associated with a higher likelihood of missing AFib,” he said.
The study was published in the Canadian Journal of Cardiology.
Abnormalities affected detection
The investigators tested the accuracy of the Apple Watch (Apple, Cupertino, California) in detecting AFib in patients with various ECG anomalies. All participants underwent 12-lead ECG, followed by a 30-second ECG tracing with an Apple Watch Series 5. The smartwatch’s automated AFib detection algorithm gave a result of “no signs of AFib,” “AFib,” or “not checked for AFib (unclassified).”
Unclassified recordings resulted from “low heart rate” (below 50 beats/min), “high heart rate” (above 150 beats/min), “poor recording,” or “inconclusive recording.”
The smartwatch recordings were reviewed by a blinded electrophysiologist who interpreted each tracing and assigned a diagnosis of “AFib,” “absence of AFib,” or “diagnosis unclear.” To assess interobserver agreement, a second blinded electrophysiologist interpreted 100 randomly selected tracings.
Among the 734 patients (mean age, 66; 58% men) enrolled, 539 (73%) were in normal sinus rhythm (SR), 154 (21%) in AFib, 33 in atrial flutter or atrial tachycardia, 3 in ventricular tachycardia, and 5 in junctional tachycardia.
Furthermore, 65 (8.9%) had sinus node dysfunction, 21 (2.9%) had second- or third-degree AV block, 39 (5.3%) had a ventricular paced rhythm, 54 (7.4%) had premature ventricular contractions (PVCs), and 132 (18%) had IVCD (right or left bundle branch block or nonspecific IVCD).
Of the 539 patients in normal SR, 437 recordings were correctly diagnosed by the smartwatch, 7 were diagnosed incorrectly as AFib, and 95 were not classified.
Of the 187 patients in AFib, 129 were correctly diagnosed, 17 were incorrectly diagnosed as SR, and 41 were not classified.
When unclassified ECGs were considered false results, the smartwatch had a sensitivity of 69% and specificity of 81% for AFib detection. When unclassified ECGs were excluded from the analysis, sensitivity was 88%, and specificity was 98%.
Compared with patients without the abnormality, the relative risk of having false positive tracings was higher for patients with premature atrial contractions (PACs) or PVCs (risk ratio, 2.9), sinus node dysfunction (RR, 3.71), and AV block (RR, 7.8).
Fifty-eight patients with AFib were classified as SR or inconclusive by the smartwatch. Among them, 21 (36%) had an IVCD, 7 (12%) had a ventricular paced rhythm, and 5 (9%) had PACs or PVCs.
The risk of having false negative tracings (missed AF) was higher for patients with IVCD (RR, 2.6) and pacing (RR, 2.47), compared with those without the abnormality.
‘A powerful tool’
Overall, cardiac electrophysiologists showed high agreement in differentiating between AFib and non-AFib, with high interobserver reproducibility. A manual diagnosis was not possible for 10% of tracings because of either poor ECG quality (3%) or unclear P-waves (7%).
Fifty-nine of the 580 patients in SR were misclassified as AFib by the experts, and 5 of the 154 patients in AFib were misclassified as SR.
“Our results show that the presence of sinus node dysfunction, second- or third-degree AV block, ventricular paced rhythm, PVCs, and IVCD were more frequently represented in smartwatch misdiagnoses,” wrote the authors. “Patients with PVCs were three times as likely to have false positive AFib diagnoses.”
Study limitations included the single-center nature of the study and the fact that patients were recruited in a cardiology office. The latter factor may have influenced the incidence of ECG abnormalities, which was much higher than for the average smartwatch user.
“Even with its limitations, the smartwatch remains a powerful tool that is able to detect AFib and multiple other abnormalities,” said Dr. Strik. “Missed diagnosis of AFib may be less important in real life because of repeated measurements, and algorithms will continue to improve.”
Technology improving
Richard C. Becker, MD, director and physician in chief of the University of Cincinnati Heart, Lung, and Vascular Institute, said, “This is exactly the kind of investigation required to improve upon existing detection algorithms that will someday facilitate routine use in patient care. An ability to detect AFib in a large proportion of those with the heart rhythm abnormality is encouraging.”
The findings should not detract from well-conducted studies in otherwise healthy individuals of varied age in whom AFib was accurately detected, he added. “Similarly, an automatic diagnosis algorithm for AF, pending optimization and validation in a large and diverse cohort, should be viewed as a communication tool between patients and health care providers.”
Patients at risk for developing AFib could benefit from continuous monitoring using a smartwatch, said Dr. Becker. “Pre-existing heart rhythm abnormalities must be taken into consideration. Optimal utilization of emerging technology to include wearables requires an understanding of performance and limitations. It is best undertaken in coordination with a health care provider.”
Andrés F. Miranda-Arboleda, MD, and Adrian Baranchuk, MD, of Kingston Health Sciences Center, Canada, conclude in an accompanying editorial, “In a certain manner, the smartwatch algorithms for the detection of AFib in patients with cardiovascular conditions are not yet smart enough ... but they may soon be.”
The study was supported by the French government. Dr. Strik, Dr. Miranda-Arboleda, Dr. Baranchuk, and Dr. Becker reported no conflicts of interest.
A version of this article first appeared on Medscape.com.
The ability of an Apple Watch to detect atrial fibrillation (AFib) is significantly affected by underlying ECG abnormalities such as sinus node dysfunction, atrioventricular (AV) block, or intraventricular conduction delay (IVCD), a single-center study suggests.
“We were surprised to find that in one in every five patients, the smartwatch ECG failed to produce an automatic diagnosis,” study author Marc Strik, MD, PhD, a clinician at Bordeaux University Hospital in Pessac, France, told this news organization. “This [failure] was mostly due to insufficient quality of the tracing [60%], but in a third of cases, [34%], it was due to bradycardia, and in some cases, tachycardia [6%].
“We were also surprised to find that the existence of ventricular conduction disease was associated with a higher likelihood of missing AFib,” he said.
The study was published in the Canadian Journal of Cardiology.
Abnormalities affected detection
The investigators tested the accuracy of the Apple Watch (Apple, Cupertino, California) in detecting AFib in patients with various ECG anomalies. All participants underwent 12-lead ECG, followed by a 30-second ECG tracing with an Apple Watch Series 5. The smartwatch’s automated AFib detection algorithm gave a result of “no signs of AFib,” “AFib,” or “not checked for AFib (unclassified).”
Unclassified recordings resulted from “low heart rate” (below 50 beats/min), “high heart rate” (above 150 beats/min), “poor recording,” or “inconclusive recording.”
The smartwatch recordings were reviewed by a blinded electrophysiologist who interpreted each tracing and assigned a diagnosis of “AFib,” “absence of AFib,” or “diagnosis unclear.” To assess interobserver agreement, a second blinded electrophysiologist interpreted 100 randomly selected tracings.
Among the 734 patients (mean age, 66; 58% men) enrolled, 539 (73%) were in normal sinus rhythm (SR), 154 (21%) in AFib, 33 in atrial flutter or atrial tachycardia, 3 in ventricular tachycardia, and 5 in junctional tachycardia.
Furthermore, 65 (8.9%) had sinus node dysfunction, 21 (2.9%) had second- or third-degree AV block, 39 (5.3%) had a ventricular paced rhythm, 54 (7.4%) had premature ventricular contractions (PVCs), and 132 (18%) had IVCD (right or left bundle branch block or nonspecific IVCD).
Of the 539 patients in normal SR, 437 recordings were correctly diagnosed by the smartwatch, 7 were diagnosed incorrectly as AFib, and 95 were not classified.
Of the 187 patients in AFib, 129 were correctly diagnosed, 17 were incorrectly diagnosed as SR, and 41 were not classified.
When unclassified ECGs were considered false results, the smartwatch had a sensitivity of 69% and specificity of 81% for AFib detection. When unclassified ECGs were excluded from the analysis, sensitivity was 88%, and specificity was 98%.
Compared with patients without the abnormality, the relative risk of having false positive tracings was higher for patients with premature atrial contractions (PACs) or PVCs (risk ratio, 2.9), sinus node dysfunction (RR, 3.71), and AV block (RR, 7.8).
Fifty-eight patients with AFib were classified as SR or inconclusive by the smartwatch. Among them, 21 (36%) had an IVCD, 7 (12%) had a ventricular paced rhythm, and 5 (9%) had PACs or PVCs.
The risk of having false negative tracings (missed AF) was higher for patients with IVCD (RR, 2.6) and pacing (RR, 2.47), compared with those without the abnormality.
‘A powerful tool’
Overall, cardiac electrophysiologists showed high agreement in differentiating between AFib and non-AFib, with high interobserver reproducibility. A manual diagnosis was not possible for 10% of tracings because of either poor ECG quality (3%) or unclear P-waves (7%).
Fifty-nine of the 580 patients in SR were misclassified as AFib by the experts, and 5 of the 154 patients in AFib were misclassified as SR.
“Our results show that the presence of sinus node dysfunction, second- or third-degree AV block, ventricular paced rhythm, PVCs, and IVCD were more frequently represented in smartwatch misdiagnoses,” wrote the authors. “Patients with PVCs were three times as likely to have false positive AFib diagnoses.”
Study limitations included the single-center nature of the study and the fact that patients were recruited in a cardiology office. The latter factor may have influenced the incidence of ECG abnormalities, which was much higher than for the average smartwatch user.
“Even with its limitations, the smartwatch remains a powerful tool that is able to detect AFib and multiple other abnormalities,” said Dr. Strik. “Missed diagnosis of AFib may be less important in real life because of repeated measurements, and algorithms will continue to improve.”
Technology improving
Richard C. Becker, MD, director and physician in chief of the University of Cincinnati Heart, Lung, and Vascular Institute, said, “This is exactly the kind of investigation required to improve upon existing detection algorithms that will someday facilitate routine use in patient care. An ability to detect AFib in a large proportion of those with the heart rhythm abnormality is encouraging.”
The findings should not detract from well-conducted studies in otherwise healthy individuals of varied age in whom AFib was accurately detected, he added. “Similarly, an automatic diagnosis algorithm for AF, pending optimization and validation in a large and diverse cohort, should be viewed as a communication tool between patients and health care providers.”
Patients at risk for developing AFib could benefit from continuous monitoring using a smartwatch, said Dr. Becker. “Pre-existing heart rhythm abnormalities must be taken into consideration. Optimal utilization of emerging technology to include wearables requires an understanding of performance and limitations. It is best undertaken in coordination with a health care provider.”
Andrés F. Miranda-Arboleda, MD, and Adrian Baranchuk, MD, of Kingston Health Sciences Center, Canada, conclude in an accompanying editorial, “In a certain manner, the smartwatch algorithms for the detection of AFib in patients with cardiovascular conditions are not yet smart enough ... but they may soon be.”
The study was supported by the French government. Dr. Strik, Dr. Miranda-Arboleda, Dr. Baranchuk, and Dr. Becker reported no conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM CANADIAN JOURNAL OF CARDIOLOGY
New deep dive into Paxlovid interactions with CVD meds
Nirmatrelvir/ritonavir (Paxlovid) has been a game changer for high-risk patients with early COVID-19 symptoms but has significant interactions with commonly used cardiovascular medications, a new paper cautions.
COVID-19 patients with cardiovascular disease (CVD) or risk factors such as diabetes, hypertension, and chronic kidney disease are at high risk of severe disease and account for the lion’s share of those receiving Paxlovid. Data from the initial EPIC-HR trial and recent real-world data also suggest they’re among the most likely to benefit from the oral antiviral, regardless of their COVID-19 vaccination status.
“But at the same time, it unfortunately interacts with many very commonly prescribed cardiovascular medications and with many of them in a very clinically meaningful way, which may lead to serious adverse consequences,” senior author Sarju Ganatra, MD, said in an interview. “So, while it’s being prescribed with a good intention to help these people, we may actually end up doing more harm than good.
“We don’t want to deter people from getting their necessary COVID-19 treatment, which is excellent for the most part these days as an outpatient,” he added. “So, we felt the need to make a comprehensive list of cardiac medications and level of interactions with Paxlovid and also to help the clinicians and prescribers at the point of care to make the clinical decision of what modifications they may need to do.”
The paper, published online in the Journal of the American College of Cardiology, details drug-drug interactions with some 80 CV medications including statins, antihypertensive agents, heart failure therapies, and antiplatelet/anticoagulants.
It also includes a color-coded figure denoting whether a drug is safe to coadminister with Paxlovid, may potentially interact and require a dose adjustment or temporary discontinuation, or is contraindicated.
Among the commonly used blood thinners, for example, the paper notes that Paxlovid significantly increases drug levels of the direct oral anticoagulants (DOACs) apixaban, rivaroxaban, edoxaban, and dabigatran and, thus, increases the risk of bleeding.
“It can still be administered, if it’s necessary, but the dose of the DOAC either needs to be reduced or held depending on what they are getting it for, whether they’re getting it for pulmonary embolism or atrial fibrillation, and we adjust for all those things in the table in the paper,” said Dr. Ganatra, from Lahey Hospital and Medical Center, Burlington, Mass.
When the DOAC can’t be interrupted or dose adjusted, however, Paxlovid should not be given, the experts said. The antiviral is safe to use with enoxaparin, a low-molecular-weight heparin, but can increase or decrease levels of warfarin and should be used with close international normalized ratio monitoring.
For patients on antiplatelet agents, clinicians are advised to avoid prescribing nirmatrelvir/ritonavir to those on ticagrelor or clopidogrel unless the agents can be replaced by prasugrel.
Ritonavir – an inhibitor of cytochrome P 450 enzymes, particularly CYP3A4 – poses an increased risk of bleeding when given with ticagrelor, a CYP3A4 substrate, and decreases the active metabolite of clopidogrel, cutting its platelet inhibition by 20%. Although there’s a twofold decrease in the maximum concentration of prasugrel in patients on ritonavir, this does not affect its antiplatelet activity, the paper explains.
Among the lipid-lowering agents, experts suggested temporarily withholding atorvastatin, rosuvastatin, simvastatin, and lovastatin because of an increased risk for myopathy and liver toxicity but say that other statins, fibrates, ezetimibe, and the proprotein convertase subtilisin/kexin type 9 inhibitors evolocumab and alirocumab are safe to coadminister with Paxlovid.
While statins typically leave the body within hours, most of the antiarrhythmic drugs, except for sotalol, are not safe to give with Paxlovid, Dr. Ganatra said. It’s technically not feasible to hold these drugs because most have long half-lives, reaching about 100 days, for example, for amiodarone.
“It’s going to hang around in your system for a long time, so you don’t want to be falsely reassured that you’re holding the drug and it’s going to be fine to go back slowly,” he said. “You need to look for alternative therapies in those scenarios for COVID-19 treatment, which could be other antivirals, or a monoclonal antibody individualized to the patient’s risk.”
Although there’s limited clinical information regarding interaction-related adverse events with Paxlovid, the team used pharmacokinetics and pharmacodynamics data to provide the guidance. Serious adverse events are also well documented for ritonavir, which has been prescribed for years to treat HIV, Dr. Ganatra noted.
The Infectious Disease Society of America also published guidance on the management of potential drug interactions with Paxlovid in May and, earlier in October, the Food and Drug Administration updated its Paxlovid patient eligibility screening checklist.
Still, most prescribers are actually primary care physicians and even pharmacists, who may not be completely attuned, said Dr. Ganatra, who noted that some centers have started programs to help connect primary care physicians with their cardiology colleagues to check on CV drugs in their COVID-19 patients.
“We need to be thinking more broadly and at a system level where the hospital or health care system leverages the electronic health record systems,” he said. “Most of them are sophisticated enough to incorporate simple drug-drug interaction information, so if you try to prescribe someone Paxlovid and it’s a heart transplant patient who is on immunosuppressive therapy or a patient on a blood thinner, then it should give you a warning ... or at least give them a link to our paper or other valuable resources.
“If someone is on a blood thinner and the blood thinner level goes up by ninefold, we can only imagine what we would be dealing with,” Dr. Ganatra said. “So, these interactions should be taken very seriously and I think it’s worth the time and investment.”
The authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Nirmatrelvir/ritonavir (Paxlovid) has been a game changer for high-risk patients with early COVID-19 symptoms but has significant interactions with commonly used cardiovascular medications, a new paper cautions.
COVID-19 patients with cardiovascular disease (CVD) or risk factors such as diabetes, hypertension, and chronic kidney disease are at high risk of severe disease and account for the lion’s share of those receiving Paxlovid. Data from the initial EPIC-HR trial and recent real-world data also suggest they’re among the most likely to benefit from the oral antiviral, regardless of their COVID-19 vaccination status.
“But at the same time, it unfortunately interacts with many very commonly prescribed cardiovascular medications and with many of them in a very clinically meaningful way, which may lead to serious adverse consequences,” senior author Sarju Ganatra, MD, said in an interview. “So, while it’s being prescribed with a good intention to help these people, we may actually end up doing more harm than good.
“We don’t want to deter people from getting their necessary COVID-19 treatment, which is excellent for the most part these days as an outpatient,” he added. “So, we felt the need to make a comprehensive list of cardiac medications and level of interactions with Paxlovid and also to help the clinicians and prescribers at the point of care to make the clinical decision of what modifications they may need to do.”
The paper, published online in the Journal of the American College of Cardiology, details drug-drug interactions with some 80 CV medications including statins, antihypertensive agents, heart failure therapies, and antiplatelet/anticoagulants.
It also includes a color-coded figure denoting whether a drug is safe to coadminister with Paxlovid, may potentially interact and require a dose adjustment or temporary discontinuation, or is contraindicated.
Among the commonly used blood thinners, for example, the paper notes that Paxlovid significantly increases drug levels of the direct oral anticoagulants (DOACs) apixaban, rivaroxaban, edoxaban, and dabigatran and, thus, increases the risk of bleeding.
“It can still be administered, if it’s necessary, but the dose of the DOAC either needs to be reduced or held depending on what they are getting it for, whether they’re getting it for pulmonary embolism or atrial fibrillation, and we adjust for all those things in the table in the paper,” said Dr. Ganatra, from Lahey Hospital and Medical Center, Burlington, Mass.
When the DOAC can’t be interrupted or dose adjusted, however, Paxlovid should not be given, the experts said. The antiviral is safe to use with enoxaparin, a low-molecular-weight heparin, but can increase or decrease levels of warfarin and should be used with close international normalized ratio monitoring.
For patients on antiplatelet agents, clinicians are advised to avoid prescribing nirmatrelvir/ritonavir to those on ticagrelor or clopidogrel unless the agents can be replaced by prasugrel.
Ritonavir – an inhibitor of cytochrome P 450 enzymes, particularly CYP3A4 – poses an increased risk of bleeding when given with ticagrelor, a CYP3A4 substrate, and decreases the active metabolite of clopidogrel, cutting its platelet inhibition by 20%. Although there’s a twofold decrease in the maximum concentration of prasugrel in patients on ritonavir, this does not affect its antiplatelet activity, the paper explains.
Among the lipid-lowering agents, experts suggested temporarily withholding atorvastatin, rosuvastatin, simvastatin, and lovastatin because of an increased risk for myopathy and liver toxicity but say that other statins, fibrates, ezetimibe, and the proprotein convertase subtilisin/kexin type 9 inhibitors evolocumab and alirocumab are safe to coadminister with Paxlovid.
While statins typically leave the body within hours, most of the antiarrhythmic drugs, except for sotalol, are not safe to give with Paxlovid, Dr. Ganatra said. It’s technically not feasible to hold these drugs because most have long half-lives, reaching about 100 days, for example, for amiodarone.
“It’s going to hang around in your system for a long time, so you don’t want to be falsely reassured that you’re holding the drug and it’s going to be fine to go back slowly,” he said. “You need to look for alternative therapies in those scenarios for COVID-19 treatment, which could be other antivirals, or a monoclonal antibody individualized to the patient’s risk.”
Although there’s limited clinical information regarding interaction-related adverse events with Paxlovid, the team used pharmacokinetics and pharmacodynamics data to provide the guidance. Serious adverse events are also well documented for ritonavir, which has been prescribed for years to treat HIV, Dr. Ganatra noted.
The Infectious Disease Society of America also published guidance on the management of potential drug interactions with Paxlovid in May and, earlier in October, the Food and Drug Administration updated its Paxlovid patient eligibility screening checklist.
Still, most prescribers are actually primary care physicians and even pharmacists, who may not be completely attuned, said Dr. Ganatra, who noted that some centers have started programs to help connect primary care physicians with their cardiology colleagues to check on CV drugs in their COVID-19 patients.
“We need to be thinking more broadly and at a system level where the hospital or health care system leverages the electronic health record systems,” he said. “Most of them are sophisticated enough to incorporate simple drug-drug interaction information, so if you try to prescribe someone Paxlovid and it’s a heart transplant patient who is on immunosuppressive therapy or a patient on a blood thinner, then it should give you a warning ... or at least give them a link to our paper or other valuable resources.
“If someone is on a blood thinner and the blood thinner level goes up by ninefold, we can only imagine what we would be dealing with,” Dr. Ganatra said. “So, these interactions should be taken very seriously and I think it’s worth the time and investment.”
The authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Nirmatrelvir/ritonavir (Paxlovid) has been a game changer for high-risk patients with early COVID-19 symptoms but has significant interactions with commonly used cardiovascular medications, a new paper cautions.
COVID-19 patients with cardiovascular disease (CVD) or risk factors such as diabetes, hypertension, and chronic kidney disease are at high risk of severe disease and account for the lion’s share of those receiving Paxlovid. Data from the initial EPIC-HR trial and recent real-world data also suggest they’re among the most likely to benefit from the oral antiviral, regardless of their COVID-19 vaccination status.
“But at the same time, it unfortunately interacts with many very commonly prescribed cardiovascular medications and with many of them in a very clinically meaningful way, which may lead to serious adverse consequences,” senior author Sarju Ganatra, MD, said in an interview. “So, while it’s being prescribed with a good intention to help these people, we may actually end up doing more harm than good.
“We don’t want to deter people from getting their necessary COVID-19 treatment, which is excellent for the most part these days as an outpatient,” he added. “So, we felt the need to make a comprehensive list of cardiac medications and level of interactions with Paxlovid and also to help the clinicians and prescribers at the point of care to make the clinical decision of what modifications they may need to do.”
The paper, published online in the Journal of the American College of Cardiology, details drug-drug interactions with some 80 CV medications including statins, antihypertensive agents, heart failure therapies, and antiplatelet/anticoagulants.
It also includes a color-coded figure denoting whether a drug is safe to coadminister with Paxlovid, may potentially interact and require a dose adjustment or temporary discontinuation, or is contraindicated.
Among the commonly used blood thinners, for example, the paper notes that Paxlovid significantly increases drug levels of the direct oral anticoagulants (DOACs) apixaban, rivaroxaban, edoxaban, and dabigatran and, thus, increases the risk of bleeding.
“It can still be administered, if it’s necessary, but the dose of the DOAC either needs to be reduced or held depending on what they are getting it for, whether they’re getting it for pulmonary embolism or atrial fibrillation, and we adjust for all those things in the table in the paper,” said Dr. Ganatra, from Lahey Hospital and Medical Center, Burlington, Mass.
When the DOAC can’t be interrupted or dose adjusted, however, Paxlovid should not be given, the experts said. The antiviral is safe to use with enoxaparin, a low-molecular-weight heparin, but can increase or decrease levels of warfarin and should be used with close international normalized ratio monitoring.
For patients on antiplatelet agents, clinicians are advised to avoid prescribing nirmatrelvir/ritonavir to those on ticagrelor or clopidogrel unless the agents can be replaced by prasugrel.
Ritonavir – an inhibitor of cytochrome P 450 enzymes, particularly CYP3A4 – poses an increased risk of bleeding when given with ticagrelor, a CYP3A4 substrate, and decreases the active metabolite of clopidogrel, cutting its platelet inhibition by 20%. Although there’s a twofold decrease in the maximum concentration of prasugrel in patients on ritonavir, this does not affect its antiplatelet activity, the paper explains.
Among the lipid-lowering agents, experts suggested temporarily withholding atorvastatin, rosuvastatin, simvastatin, and lovastatin because of an increased risk for myopathy and liver toxicity but say that other statins, fibrates, ezetimibe, and the proprotein convertase subtilisin/kexin type 9 inhibitors evolocumab and alirocumab are safe to coadminister with Paxlovid.
While statins typically leave the body within hours, most of the antiarrhythmic drugs, except for sotalol, are not safe to give with Paxlovid, Dr. Ganatra said. It’s technically not feasible to hold these drugs because most have long half-lives, reaching about 100 days, for example, for amiodarone.
“It’s going to hang around in your system for a long time, so you don’t want to be falsely reassured that you’re holding the drug and it’s going to be fine to go back slowly,” he said. “You need to look for alternative therapies in those scenarios for COVID-19 treatment, which could be other antivirals, or a monoclonal antibody individualized to the patient’s risk.”
Although there’s limited clinical information regarding interaction-related adverse events with Paxlovid, the team used pharmacokinetics and pharmacodynamics data to provide the guidance. Serious adverse events are also well documented for ritonavir, which has been prescribed for years to treat HIV, Dr. Ganatra noted.
The Infectious Disease Society of America also published guidance on the management of potential drug interactions with Paxlovid in May and, earlier in October, the Food and Drug Administration updated its Paxlovid patient eligibility screening checklist.
Still, most prescribers are actually primary care physicians and even pharmacists, who may not be completely attuned, said Dr. Ganatra, who noted that some centers have started programs to help connect primary care physicians with their cardiology colleagues to check on CV drugs in their COVID-19 patients.
“We need to be thinking more broadly and at a system level where the hospital or health care system leverages the electronic health record systems,” he said. “Most of them are sophisticated enough to incorporate simple drug-drug interaction information, so if you try to prescribe someone Paxlovid and it’s a heart transplant patient who is on immunosuppressive therapy or a patient on a blood thinner, then it should give you a warning ... or at least give them a link to our paper or other valuable resources.
“If someone is on a blood thinner and the blood thinner level goes up by ninefold, we can only imagine what we would be dealing with,” Dr. Ganatra said. “So, these interactions should be taken very seriously and I think it’s worth the time and investment.”
The authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Starting a blog
. Health information is one of the most popular topics people search for online. Starting a physician blog can provide your practice with promotional and marketing benefits that you may have a difficult time finding elsewhere. A blog can be an effective way to drive traffic to your website, establish yourself as an authority or expert in a particular area, and stay on the radar with your patients. However, there are a few things you should think about before you start.
Start by determining what you want to accomplish. Do you want to reach quantitative milestones, like a certain number of followers, or are you looking to increase your website traffic from potential patients? One goal will probably be to augment the health knowledge of your patients. Decide early on what your benchmarks will be and how you will track them.
Next, determine who your potential readers are. Initially, most will probably be local (your existing patient base and their family and friends), but your audience may expand geographically as your blog gains in popularity.
By now, you probably realize that blogging will require a significant commitment, over and above the time needed to write the content. Decide whether you have the time and energy to take this on yourself, or whether help will be needed. Ideally, you should have one person in charge of all your social media efforts, so that everything is consistent and has the same voice. That person can be in-house, or you can outsource to any of the many companies that administer blogs and other media functions. (As always, I have no financial interest in any company or service mentioned in this column.)
The advantage of hiring an outside administrator is that a professionally designed blog will be far more attractive and polished than anything you could build yourself. Furthermore, an experienced designer will employ “search engine optimization” (SEO), meaning that content will be created using key words and phrases that will make it readily visible to search engine users.
You can leave design and SEO to the pros, but don’t delegate the content itself; as captain of the ship you are responsible for all the facts and opinions on your blog. You may not be up to writing everything yourself, but anything you don’t write personally needs to be scrutinized by you personally to make sure that it is factually accurate and reflects your personal view. And remember that, once it’s online, it’s online forever; consider the ramifications of anything you post on any site – yours or others – before hitting the “send” button. “The most damaging item about you,” one consultant told me, “could well be something you post yourself.” Just ask any of several prominent politicians who have famously sabotaged their own careers online.
That said, don’t be shy about creating content. Patients appreciate factual information, but they value your opinions too. Give people content that will be of interest or benefit to them. This can include health-related tips, reminders, suggestions, whatever. If they are interested in it, they will keep reading and may even share it with others. You should also write about subjects – medical and otherwise – that interest you personally. If you have expertise in a particular field, be sure to write about that.
Your practice is a local business, so localize your blog to attract people from your area. Be sure to include local city keywords in your writing. You may also want to post about local events in which your practice is involved.
Try to avoid political diatribes. While most physicians have strong political opinions, and some are not shy about expressing them, there are many venues that are more appropriate for those discussions than medical blogs. Also avoid outright sales pitches. It’s fine to describe procedures that you offer, but aggressive solicitation will only turn readers off.
Keep any medical advice in general terms; don’t use any specific examples that might make a patient identifiable and generate a HIPAA violation.
If you are having trouble growing your readership, use your practice’s Facebook page to push blog updates into patients’ feeds. Additionally, track Twitter hashtags that are relevant to your practice, and use them to find existing online communities with an interest in your blog’s topics.
Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at dermnews@mdedge.com.
*This article was updated 10/17/2022.
. Health information is one of the most popular topics people search for online. Starting a physician blog can provide your practice with promotional and marketing benefits that you may have a difficult time finding elsewhere. A blog can be an effective way to drive traffic to your website, establish yourself as an authority or expert in a particular area, and stay on the radar with your patients. However, there are a few things you should think about before you start.
Start by determining what you want to accomplish. Do you want to reach quantitative milestones, like a certain number of followers, or are you looking to increase your website traffic from potential patients? One goal will probably be to augment the health knowledge of your patients. Decide early on what your benchmarks will be and how you will track them.
Next, determine who your potential readers are. Initially, most will probably be local (your existing patient base and their family and friends), but your audience may expand geographically as your blog gains in popularity.
By now, you probably realize that blogging will require a significant commitment, over and above the time needed to write the content. Decide whether you have the time and energy to take this on yourself, or whether help will be needed. Ideally, you should have one person in charge of all your social media efforts, so that everything is consistent and has the same voice. That person can be in-house, or you can outsource to any of the many companies that administer blogs and other media functions. (As always, I have no financial interest in any company or service mentioned in this column.)
The advantage of hiring an outside administrator is that a professionally designed blog will be far more attractive and polished than anything you could build yourself. Furthermore, an experienced designer will employ “search engine optimization” (SEO), meaning that content will be created using key words and phrases that will make it readily visible to search engine users.
You can leave design and SEO to the pros, but don’t delegate the content itself; as captain of the ship you are responsible for all the facts and opinions on your blog. You may not be up to writing everything yourself, but anything you don’t write personally needs to be scrutinized by you personally to make sure that it is factually accurate and reflects your personal view. And remember that, once it’s online, it’s online forever; consider the ramifications of anything you post on any site – yours or others – before hitting the “send” button. “The most damaging item about you,” one consultant told me, “could well be something you post yourself.” Just ask any of several prominent politicians who have famously sabotaged their own careers online.
That said, don’t be shy about creating content. Patients appreciate factual information, but they value your opinions too. Give people content that will be of interest or benefit to them. This can include health-related tips, reminders, suggestions, whatever. If they are interested in it, they will keep reading and may even share it with others. You should also write about subjects – medical and otherwise – that interest you personally. If you have expertise in a particular field, be sure to write about that.
Your practice is a local business, so localize your blog to attract people from your area. Be sure to include local city keywords in your writing. You may also want to post about local events in which your practice is involved.
Try to avoid political diatribes. While most physicians have strong political opinions, and some are not shy about expressing them, there are many venues that are more appropriate for those discussions than medical blogs. Also avoid outright sales pitches. It’s fine to describe procedures that you offer, but aggressive solicitation will only turn readers off.
Keep any medical advice in general terms; don’t use any specific examples that might make a patient identifiable and generate a HIPAA violation.
If you are having trouble growing your readership, use your practice’s Facebook page to push blog updates into patients’ feeds. Additionally, track Twitter hashtags that are relevant to your practice, and use them to find existing online communities with an interest in your blog’s topics.
Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at dermnews@mdedge.com.
*This article was updated 10/17/2022.
. Health information is one of the most popular topics people search for online. Starting a physician blog can provide your practice with promotional and marketing benefits that you may have a difficult time finding elsewhere. A blog can be an effective way to drive traffic to your website, establish yourself as an authority or expert in a particular area, and stay on the radar with your patients. However, there are a few things you should think about before you start.
Start by determining what you want to accomplish. Do you want to reach quantitative milestones, like a certain number of followers, or are you looking to increase your website traffic from potential patients? One goal will probably be to augment the health knowledge of your patients. Decide early on what your benchmarks will be and how you will track them.
Next, determine who your potential readers are. Initially, most will probably be local (your existing patient base and their family and friends), but your audience may expand geographically as your blog gains in popularity.
By now, you probably realize that blogging will require a significant commitment, over and above the time needed to write the content. Decide whether you have the time and energy to take this on yourself, or whether help will be needed. Ideally, you should have one person in charge of all your social media efforts, so that everything is consistent and has the same voice. That person can be in-house, or you can outsource to any of the many companies that administer blogs and other media functions. (As always, I have no financial interest in any company or service mentioned in this column.)
The advantage of hiring an outside administrator is that a professionally designed blog will be far more attractive and polished than anything you could build yourself. Furthermore, an experienced designer will employ “search engine optimization” (SEO), meaning that content will be created using key words and phrases that will make it readily visible to search engine users.
You can leave design and SEO to the pros, but don’t delegate the content itself; as captain of the ship you are responsible for all the facts and opinions on your blog. You may not be up to writing everything yourself, but anything you don’t write personally needs to be scrutinized by you personally to make sure that it is factually accurate and reflects your personal view. And remember that, once it’s online, it’s online forever; consider the ramifications of anything you post on any site – yours or others – before hitting the “send” button. “The most damaging item about you,” one consultant told me, “could well be something you post yourself.” Just ask any of several prominent politicians who have famously sabotaged their own careers online.
That said, don’t be shy about creating content. Patients appreciate factual information, but they value your opinions too. Give people content that will be of interest or benefit to them. This can include health-related tips, reminders, suggestions, whatever. If they are interested in it, they will keep reading and may even share it with others. You should also write about subjects – medical and otherwise – that interest you personally. If you have expertise in a particular field, be sure to write about that.
Your practice is a local business, so localize your blog to attract people from your area. Be sure to include local city keywords in your writing. You may also want to post about local events in which your practice is involved.
Try to avoid political diatribes. While most physicians have strong political opinions, and some are not shy about expressing them, there are many venues that are more appropriate for those discussions than medical blogs. Also avoid outright sales pitches. It’s fine to describe procedures that you offer, but aggressive solicitation will only turn readers off.
Keep any medical advice in general terms; don’t use any specific examples that might make a patient identifiable and generate a HIPAA violation.
If you are having trouble growing your readership, use your practice’s Facebook page to push blog updates into patients’ feeds. Additionally, track Twitter hashtags that are relevant to your practice, and use them to find existing online communities with an interest in your blog’s topics.
Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at dermnews@mdedge.com.
*This article was updated 10/17/2022.
Novel stepwise method found to benefit patients with severe rhinophyma
DENVER –
Rhinophyma occurs primarily in the sixth and seventh decades of life and is marked by facial hypertrophy that leads to tumor-like growth, inflammation, fibrosis, and loss of the cosmetic nasal subunits. “When it becomes severe it leads to a degree of embarrassment as well,” one of the study authors, Patricia Richey, MD, said during an oral abstract session at the annual meeting of the American Society for Dermatologic Surgery. “We found that our method has been efficacious, but most often, and more importantly, leads to an improvement in the patient’s quality of life.”
To date, clinicians have used fully ablative lasers to treat varying degrees of rhinophyma but at a cost of prolonged healing time and higher rates of scarring and pigment or textural changes. However, not all dermatologists use full-field ablative lasers in their practices.
“Fractionated ablative lasers have been used in the past for mild to moderate rhinophyma, but they cannot ablate to 100% density, which would be necessary to debulk the marked hypertrophy present in our patients,” said Dr. Richey, who practices Mohs surgery and cosmetic dermatology in Washington, D.C., and conducts research for the Wellman Center for Photomedicine and the Dermatology Laser and Cosmetic Center at Massachusetts General Hospital, Boston. “That’s why we added a surgical component.”
She and colleague Mathew M. Avram, MD, JD, developed a three-step method for treating severe rhinophyma that they performed on three elderly patients. Step 1 is the surgical debulk. Following infiltration of local anesthesia, a razor blade or 15-blade is used to excise the most prominent lobules of hypertrophied sebaceous tissue down to the fibrofatty layer of the nose as a partial thickness excision that does not reach the level of the perichondrium or cartilage. “Hemostasis is achieved with electrocoagulation and application of petrolatum ointment, followed by a pressure dressing,” Dr. Richey said. “The location of the debulk varies by patient.”
Step 2 involves fractionated ablative laser treatment 4 weeks later with either the CO2 or erbium:YAG (Er:YAG) 2,940-nm laser. According to Dr. Richey, the typical setting for the fractionated CO2 is a fluence of 70mJ/cm2 and a high density, performing six out of four passes with 60 seconds between each pass, “though these settings may vary based on the patient presentation,” she said.
The treatment level ranges from 5 (14% density) to 10 (70% density, for the most severe cases). Meanwhile, a representative setting for the ablative fractionated Er:YAG 2,940-nm laser is 250 mcm, no coagulation, 5.5% density, and one pass. “If a second surgical debulk is performed on the same day as ablative laser treatment, the sites of shave removal are typically avoided with the laser,” she said. If a certain portion of the nose has recently healed following surgical debulk 4 weeks prior, they may perform only two passes in this region.
In an interview, Dr. Avram, who directs the MGH Dermatology Laser and Cosmetic Center, characterized the staged method as providing “transformative change to severe, cosmetically disfiguring rhinophyma. The ablative fractional laser provides more fine-tuned contouring.”
The three patients studied had an average of three to four monthly treatments. “There is typically a great deal of improvement by the second treatment,” Dr. Richey said. Add-on treatments may include low voltage electrodessication at 1.8 watts for patients with well-demarcated papules of sebaceous hyperplasia, and a vascular laser such as the pulsed dye laser if telangiectasias are present.
One limitation of the stepwise method, she said, is that the surgical debulk typically results in a scar, “but it’s rarely noticeable if carefully performed, likely due to fractionated ablative use during the scar remodeling period. It’s important to set expectations with your patient at the initial consult. We always discuss treatment goals and that while we aim achieve the most desirable outcome possible, we’re never going to get them back to having a completely normal nose. They’re always going to have some mild or moderate rhinophymatous changes present.”
Vincent Richer, MD, a Vancouver-based medical and cosmetic dermatologist who was asked to comment on these results, characterized the stepwise method as promising. “Though more treatments are required, the easier recovery, safe outcomes in the case presented and excellent cosmetic result made it an interesting alternative when fully ablative resurfacing is daunting, either for patients or physicians involved,” he said in an interview.
The researchers reported having no relevant disclosures. Dr. Richer disclosed that he performs clinical trials for AbbVie/Allergan, Galderma, Leo Pharma, Pfizer, and is a member of advisory board for Bausch, Celgene, Eli Lilly, Galderma, Janssen, Johnson & Johnson, Leo Pharma, L’Oréal, and Sanofi. He is also a consultant to AbbVie/Allergan, Bausch, Celgene, Eli Lilly, Galderma, Janssen, Johnson & Johnson, Leo Pharma, L’Oréal, Merz, and Sanofi.
DENVER –
Rhinophyma occurs primarily in the sixth and seventh decades of life and is marked by facial hypertrophy that leads to tumor-like growth, inflammation, fibrosis, and loss of the cosmetic nasal subunits. “When it becomes severe it leads to a degree of embarrassment as well,” one of the study authors, Patricia Richey, MD, said during an oral abstract session at the annual meeting of the American Society for Dermatologic Surgery. “We found that our method has been efficacious, but most often, and more importantly, leads to an improvement in the patient’s quality of life.”
To date, clinicians have used fully ablative lasers to treat varying degrees of rhinophyma but at a cost of prolonged healing time and higher rates of scarring and pigment or textural changes. However, not all dermatologists use full-field ablative lasers in their practices.
“Fractionated ablative lasers have been used in the past for mild to moderate rhinophyma, but they cannot ablate to 100% density, which would be necessary to debulk the marked hypertrophy present in our patients,” said Dr. Richey, who practices Mohs surgery and cosmetic dermatology in Washington, D.C., and conducts research for the Wellman Center for Photomedicine and the Dermatology Laser and Cosmetic Center at Massachusetts General Hospital, Boston. “That’s why we added a surgical component.”
She and colleague Mathew M. Avram, MD, JD, developed a three-step method for treating severe rhinophyma that they performed on three elderly patients. Step 1 is the surgical debulk. Following infiltration of local anesthesia, a razor blade or 15-blade is used to excise the most prominent lobules of hypertrophied sebaceous tissue down to the fibrofatty layer of the nose as a partial thickness excision that does not reach the level of the perichondrium or cartilage. “Hemostasis is achieved with electrocoagulation and application of petrolatum ointment, followed by a pressure dressing,” Dr. Richey said. “The location of the debulk varies by patient.”
Step 2 involves fractionated ablative laser treatment 4 weeks later with either the CO2 or erbium:YAG (Er:YAG) 2,940-nm laser. According to Dr. Richey, the typical setting for the fractionated CO2 is a fluence of 70mJ/cm2 and a high density, performing six out of four passes with 60 seconds between each pass, “though these settings may vary based on the patient presentation,” she said.
The treatment level ranges from 5 (14% density) to 10 (70% density, for the most severe cases). Meanwhile, a representative setting for the ablative fractionated Er:YAG 2,940-nm laser is 250 mcm, no coagulation, 5.5% density, and one pass. “If a second surgical debulk is performed on the same day as ablative laser treatment, the sites of shave removal are typically avoided with the laser,” she said. If a certain portion of the nose has recently healed following surgical debulk 4 weeks prior, they may perform only two passes in this region.
In an interview, Dr. Avram, who directs the MGH Dermatology Laser and Cosmetic Center, characterized the staged method as providing “transformative change to severe, cosmetically disfiguring rhinophyma. The ablative fractional laser provides more fine-tuned contouring.”
The three patients studied had an average of three to four monthly treatments. “There is typically a great deal of improvement by the second treatment,” Dr. Richey said. Add-on treatments may include low voltage electrodessication at 1.8 watts for patients with well-demarcated papules of sebaceous hyperplasia, and a vascular laser such as the pulsed dye laser if telangiectasias are present.
One limitation of the stepwise method, she said, is that the surgical debulk typically results in a scar, “but it’s rarely noticeable if carefully performed, likely due to fractionated ablative use during the scar remodeling period. It’s important to set expectations with your patient at the initial consult. We always discuss treatment goals and that while we aim achieve the most desirable outcome possible, we’re never going to get them back to having a completely normal nose. They’re always going to have some mild or moderate rhinophymatous changes present.”
Vincent Richer, MD, a Vancouver-based medical and cosmetic dermatologist who was asked to comment on these results, characterized the stepwise method as promising. “Though more treatments are required, the easier recovery, safe outcomes in the case presented and excellent cosmetic result made it an interesting alternative when fully ablative resurfacing is daunting, either for patients or physicians involved,” he said in an interview.
The researchers reported having no relevant disclosures. Dr. Richer disclosed that he performs clinical trials for AbbVie/Allergan, Galderma, Leo Pharma, Pfizer, and is a member of advisory board for Bausch, Celgene, Eli Lilly, Galderma, Janssen, Johnson & Johnson, Leo Pharma, L’Oréal, and Sanofi. He is also a consultant to AbbVie/Allergan, Bausch, Celgene, Eli Lilly, Galderma, Janssen, Johnson & Johnson, Leo Pharma, L’Oréal, Merz, and Sanofi.
DENVER –
Rhinophyma occurs primarily in the sixth and seventh decades of life and is marked by facial hypertrophy that leads to tumor-like growth, inflammation, fibrosis, and loss of the cosmetic nasal subunits. “When it becomes severe it leads to a degree of embarrassment as well,” one of the study authors, Patricia Richey, MD, said during an oral abstract session at the annual meeting of the American Society for Dermatologic Surgery. “We found that our method has been efficacious, but most often, and more importantly, leads to an improvement in the patient’s quality of life.”
To date, clinicians have used fully ablative lasers to treat varying degrees of rhinophyma but at a cost of prolonged healing time and higher rates of scarring and pigment or textural changes. However, not all dermatologists use full-field ablative lasers in their practices.
“Fractionated ablative lasers have been used in the past for mild to moderate rhinophyma, but they cannot ablate to 100% density, which would be necessary to debulk the marked hypertrophy present in our patients,” said Dr. Richey, who practices Mohs surgery and cosmetic dermatology in Washington, D.C., and conducts research for the Wellman Center for Photomedicine and the Dermatology Laser and Cosmetic Center at Massachusetts General Hospital, Boston. “That’s why we added a surgical component.”
She and colleague Mathew M. Avram, MD, JD, developed a three-step method for treating severe rhinophyma that they performed on three elderly patients. Step 1 is the surgical debulk. Following infiltration of local anesthesia, a razor blade or 15-blade is used to excise the most prominent lobules of hypertrophied sebaceous tissue down to the fibrofatty layer of the nose as a partial thickness excision that does not reach the level of the perichondrium or cartilage. “Hemostasis is achieved with electrocoagulation and application of petrolatum ointment, followed by a pressure dressing,” Dr. Richey said. “The location of the debulk varies by patient.”
Step 2 involves fractionated ablative laser treatment 4 weeks later with either the CO2 or erbium:YAG (Er:YAG) 2,940-nm laser. According to Dr. Richey, the typical setting for the fractionated CO2 is a fluence of 70mJ/cm2 and a high density, performing six out of four passes with 60 seconds between each pass, “though these settings may vary based on the patient presentation,” she said.
The treatment level ranges from 5 (14% density) to 10 (70% density, for the most severe cases). Meanwhile, a representative setting for the ablative fractionated Er:YAG 2,940-nm laser is 250 mcm, no coagulation, 5.5% density, and one pass. “If a second surgical debulk is performed on the same day as ablative laser treatment, the sites of shave removal are typically avoided with the laser,” she said. If a certain portion of the nose has recently healed following surgical debulk 4 weeks prior, they may perform only two passes in this region.
In an interview, Dr. Avram, who directs the MGH Dermatology Laser and Cosmetic Center, characterized the staged method as providing “transformative change to severe, cosmetically disfiguring rhinophyma. The ablative fractional laser provides more fine-tuned contouring.”
The three patients studied had an average of three to four monthly treatments. “There is typically a great deal of improvement by the second treatment,” Dr. Richey said. Add-on treatments may include low voltage electrodessication at 1.8 watts for patients with well-demarcated papules of sebaceous hyperplasia, and a vascular laser such as the pulsed dye laser if telangiectasias are present.
One limitation of the stepwise method, she said, is that the surgical debulk typically results in a scar, “but it’s rarely noticeable if carefully performed, likely due to fractionated ablative use during the scar remodeling period. It’s important to set expectations with your patient at the initial consult. We always discuss treatment goals and that while we aim achieve the most desirable outcome possible, we’re never going to get them back to having a completely normal nose. They’re always going to have some mild or moderate rhinophymatous changes present.”
Vincent Richer, MD, a Vancouver-based medical and cosmetic dermatologist who was asked to comment on these results, characterized the stepwise method as promising. “Though more treatments are required, the easier recovery, safe outcomes in the case presented and excellent cosmetic result made it an interesting alternative when fully ablative resurfacing is daunting, either for patients or physicians involved,” he said in an interview.
The researchers reported having no relevant disclosures. Dr. Richer disclosed that he performs clinical trials for AbbVie/Allergan, Galderma, Leo Pharma, Pfizer, and is a member of advisory board for Bausch, Celgene, Eli Lilly, Galderma, Janssen, Johnson & Johnson, Leo Pharma, L’Oréal, and Sanofi. He is also a consultant to AbbVie/Allergan, Bausch, Celgene, Eli Lilly, Galderma, Janssen, Johnson & Johnson, Leo Pharma, L’Oréal, Merz, and Sanofi.
AT ASDS 2022
Vedolizumab linked to increased treatment failure in older patients with Crohn’s
Findings indicate that vedolizumab is associated with an increased risk for treatment failure in older patients with inflammatory bowel disease (IBD), as compared with tumor necrosis factor (TNF) antagonists, according to a new study published in JAMA Network Open.
Although the incidence and prevalence of IBD among older adults are rapidly increasing, there is a lack of evidence-based treatment guidance for these patients, who represent less than 5% of participants in IBD-related clinical trials, wrote Siddharth Singh, MD, a gastroenterologist and assistant professor of medicine at the University of California, San Diego, and colleagues.
“Older patients are frequently undertreated and mismanaged with long-term corticosteroid use and limited use of steroid-sparing therapies owing to patients’ and clinicians’ concerns about the safety of immunosuppressive therapy,” the authors wrote. “There is considerable need for evidence-based treatment guidance for older patients with IBD.”
The researchers undertook an observational study of the comparative effectiveness of vedolizumab versus TNF antagonists (namely infliximab, adalimumab, and golimumab) among older patients with IBD in Denmark. Using the Danish National Patient Register, the authors included 754 patients aged 50 years and older who received treatment between 2005 and 2018.
The primary effectiveness outcome was treatment failure, defined as the composite 1-year risk of IBD-related hospitalization, IBD-related surgery, or a new corticosteroid prescription more than 6 weeks after initiation of treatment with a biologic. Secondary effectiveness outcomes included time to each component included in the composite score.
The primary safety outcome was the risk of serious infections, defined as those that required hospitalization. Secondary safety outcomes were risk of cancer and major adverse cardiovascular or venous thromboembolic events.
The researchers conducted a 1:1 propensity score-matched analysis, accounting for patient, disease, and treatment factors. The 754 patients included 377 incident users of vedolizumab, including 177 with Crohn’s disease; and 377 incident users of TNF antagonists, including 182 with Crohn’s disease. The average follow-up after treatment initiation occurred between 32 and 40 weeks.
Notably, patients treated with vedolizumab were more likely than those treated with TNF antagonists to have multimorbidity, at 16.2% versus 14.1%, and a higher burden of frailty, at 2.7% versus 1.9%. No significant differences were observed in the proportion of patients with recent immunomodulator and corticosteroid exposure.
Overall, vedolizumab was associated with a 31% increased risk of treatment failure (45.4%), compared with TNF antagonists (34.7%). This included an increased risk of IBD-related hospitalization (27.8% versus 16.3%) and IBD-related major abdominal surgery (21.3% versus 8%).
Among patients with Crohn’s disease, vedolizumab was associated with a 77% increased risk of treatment failure, as well as a greater need for corticosteroids. There was no significant difference in the risk of treatment failure or need for corticosteroids in patients with ulcerative colitis
No significant differences were seen in the risk of serious infections between patients treated with vedolizumab or TNF antagonists, at 8.2% versus 8.7%. This didn’t change by IBD phenotype, age at time of biologic therapy initiation, or treatment with biologic monotherapy versus combination therapy with immunomodulators.
The overall incidence of major adverse cardiovascular or venous thromboembolic events was similar among the groups. Rates of new malignant neoplasms were low, with fewer than five events.
In a subgroup analysis based on the Charlson Comorbidity Index, vedolizumab was associated with a 63% increased risk of treatment failure for patients without comorbidities but not for patients with comorbidities.
“This study adds to the body of literature comparing vedolizumab and anti-TNF in older adults. The findings have been mixed, in some part due to differences in study designs,” said Ashwin N. Ananthakrishnan, MBBS, MPH, associate professor of medicine at Harvard Medical School and a gastroenterologist at Massachusetts General Hospital, both in Boston.
Dr. Ananthakrishnan, who wasn’t involved with this study, has previously researched the two treatments and found that they are comparably safe in older adults. In fact, among patients with significant comorbidity, vedolizumab may be safer. However, the Danish study wasn’t powered to describe that, he said. Moreover, patient characteristics and treatment approaches likely differ between the United States and Denmark.
“Overall, the findings are reassuring. Often when we treat older adults, the emphasis is on safety,” he said. “But by highlighting the difference in clinical response rates – their findings being consistent with a study we published a few years ago – it highlights the importance of also considering efficacy and onset of action for specific disease phenotypes in treatment selection.”
Dr. Ananthakrishnan and colleagues are currently developing clinical tools for risk stratification and prognostication in older adults with IBD, including functional and frailty assessments. “Biologically, older adults may be particularly vulnerable to specific treatment risks such as infections and cancer, but they are also vulnerable to the consequences of untreated disease, including loss of functional independence and frailty,” he explained. “Thus, arriving at the right risk to benefit balance is critically important when making treatment decisions for older adults.”
The study by Dr. Singh and colleagues was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and the Danish National Research Foundation. Dr. Singh reported receiving grants from pharmaceutical companies unrelated to the study, as well as support from the International Organization for the Study of Inflammatory Bowel Disease Operating Grant and Litwin Pioneers in IBD. No other disclosures were reported. Dr. Ananthakrishnan reported no relevant disclosures.
Findings indicate that vedolizumab is associated with an increased risk for treatment failure in older patients with inflammatory bowel disease (IBD), as compared with tumor necrosis factor (TNF) antagonists, according to a new study published in JAMA Network Open.
Although the incidence and prevalence of IBD among older adults are rapidly increasing, there is a lack of evidence-based treatment guidance for these patients, who represent less than 5% of participants in IBD-related clinical trials, wrote Siddharth Singh, MD, a gastroenterologist and assistant professor of medicine at the University of California, San Diego, and colleagues.
“Older patients are frequently undertreated and mismanaged with long-term corticosteroid use and limited use of steroid-sparing therapies owing to patients’ and clinicians’ concerns about the safety of immunosuppressive therapy,” the authors wrote. “There is considerable need for evidence-based treatment guidance for older patients with IBD.”
The researchers undertook an observational study of the comparative effectiveness of vedolizumab versus TNF antagonists (namely infliximab, adalimumab, and golimumab) among older patients with IBD in Denmark. Using the Danish National Patient Register, the authors included 754 patients aged 50 years and older who received treatment between 2005 and 2018.
The primary effectiveness outcome was treatment failure, defined as the composite 1-year risk of IBD-related hospitalization, IBD-related surgery, or a new corticosteroid prescription more than 6 weeks after initiation of treatment with a biologic. Secondary effectiveness outcomes included time to each component included in the composite score.
The primary safety outcome was the risk of serious infections, defined as those that required hospitalization. Secondary safety outcomes were risk of cancer and major adverse cardiovascular or venous thromboembolic events.
The researchers conducted a 1:1 propensity score-matched analysis, accounting for patient, disease, and treatment factors. The 754 patients included 377 incident users of vedolizumab, including 177 with Crohn’s disease; and 377 incident users of TNF antagonists, including 182 with Crohn’s disease. The average follow-up after treatment initiation occurred between 32 and 40 weeks.
Notably, patients treated with vedolizumab were more likely than those treated with TNF antagonists to have multimorbidity, at 16.2% versus 14.1%, and a higher burden of frailty, at 2.7% versus 1.9%. No significant differences were observed in the proportion of patients with recent immunomodulator and corticosteroid exposure.
Overall, vedolizumab was associated with a 31% increased risk of treatment failure (45.4%), compared with TNF antagonists (34.7%). This included an increased risk of IBD-related hospitalization (27.8% versus 16.3%) and IBD-related major abdominal surgery (21.3% versus 8%).
Among patients with Crohn’s disease, vedolizumab was associated with a 77% increased risk of treatment failure, as well as a greater need for corticosteroids. There was no significant difference in the risk of treatment failure or need for corticosteroids in patients with ulcerative colitis
No significant differences were seen in the risk of serious infections between patients treated with vedolizumab or TNF antagonists, at 8.2% versus 8.7%. This didn’t change by IBD phenotype, age at time of biologic therapy initiation, or treatment with biologic monotherapy versus combination therapy with immunomodulators.
The overall incidence of major adverse cardiovascular or venous thromboembolic events was similar among the groups. Rates of new malignant neoplasms were low, with fewer than five events.
In a subgroup analysis based on the Charlson Comorbidity Index, vedolizumab was associated with a 63% increased risk of treatment failure for patients without comorbidities but not for patients with comorbidities.
“This study adds to the body of literature comparing vedolizumab and anti-TNF in older adults. The findings have been mixed, in some part due to differences in study designs,” said Ashwin N. Ananthakrishnan, MBBS, MPH, associate professor of medicine at Harvard Medical School and a gastroenterologist at Massachusetts General Hospital, both in Boston.
Dr. Ananthakrishnan, who wasn’t involved with this study, has previously researched the two treatments and found that they are comparably safe in older adults. In fact, among patients with significant comorbidity, vedolizumab may be safer. However, the Danish study wasn’t powered to describe that, he said. Moreover, patient characteristics and treatment approaches likely differ between the United States and Denmark.
“Overall, the findings are reassuring. Often when we treat older adults, the emphasis is on safety,” he said. “But by highlighting the difference in clinical response rates – their findings being consistent with a study we published a few years ago – it highlights the importance of also considering efficacy and onset of action for specific disease phenotypes in treatment selection.”
Dr. Ananthakrishnan and colleagues are currently developing clinical tools for risk stratification and prognostication in older adults with IBD, including functional and frailty assessments. “Biologically, older adults may be particularly vulnerable to specific treatment risks such as infections and cancer, but they are also vulnerable to the consequences of untreated disease, including loss of functional independence and frailty,” he explained. “Thus, arriving at the right risk to benefit balance is critically important when making treatment decisions for older adults.”
The study by Dr. Singh and colleagues was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and the Danish National Research Foundation. Dr. Singh reported receiving grants from pharmaceutical companies unrelated to the study, as well as support from the International Organization for the Study of Inflammatory Bowel Disease Operating Grant and Litwin Pioneers in IBD. No other disclosures were reported. Dr. Ananthakrishnan reported no relevant disclosures.
Findings indicate that vedolizumab is associated with an increased risk for treatment failure in older patients with inflammatory bowel disease (IBD), as compared with tumor necrosis factor (TNF) antagonists, according to a new study published in JAMA Network Open.
Although the incidence and prevalence of IBD among older adults are rapidly increasing, there is a lack of evidence-based treatment guidance for these patients, who represent less than 5% of participants in IBD-related clinical trials, wrote Siddharth Singh, MD, a gastroenterologist and assistant professor of medicine at the University of California, San Diego, and colleagues.
“Older patients are frequently undertreated and mismanaged with long-term corticosteroid use and limited use of steroid-sparing therapies owing to patients’ and clinicians’ concerns about the safety of immunosuppressive therapy,” the authors wrote. “There is considerable need for evidence-based treatment guidance for older patients with IBD.”
The researchers undertook an observational study of the comparative effectiveness of vedolizumab versus TNF antagonists (namely infliximab, adalimumab, and golimumab) among older patients with IBD in Denmark. Using the Danish National Patient Register, the authors included 754 patients aged 50 years and older who received treatment between 2005 and 2018.
The primary effectiveness outcome was treatment failure, defined as the composite 1-year risk of IBD-related hospitalization, IBD-related surgery, or a new corticosteroid prescription more than 6 weeks after initiation of treatment with a biologic. Secondary effectiveness outcomes included time to each component included in the composite score.
The primary safety outcome was the risk of serious infections, defined as those that required hospitalization. Secondary safety outcomes were risk of cancer and major adverse cardiovascular or venous thromboembolic events.
The researchers conducted a 1:1 propensity score-matched analysis, accounting for patient, disease, and treatment factors. The 754 patients included 377 incident users of vedolizumab, including 177 with Crohn’s disease; and 377 incident users of TNF antagonists, including 182 with Crohn’s disease. The average follow-up after treatment initiation occurred between 32 and 40 weeks.
Notably, patients treated with vedolizumab were more likely than those treated with TNF antagonists to have multimorbidity, at 16.2% versus 14.1%, and a higher burden of frailty, at 2.7% versus 1.9%. No significant differences were observed in the proportion of patients with recent immunomodulator and corticosteroid exposure.
Overall, vedolizumab was associated with a 31% increased risk of treatment failure (45.4%), compared with TNF antagonists (34.7%). This included an increased risk of IBD-related hospitalization (27.8% versus 16.3%) and IBD-related major abdominal surgery (21.3% versus 8%).
Among patients with Crohn’s disease, vedolizumab was associated with a 77% increased risk of treatment failure, as well as a greater need for corticosteroids. There was no significant difference in the risk of treatment failure or need for corticosteroids in patients with ulcerative colitis
No significant differences were seen in the risk of serious infections between patients treated with vedolizumab or TNF antagonists, at 8.2% versus 8.7%. This didn’t change by IBD phenotype, age at time of biologic therapy initiation, or treatment with biologic monotherapy versus combination therapy with immunomodulators.
The overall incidence of major adverse cardiovascular or venous thromboembolic events was similar among the groups. Rates of new malignant neoplasms were low, with fewer than five events.
In a subgroup analysis based on the Charlson Comorbidity Index, vedolizumab was associated with a 63% increased risk of treatment failure for patients without comorbidities but not for patients with comorbidities.
“This study adds to the body of literature comparing vedolizumab and anti-TNF in older adults. The findings have been mixed, in some part due to differences in study designs,” said Ashwin N. Ananthakrishnan, MBBS, MPH, associate professor of medicine at Harvard Medical School and a gastroenterologist at Massachusetts General Hospital, both in Boston.
Dr. Ananthakrishnan, who wasn’t involved with this study, has previously researched the two treatments and found that they are comparably safe in older adults. In fact, among patients with significant comorbidity, vedolizumab may be safer. However, the Danish study wasn’t powered to describe that, he said. Moreover, patient characteristics and treatment approaches likely differ between the United States and Denmark.
“Overall, the findings are reassuring. Often when we treat older adults, the emphasis is on safety,” he said. “But by highlighting the difference in clinical response rates – their findings being consistent with a study we published a few years ago – it highlights the importance of also considering efficacy and onset of action for specific disease phenotypes in treatment selection.”
Dr. Ananthakrishnan and colleagues are currently developing clinical tools for risk stratification and prognostication in older adults with IBD, including functional and frailty assessments. “Biologically, older adults may be particularly vulnerable to specific treatment risks such as infections and cancer, but they are also vulnerable to the consequences of untreated disease, including loss of functional independence and frailty,” he explained. “Thus, arriving at the right risk to benefit balance is critically important when making treatment decisions for older adults.”
The study by Dr. Singh and colleagues was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and the Danish National Research Foundation. Dr. Singh reported receiving grants from pharmaceutical companies unrelated to the study, as well as support from the International Organization for the Study of Inflammatory Bowel Disease Operating Grant and Litwin Pioneers in IBD. No other disclosures were reported. Dr. Ananthakrishnan reported no relevant disclosures.
FROM JAMA NETWORK OPEN
Tourette syndrome: Diagnosis is key for best care
Tourette syndrome, attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and autism spectrum disorder (ASD) share significant overlap in symptomatology, and it can be challenging at times to distinguish between these conditions. Being able to do so, however, can help guide more targeted interventions and accommodations to optimize a patient’s level of functioning.
Case example
A healthy, bright 6-year-old boy is referred by his family doctor to an academic medical center for a full team evaluation because of suspicion of ASD, after having already been diagnosed with ADHD at the age of 5. His difficulties with inattention, impulsivity, and hyperactivity, as well as his behavioral rigidities and sensory avoidant and sensory seeking behaviors have caused functional impairments for him in his kindergarten classroom. He has been penalized with removal of recess on more than one occasion. A low dose of a stimulant had been tried but resulted in a perceived increase in disruptive behaviors.
The boy, while hyperkinetic and often paying poor attention, is quite capable of high-quality and well-modulated eye contact paired with typical social referencing and reciprocity when actively engaging with the examiner and his parents. He does have a reported history of serial fixated interests and some repetitive behaviors but is also noted to be flexible in his interpersonal style, maintains other varied and typical interests, easily directs affect, utilizes a wide array of fluid gestures paired naturally with verbal communication, and shares enjoyment with smoothly coordinated gaze. He has mild articulation errors but uses pronouns appropriately and has no scripted speech or echolalia, though does engage in some whispered palilalia intermittently.
He is generally quite cooperative and redirectable when focused and has a completely normal physical and neurologic examination. During the visit, the doctor notices the boy making an intermittent honking sound, which parents report as an attention-seeking strategy during times of stress. Further physician-guided information gathering around other repetitive noises and movements elicits a history of engagement in repetitive hand-to-groin movements, some exaggerated blinking, and a number of other waxing and waning subtle motor and phonic tics with onset in preschool. These noises and movements have generally been identified as “fidgeting” and “misbehaving” by well-meaning caregivers in the home and school environments.
Both Tourette syndrome and ASD are more common in males, with stereotyped patterns of movements and behaviors; anxious, obsessive, and compulsive behaviors resulting in behavioral rigidities; sensory sensitivities; and increased rates of hyperkinesis with decreased impulse control which result in increased sensory-seeking behaviors. Diagnostic criteria for Tourette syndrome are met when a child has had multiple motor tics and at least one phonic tic present for at least 1 year, with tic-free intervals lasting no longer than 3 months, and with onset before the age of 18. Typically, tics emerge in late preschool and early grade school, and some children even develop repetitive movements as early as toddlerhood. Tics tend to worsen around the peripubertal era, then often generally improve in the teen years. Tic types, frequency, and severity general fluctuate over time.
Forty percent of children with Tourette syndrome also meet criteria for OCD, with many more having OCD traits, and about 65% of children with Tourette syndrome also meet criteria for ADHD, with many more having ADHD traits. OCD can lead to more rigid and directive social interactions in children as well as obsessive interests, just as ADHD can lead to less socially attuned and less cooperative behaviors, even in children who do not meet criteria for ASD.
For example, a child with OCD in the absence of ASD may still “police” other kids in class and be overly focused on the rules of a game, which may become a social liability. Likewise, a child with ADHD in the absence of ASD may be so distractible that focusing on what other kids are saying and their paired facial expressions is compromised, leading to poor-quality social reciprocity during interactions with peers. Given the remarkable overlap in shared symptoms, it is essential for pediatric providers to consider Tourette syndrome in the differential for any child with repetitive movements and behaviors in addition to ASD and a wide array of other neurodevelopment differences, including global developmental delays and intellectual disabilities. This is of particular importance as the diagnosis of Tourette syndrome can be used to gain access to developmental disability services if the condition has resulted in true adaptive impairments.
It is determined that the boy does in fact meet criteria for ADHD, but also for OCD and Tourette syndrome. Both his Autism Diagnostic Observation Schedule and DSM-5–influenced autism interview are found to be in the nonclinical ranges, given his quality of communication, social engagement, imaginative play, and varied interests. A diagnosis of ASD is not felt to be an appropriate conceptualization of his neurodevelopmental differences. He is started on a low dose of guanfacine, which induces a decline in tics, impulsivity, and hyperkinesis. He is given a 504 plan in school that includes scheduled “tic breaks,” sensory fidgets for use in the classroom, extra movement opportunities as needed, and utilization of a gentle cueing system between him and his teacher for low-key redirection of disruptive behaviors. He is no longer penalized for inattention or tics, and his 504 plan protects him from the use of recess removal as a behavioral modification strategy.
His parents enroll him in the community swim program for extra exercise, focus on decreasing screen time, and give him an earlier bedtime to help decrease his tics and rigidities, while improving his ability to self-regulate. Eventually, a low dose of a newer-generation stimulant is added to his guanfacine, with excellent results and only a mild increase in tolerable tics.
The child in the vignette did well with a 504 plan based on his medical diagnoses, though if related learning difficulties had persisted, eligibility under Other Health Impaired could be used to provide eligibility for an Individualized Education Plan. Alpha-agonists can be helpful for symptom control in those with Tourette syndrome by simultaneously treating tics, hyperkinesis, and impulsivity, while decreasing the risk of tic exacerbation with use of stimulants. Overall, understanding the neurodiversity related to Tourette syndrome can help providers advocate for home and community-based supports to optimize general functioning and quality of life.
Dr. Roth is a developmental and behavioral pediatrician in Eugene, Ore. She has no conflicts of interest.
References
Darrow S et al. J Am Acad Child Adolescent Psych. 2017;56(7):610-7.
AAP Section on Developmental and Behavioral Pediatrics. Developmental and Behavioral Pediatrics. Voigt RG et al, eds. 2018: American Academy of Pediatrics.
Tourette syndrome, attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and autism spectrum disorder (ASD) share significant overlap in symptomatology, and it can be challenging at times to distinguish between these conditions. Being able to do so, however, can help guide more targeted interventions and accommodations to optimize a patient’s level of functioning.
Case example
A healthy, bright 6-year-old boy is referred by his family doctor to an academic medical center for a full team evaluation because of suspicion of ASD, after having already been diagnosed with ADHD at the age of 5. His difficulties with inattention, impulsivity, and hyperactivity, as well as his behavioral rigidities and sensory avoidant and sensory seeking behaviors have caused functional impairments for him in his kindergarten classroom. He has been penalized with removal of recess on more than one occasion. A low dose of a stimulant had been tried but resulted in a perceived increase in disruptive behaviors.
The boy, while hyperkinetic and often paying poor attention, is quite capable of high-quality and well-modulated eye contact paired with typical social referencing and reciprocity when actively engaging with the examiner and his parents. He does have a reported history of serial fixated interests and some repetitive behaviors but is also noted to be flexible in his interpersonal style, maintains other varied and typical interests, easily directs affect, utilizes a wide array of fluid gestures paired naturally with verbal communication, and shares enjoyment with smoothly coordinated gaze. He has mild articulation errors but uses pronouns appropriately and has no scripted speech or echolalia, though does engage in some whispered palilalia intermittently.
He is generally quite cooperative and redirectable when focused and has a completely normal physical and neurologic examination. During the visit, the doctor notices the boy making an intermittent honking sound, which parents report as an attention-seeking strategy during times of stress. Further physician-guided information gathering around other repetitive noises and movements elicits a history of engagement in repetitive hand-to-groin movements, some exaggerated blinking, and a number of other waxing and waning subtle motor and phonic tics with onset in preschool. These noises and movements have generally been identified as “fidgeting” and “misbehaving” by well-meaning caregivers in the home and school environments.
Both Tourette syndrome and ASD are more common in males, with stereotyped patterns of movements and behaviors; anxious, obsessive, and compulsive behaviors resulting in behavioral rigidities; sensory sensitivities; and increased rates of hyperkinesis with decreased impulse control which result in increased sensory-seeking behaviors. Diagnostic criteria for Tourette syndrome are met when a child has had multiple motor tics and at least one phonic tic present for at least 1 year, with tic-free intervals lasting no longer than 3 months, and with onset before the age of 18. Typically, tics emerge in late preschool and early grade school, and some children even develop repetitive movements as early as toddlerhood. Tics tend to worsen around the peripubertal era, then often generally improve in the teen years. Tic types, frequency, and severity general fluctuate over time.
Forty percent of children with Tourette syndrome also meet criteria for OCD, with many more having OCD traits, and about 65% of children with Tourette syndrome also meet criteria for ADHD, with many more having ADHD traits. OCD can lead to more rigid and directive social interactions in children as well as obsessive interests, just as ADHD can lead to less socially attuned and less cooperative behaviors, even in children who do not meet criteria for ASD.
For example, a child with OCD in the absence of ASD may still “police” other kids in class and be overly focused on the rules of a game, which may become a social liability. Likewise, a child with ADHD in the absence of ASD may be so distractible that focusing on what other kids are saying and their paired facial expressions is compromised, leading to poor-quality social reciprocity during interactions with peers. Given the remarkable overlap in shared symptoms, it is essential for pediatric providers to consider Tourette syndrome in the differential for any child with repetitive movements and behaviors in addition to ASD and a wide array of other neurodevelopment differences, including global developmental delays and intellectual disabilities. This is of particular importance as the diagnosis of Tourette syndrome can be used to gain access to developmental disability services if the condition has resulted in true adaptive impairments.
It is determined that the boy does in fact meet criteria for ADHD, but also for OCD and Tourette syndrome. Both his Autism Diagnostic Observation Schedule and DSM-5–influenced autism interview are found to be in the nonclinical ranges, given his quality of communication, social engagement, imaginative play, and varied interests. A diagnosis of ASD is not felt to be an appropriate conceptualization of his neurodevelopmental differences. He is started on a low dose of guanfacine, which induces a decline in tics, impulsivity, and hyperkinesis. He is given a 504 plan in school that includes scheduled “tic breaks,” sensory fidgets for use in the classroom, extra movement opportunities as needed, and utilization of a gentle cueing system between him and his teacher for low-key redirection of disruptive behaviors. He is no longer penalized for inattention or tics, and his 504 plan protects him from the use of recess removal as a behavioral modification strategy.
His parents enroll him in the community swim program for extra exercise, focus on decreasing screen time, and give him an earlier bedtime to help decrease his tics and rigidities, while improving his ability to self-regulate. Eventually, a low dose of a newer-generation stimulant is added to his guanfacine, with excellent results and only a mild increase in tolerable tics.
The child in the vignette did well with a 504 plan based on his medical diagnoses, though if related learning difficulties had persisted, eligibility under Other Health Impaired could be used to provide eligibility for an Individualized Education Plan. Alpha-agonists can be helpful for symptom control in those with Tourette syndrome by simultaneously treating tics, hyperkinesis, and impulsivity, while decreasing the risk of tic exacerbation with use of stimulants. Overall, understanding the neurodiversity related to Tourette syndrome can help providers advocate for home and community-based supports to optimize general functioning and quality of life.
Dr. Roth is a developmental and behavioral pediatrician in Eugene, Ore. She has no conflicts of interest.
References
Darrow S et al. J Am Acad Child Adolescent Psych. 2017;56(7):610-7.
AAP Section on Developmental and Behavioral Pediatrics. Developmental and Behavioral Pediatrics. Voigt RG et al, eds. 2018: American Academy of Pediatrics.
Tourette syndrome, attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and autism spectrum disorder (ASD) share significant overlap in symptomatology, and it can be challenging at times to distinguish between these conditions. Being able to do so, however, can help guide more targeted interventions and accommodations to optimize a patient’s level of functioning.
Case example
A healthy, bright 6-year-old boy is referred by his family doctor to an academic medical center for a full team evaluation because of suspicion of ASD, after having already been diagnosed with ADHD at the age of 5. His difficulties with inattention, impulsivity, and hyperactivity, as well as his behavioral rigidities and sensory avoidant and sensory seeking behaviors have caused functional impairments for him in his kindergarten classroom. He has been penalized with removal of recess on more than one occasion. A low dose of a stimulant had been tried but resulted in a perceived increase in disruptive behaviors.
The boy, while hyperkinetic and often paying poor attention, is quite capable of high-quality and well-modulated eye contact paired with typical social referencing and reciprocity when actively engaging with the examiner and his parents. He does have a reported history of serial fixated interests and some repetitive behaviors but is also noted to be flexible in his interpersonal style, maintains other varied and typical interests, easily directs affect, utilizes a wide array of fluid gestures paired naturally with verbal communication, and shares enjoyment with smoothly coordinated gaze. He has mild articulation errors but uses pronouns appropriately and has no scripted speech or echolalia, though does engage in some whispered palilalia intermittently.
He is generally quite cooperative and redirectable when focused and has a completely normal physical and neurologic examination. During the visit, the doctor notices the boy making an intermittent honking sound, which parents report as an attention-seeking strategy during times of stress. Further physician-guided information gathering around other repetitive noises and movements elicits a history of engagement in repetitive hand-to-groin movements, some exaggerated blinking, and a number of other waxing and waning subtle motor and phonic tics with onset in preschool. These noises and movements have generally been identified as “fidgeting” and “misbehaving” by well-meaning caregivers in the home and school environments.
Both Tourette syndrome and ASD are more common in males, with stereotyped patterns of movements and behaviors; anxious, obsessive, and compulsive behaviors resulting in behavioral rigidities; sensory sensitivities; and increased rates of hyperkinesis with decreased impulse control which result in increased sensory-seeking behaviors. Diagnostic criteria for Tourette syndrome are met when a child has had multiple motor tics and at least one phonic tic present for at least 1 year, with tic-free intervals lasting no longer than 3 months, and with onset before the age of 18. Typically, tics emerge in late preschool and early grade school, and some children even develop repetitive movements as early as toddlerhood. Tics tend to worsen around the peripubertal era, then often generally improve in the teen years. Tic types, frequency, and severity general fluctuate over time.
Forty percent of children with Tourette syndrome also meet criteria for OCD, with many more having OCD traits, and about 65% of children with Tourette syndrome also meet criteria for ADHD, with many more having ADHD traits. OCD can lead to more rigid and directive social interactions in children as well as obsessive interests, just as ADHD can lead to less socially attuned and less cooperative behaviors, even in children who do not meet criteria for ASD.
For example, a child with OCD in the absence of ASD may still “police” other kids in class and be overly focused on the rules of a game, which may become a social liability. Likewise, a child with ADHD in the absence of ASD may be so distractible that focusing on what other kids are saying and their paired facial expressions is compromised, leading to poor-quality social reciprocity during interactions with peers. Given the remarkable overlap in shared symptoms, it is essential for pediatric providers to consider Tourette syndrome in the differential for any child with repetitive movements and behaviors in addition to ASD and a wide array of other neurodevelopment differences, including global developmental delays and intellectual disabilities. This is of particular importance as the diagnosis of Tourette syndrome can be used to gain access to developmental disability services if the condition has resulted in true adaptive impairments.
It is determined that the boy does in fact meet criteria for ADHD, but also for OCD and Tourette syndrome. Both his Autism Diagnostic Observation Schedule and DSM-5–influenced autism interview are found to be in the nonclinical ranges, given his quality of communication, social engagement, imaginative play, and varied interests. A diagnosis of ASD is not felt to be an appropriate conceptualization of his neurodevelopmental differences. He is started on a low dose of guanfacine, which induces a decline in tics, impulsivity, and hyperkinesis. He is given a 504 plan in school that includes scheduled “tic breaks,” sensory fidgets for use in the classroom, extra movement opportunities as needed, and utilization of a gentle cueing system between him and his teacher for low-key redirection of disruptive behaviors. He is no longer penalized for inattention or tics, and his 504 plan protects him from the use of recess removal as a behavioral modification strategy.
His parents enroll him in the community swim program for extra exercise, focus on decreasing screen time, and give him an earlier bedtime to help decrease his tics and rigidities, while improving his ability to self-regulate. Eventually, a low dose of a newer-generation stimulant is added to his guanfacine, with excellent results and only a mild increase in tolerable tics.
The child in the vignette did well with a 504 plan based on his medical diagnoses, though if related learning difficulties had persisted, eligibility under Other Health Impaired could be used to provide eligibility for an Individualized Education Plan. Alpha-agonists can be helpful for symptom control in those with Tourette syndrome by simultaneously treating tics, hyperkinesis, and impulsivity, while decreasing the risk of tic exacerbation with use of stimulants. Overall, understanding the neurodiversity related to Tourette syndrome can help providers advocate for home and community-based supports to optimize general functioning and quality of life.
Dr. Roth is a developmental and behavioral pediatrician in Eugene, Ore. She has no conflicts of interest.
References
Darrow S et al. J Am Acad Child Adolescent Psych. 2017;56(7):610-7.
AAP Section on Developmental and Behavioral Pediatrics. Developmental and Behavioral Pediatrics. Voigt RG et al, eds. 2018: American Academy of Pediatrics.
Patients differ with providers on definitions for IBD remission
Patients’ reports of remission from inflammatory bowel disease (IBD) don’t always line up with remission as defined by patient-reported outcomes (PROs) or physician global assessment (PGA), according to a study published in Inflammatory Bowel Diseases.
Patients have various definitions of remission, which may focus on symptom improvement and the impact on daily activities, while physicians tend to focus on test results. “Examining patient-reported remission may be a valuable approach to better understand remission from the perspective of patients and can assist in aligning shared decision-making between patients and health care providers,” wrote Kendra Kamp, PhD, assistant professor of biobehavioral nursing and health informatics at the University of Washington, and colleagues, on behalf of the IBD Qorus.
In a retrospective study, Dr. Kamp and colleagues analyzed 3,257 deidentified surveys from 2,004 patients who participated in the Crohn’s and Colitis Foundation’s IBD Qorus Learning Health System between September 2019 and February 2021. Adults with IBD who participated in the IBD Qorus received an email before their gastroenterology clinical appointment with a link to a survey that asked questions about primary concerns or goals, symptoms, well-being, recent health care utilization, and medication use.
The researchers looked at the clinical and demographic factors associated with discordance among patient-defined remission, PROs, and PGAs. Patient-defined remission was captured as a yes/no response to the question: “Do you feel your disease is currently in remission (by remission we mean a complete absence of IBD-related symptoms)?”
PROs for ulcerative colitis were measured through stool frequency and rectal bleeding, with remission defined as no blood in the stool and a normal (or fewer than normal) number of stools. For Crohn’s disease, PROs were measured through the average number of liquid stools, abdominal pain, and general well-being, with remission defined as two or fewer loose stools, no or mild abdominal pain, and feeling generally well or slightly under par.
For PGAs, clinicians selected whether the patient had normal, mild, moderate, or severe disease activity. The values were included in the analysis if the clinicians completed the assessment within 14 days of the patient’s survey.
Among the 2,004 patients, 806 had ulcerative colitis and 1,198 had Crohn’s disease. Patients with ulcerative colitis as well as those with Crohn’s disease were aged 44 years on average. Most of the patients were women: 58% with ulcerative colitis and 56% with Crohn’s disease.
Among the 1,316 visits for ulcerative colitis, 668 patients (51%) self-reported to be in remission, compared with 55% in remission based on PROs. Of the people in PRO–defined remission, 77% reported being in remission, and 23% reported active disease. Of the people with PRO–defined active disease, 81% reported active disease and 19% reported remission. Overall concordance was 79% between patient self-reported and PRO–defined remission.
Discordance in patient-defined remission for ulcerative colitis was primarily influenced by tolerance of an increased stool frequency. About 25% of patients with one or two stools more than normal reported being in remission.
A subset of 397 ulcerative colitis visits had an associated PGA score. Among patients in PGA-defined remission, 53% reported being in remission. Of those with PGA-defined active disease, 60% reported active disease. Overall, concordance was 49% between patient self-reported and PGA-defined remission.
Among the 1,947 visits for Crohn’s disease, 929 patients (48%) self-reported to be in remission, compared with 63% in remission based on PRO. Of the people in PRO-defined remission, 63% reported being in remission, although 37% reported active disease. Of the people with PRO-defined active disease, 79% reported active disease and 21% reported remission. Overall concordance was 69% between patient self-reported and patient-reported outcomes–defined remission.
Discordance in patient-defined remission for Crohn’s disease was primarily influenced by patients with a tolerance of mild to moderate symptoms.
A subset of 575 Crohn’s disease visits had an associated PGA score. Among patients in PGA-defined remission, 52% reported being in remission. Of those with PGA-defined active disease, 57% reported active disease. Overall concordance was 54% between patient self-reported and PGA-defined remission.
Several factors were associated with discordance in remission definitions. Among patients in PRO-defined remission, those who had a diagnosis of IBD for fewer than 5 years were more likely to report having active disease compared with those who had received a diagnosis more than 15 years before.
Patients with high health confidence in managing their condition were less likely to report having active disease. In addition, patients with Crohn’s disease were more likely to report having active disease if they were using prednisone or opioids or if they had an IBD-related emergency department visit in the past 6 months.
“Studies that address the discordance between patient-reported outcomes and clinician assessment in inflammatory bowel disease are important to develop a patient-centered model of practice,” said Sadeea Abbasi, MD, PhD, a gastroenterologist and IBD specialist at Cedars-Sinai Gastroenterology in Santa Monica, Calif.
Dr. Abbasi, who wasn’t involved with this study, has promoted patient advocacy in IBD management.
“Measurable objective data are not the only parameter to measure disease outcomes or individualize treatment protocols. In fact, outcomes can dramatically change if the patient’s experience is not taken into account. Studies that address this reality are crucial for physicians to be able to advocate for their patients,” she said. “The empowered physician-patient relationship is one of strength and trust and tends to be associated with the best overall outcomes.”
IBD Qorus is an initiative of the Crohn’s and Colitis Foundation and is supported by numerous pharmaceutical companies. Supporters had no involvement in the study and didn’t provide direct funding for any aspect of the study. The authors have received funding from the Crohn’s and Colitis Foundation, National Institutes of Health, and various foundations and pharmaceutical companies. Dr. Abbasi reported no relevant disclosures.
Patients’ reports of remission from inflammatory bowel disease (IBD) don’t always line up with remission as defined by patient-reported outcomes (PROs) or physician global assessment (PGA), according to a study published in Inflammatory Bowel Diseases.
Patients have various definitions of remission, which may focus on symptom improvement and the impact on daily activities, while physicians tend to focus on test results. “Examining patient-reported remission may be a valuable approach to better understand remission from the perspective of patients and can assist in aligning shared decision-making between patients and health care providers,” wrote Kendra Kamp, PhD, assistant professor of biobehavioral nursing and health informatics at the University of Washington, and colleagues, on behalf of the IBD Qorus.
In a retrospective study, Dr. Kamp and colleagues analyzed 3,257 deidentified surveys from 2,004 patients who participated in the Crohn’s and Colitis Foundation’s IBD Qorus Learning Health System between September 2019 and February 2021. Adults with IBD who participated in the IBD Qorus received an email before their gastroenterology clinical appointment with a link to a survey that asked questions about primary concerns or goals, symptoms, well-being, recent health care utilization, and medication use.
The researchers looked at the clinical and demographic factors associated with discordance among patient-defined remission, PROs, and PGAs. Patient-defined remission was captured as a yes/no response to the question: “Do you feel your disease is currently in remission (by remission we mean a complete absence of IBD-related symptoms)?”
PROs for ulcerative colitis were measured through stool frequency and rectal bleeding, with remission defined as no blood in the stool and a normal (or fewer than normal) number of stools. For Crohn’s disease, PROs were measured through the average number of liquid stools, abdominal pain, and general well-being, with remission defined as two or fewer loose stools, no or mild abdominal pain, and feeling generally well or slightly under par.
For PGAs, clinicians selected whether the patient had normal, mild, moderate, or severe disease activity. The values were included in the analysis if the clinicians completed the assessment within 14 days of the patient’s survey.
Among the 2,004 patients, 806 had ulcerative colitis and 1,198 had Crohn’s disease. Patients with ulcerative colitis as well as those with Crohn’s disease were aged 44 years on average. Most of the patients were women: 58% with ulcerative colitis and 56% with Crohn’s disease.
Among the 1,316 visits for ulcerative colitis, 668 patients (51%) self-reported to be in remission, compared with 55% in remission based on PROs. Of the people in PRO–defined remission, 77% reported being in remission, and 23% reported active disease. Of the people with PRO–defined active disease, 81% reported active disease and 19% reported remission. Overall concordance was 79% between patient self-reported and PRO–defined remission.
Discordance in patient-defined remission for ulcerative colitis was primarily influenced by tolerance of an increased stool frequency. About 25% of patients with one or two stools more than normal reported being in remission.
A subset of 397 ulcerative colitis visits had an associated PGA score. Among patients in PGA-defined remission, 53% reported being in remission. Of those with PGA-defined active disease, 60% reported active disease. Overall, concordance was 49% between patient self-reported and PGA-defined remission.
Among the 1,947 visits for Crohn’s disease, 929 patients (48%) self-reported to be in remission, compared with 63% in remission based on PRO. Of the people in PRO-defined remission, 63% reported being in remission, although 37% reported active disease. Of the people with PRO-defined active disease, 79% reported active disease and 21% reported remission. Overall concordance was 69% between patient self-reported and patient-reported outcomes–defined remission.
Discordance in patient-defined remission for Crohn’s disease was primarily influenced by patients with a tolerance of mild to moderate symptoms.
A subset of 575 Crohn’s disease visits had an associated PGA score. Among patients in PGA-defined remission, 52% reported being in remission. Of those with PGA-defined active disease, 57% reported active disease. Overall concordance was 54% between patient self-reported and PGA-defined remission.
Several factors were associated with discordance in remission definitions. Among patients in PRO-defined remission, those who had a diagnosis of IBD for fewer than 5 years were more likely to report having active disease compared with those who had received a diagnosis more than 15 years before.
Patients with high health confidence in managing their condition were less likely to report having active disease. In addition, patients with Crohn’s disease were more likely to report having active disease if they were using prednisone or opioids or if they had an IBD-related emergency department visit in the past 6 months.
“Studies that address the discordance between patient-reported outcomes and clinician assessment in inflammatory bowel disease are important to develop a patient-centered model of practice,” said Sadeea Abbasi, MD, PhD, a gastroenterologist and IBD specialist at Cedars-Sinai Gastroenterology in Santa Monica, Calif.
Dr. Abbasi, who wasn’t involved with this study, has promoted patient advocacy in IBD management.
“Measurable objective data are not the only parameter to measure disease outcomes or individualize treatment protocols. In fact, outcomes can dramatically change if the patient’s experience is not taken into account. Studies that address this reality are crucial for physicians to be able to advocate for their patients,” she said. “The empowered physician-patient relationship is one of strength and trust and tends to be associated with the best overall outcomes.”
IBD Qorus is an initiative of the Crohn’s and Colitis Foundation and is supported by numerous pharmaceutical companies. Supporters had no involvement in the study and didn’t provide direct funding for any aspect of the study. The authors have received funding from the Crohn’s and Colitis Foundation, National Institutes of Health, and various foundations and pharmaceutical companies. Dr. Abbasi reported no relevant disclosures.
Patients’ reports of remission from inflammatory bowel disease (IBD) don’t always line up with remission as defined by patient-reported outcomes (PROs) or physician global assessment (PGA), according to a study published in Inflammatory Bowel Diseases.
Patients have various definitions of remission, which may focus on symptom improvement and the impact on daily activities, while physicians tend to focus on test results. “Examining patient-reported remission may be a valuable approach to better understand remission from the perspective of patients and can assist in aligning shared decision-making between patients and health care providers,” wrote Kendra Kamp, PhD, assistant professor of biobehavioral nursing and health informatics at the University of Washington, and colleagues, on behalf of the IBD Qorus.
In a retrospective study, Dr. Kamp and colleagues analyzed 3,257 deidentified surveys from 2,004 patients who participated in the Crohn’s and Colitis Foundation’s IBD Qorus Learning Health System between September 2019 and February 2021. Adults with IBD who participated in the IBD Qorus received an email before their gastroenterology clinical appointment with a link to a survey that asked questions about primary concerns or goals, symptoms, well-being, recent health care utilization, and medication use.
The researchers looked at the clinical and demographic factors associated with discordance among patient-defined remission, PROs, and PGAs. Patient-defined remission was captured as a yes/no response to the question: “Do you feel your disease is currently in remission (by remission we mean a complete absence of IBD-related symptoms)?”
PROs for ulcerative colitis were measured through stool frequency and rectal bleeding, with remission defined as no blood in the stool and a normal (or fewer than normal) number of stools. For Crohn’s disease, PROs were measured through the average number of liquid stools, abdominal pain, and general well-being, with remission defined as two or fewer loose stools, no or mild abdominal pain, and feeling generally well or slightly under par.
For PGAs, clinicians selected whether the patient had normal, mild, moderate, or severe disease activity. The values were included in the analysis if the clinicians completed the assessment within 14 days of the patient’s survey.
Among the 2,004 patients, 806 had ulcerative colitis and 1,198 had Crohn’s disease. Patients with ulcerative colitis as well as those with Crohn’s disease were aged 44 years on average. Most of the patients were women: 58% with ulcerative colitis and 56% with Crohn’s disease.
Among the 1,316 visits for ulcerative colitis, 668 patients (51%) self-reported to be in remission, compared with 55% in remission based on PROs. Of the people in PRO–defined remission, 77% reported being in remission, and 23% reported active disease. Of the people with PRO–defined active disease, 81% reported active disease and 19% reported remission. Overall concordance was 79% between patient self-reported and PRO–defined remission.
Discordance in patient-defined remission for ulcerative colitis was primarily influenced by tolerance of an increased stool frequency. About 25% of patients with one or two stools more than normal reported being in remission.
A subset of 397 ulcerative colitis visits had an associated PGA score. Among patients in PGA-defined remission, 53% reported being in remission. Of those with PGA-defined active disease, 60% reported active disease. Overall, concordance was 49% between patient self-reported and PGA-defined remission.
Among the 1,947 visits for Crohn’s disease, 929 patients (48%) self-reported to be in remission, compared with 63% in remission based on PRO. Of the people in PRO-defined remission, 63% reported being in remission, although 37% reported active disease. Of the people with PRO-defined active disease, 79% reported active disease and 21% reported remission. Overall concordance was 69% between patient self-reported and patient-reported outcomes–defined remission.
Discordance in patient-defined remission for Crohn’s disease was primarily influenced by patients with a tolerance of mild to moderate symptoms.
A subset of 575 Crohn’s disease visits had an associated PGA score. Among patients in PGA-defined remission, 52% reported being in remission. Of those with PGA-defined active disease, 57% reported active disease. Overall concordance was 54% between patient self-reported and PGA-defined remission.
Several factors were associated with discordance in remission definitions. Among patients in PRO-defined remission, those who had a diagnosis of IBD for fewer than 5 years were more likely to report having active disease compared with those who had received a diagnosis more than 15 years before.
Patients with high health confidence in managing their condition were less likely to report having active disease. In addition, patients with Crohn’s disease were more likely to report having active disease if they were using prednisone or opioids or if they had an IBD-related emergency department visit in the past 6 months.
“Studies that address the discordance between patient-reported outcomes and clinician assessment in inflammatory bowel disease are important to develop a patient-centered model of practice,” said Sadeea Abbasi, MD, PhD, a gastroenterologist and IBD specialist at Cedars-Sinai Gastroenterology in Santa Monica, Calif.
Dr. Abbasi, who wasn’t involved with this study, has promoted patient advocacy in IBD management.
“Measurable objective data are not the only parameter to measure disease outcomes or individualize treatment protocols. In fact, outcomes can dramatically change if the patient’s experience is not taken into account. Studies that address this reality are crucial for physicians to be able to advocate for their patients,” she said. “The empowered physician-patient relationship is one of strength and trust and tends to be associated with the best overall outcomes.”
IBD Qorus is an initiative of the Crohn’s and Colitis Foundation and is supported by numerous pharmaceutical companies. Supporters had no involvement in the study and didn’t provide direct funding for any aspect of the study. The authors have received funding from the Crohn’s and Colitis Foundation, National Institutes of Health, and various foundations and pharmaceutical companies. Dr. Abbasi reported no relevant disclosures.
FROM INFLAMMATORY BOWEL DISEASES
The WPATH guidelines for treatment of adolescents with gender dysphoria have changed
The World Professional Association for Transgender Health (WPATH) is an interdisciplinary professional and educational organization devoted to transgender health. One of their activities is to produce the Standards of Care (SOC) for treatment of individuals with gender dysphoria. According to WPATH, the SOC “articulate a professional consensus about the psychiatric, psychological, medical, and surgical management of gender dysphoria and help professionals understand the parameters within which they may offer assistance to those with these conditions.” Many clinicians around the world use these guidelines to help them care for patients with gender dysphoria and diverse gender expressions.
The most recent SOC, version 8, were released on Sept. 15, 2022, after a 2-year postponement because of the pandemic. These new standards represent the first update to the SOC since version 7, which was released in 2012. Given how recent this update is, this column will attempt to summarize the changes in the new guidelines that affect children and adolescents.
One of the major differences between SOC versions 7 and 8 is that version 8 now includes a chapter specifically dedicated to the care of adolescents. Version 7 lumped children and adolescents together into one chapter. This is an important distinction for SOC 8, as it highlights that care for prepubertal youth is simply social in nature and distinct from that of pubertal adolescents. Social transition includes things such as using an affirmed name/pronouns and changing hair style and clothes. It does not include medications of any kind. Allowing these youth the time and space to explore the natural gender diversity of childhood leads to improved psychological outcomes over time and reduces adversity. Psychological support, where indicated, should be offered to gender-diverse children and their families to explore the persistence, consistence, and insistence of that child’s gender identity.
Once a child reaches puberty, medications may come into play as part of an adolescent’s transition. SOC 7 had established a minimum age of 16 before any partially reversible medications (testosterone, estrogen) were started as part of a patient’s medical transition. Starting with SOC 8, a minimum age has been removed for the initiation of gender-affirming hormone therapy. However, a patient must still have begun their natal puberty before any medication is started. A specific age was removed to acknowledge that maturity in adolescents occurs on a continuum and at different ages. SOC 8 guidelines continue to recommend that the individual’s emotional, cognitive, and psychosocial development be taken into account when determining their ability to provide consent for treatment. These individuals should still undergo a comprehensive assessment, as described below.
Similar to SOC 7, SOC 8 continues to stress the importance of a comprehensive, multidisciplinary evaluation of those adolescents who seek medical therapy as part of their transition. This allows for the exploration of additional coexisting causes of gender dysphoria, such as anxiety, depression, or other mental health conditions. If these exist, then they must be appropriately treated before any gender-affirming medical treatment is initiated. Assessments should be performed by clinicians who have training and expertise with the developmental trajectory of adolescents, as well as with common mental health conditions. These assessments are also critical, as SOC 8 acknowledges a rise in the number of adolescents who may not have had gender-diverse expression in childhood.
SOC 8 and the Endocrine Society Guidelines (see references) provide physicians and other health care professionals with a road map for addressing the needs of transgender and gender-diverse persons. By referencing these guidelines when taking care of these patients, physicians and other health care professionals will know that they are providing the most up-to-date, evidence-based care.
Dr. M. Brett Cooper is an assistant professor of pediatrics at University of Texas Southwestern, Dallas, and an adolescent medicine specialist at Children’s Medical Center Dallas.
References
SOC 8: https://www.tandfonline.com/doi/pdf/10.1080/26895269.2022.2100644
SOC 7: https://www.wpath.org/media/cms/Documents/SOC%20v7/SOC%20V7_English2012.pdf?_t=1613669341
Endocrine Society Gender Affirming Care Guidelines: https://academic.oup.com/jcem/article/102/11/3869/4157558?login=false
The World Professional Association for Transgender Health (WPATH) is an interdisciplinary professional and educational organization devoted to transgender health. One of their activities is to produce the Standards of Care (SOC) for treatment of individuals with gender dysphoria. According to WPATH, the SOC “articulate a professional consensus about the psychiatric, psychological, medical, and surgical management of gender dysphoria and help professionals understand the parameters within which they may offer assistance to those with these conditions.” Many clinicians around the world use these guidelines to help them care for patients with gender dysphoria and diverse gender expressions.
The most recent SOC, version 8, were released on Sept. 15, 2022, after a 2-year postponement because of the pandemic. These new standards represent the first update to the SOC since version 7, which was released in 2012. Given how recent this update is, this column will attempt to summarize the changes in the new guidelines that affect children and adolescents.
One of the major differences between SOC versions 7 and 8 is that version 8 now includes a chapter specifically dedicated to the care of adolescents. Version 7 lumped children and adolescents together into one chapter. This is an important distinction for SOC 8, as it highlights that care for prepubertal youth is simply social in nature and distinct from that of pubertal adolescents. Social transition includes things such as using an affirmed name/pronouns and changing hair style and clothes. It does not include medications of any kind. Allowing these youth the time and space to explore the natural gender diversity of childhood leads to improved psychological outcomes over time and reduces adversity. Psychological support, where indicated, should be offered to gender-diverse children and their families to explore the persistence, consistence, and insistence of that child’s gender identity.
Once a child reaches puberty, medications may come into play as part of an adolescent’s transition. SOC 7 had established a minimum age of 16 before any partially reversible medications (testosterone, estrogen) were started as part of a patient’s medical transition. Starting with SOC 8, a minimum age has been removed for the initiation of gender-affirming hormone therapy. However, a patient must still have begun their natal puberty before any medication is started. A specific age was removed to acknowledge that maturity in adolescents occurs on a continuum and at different ages. SOC 8 guidelines continue to recommend that the individual’s emotional, cognitive, and psychosocial development be taken into account when determining their ability to provide consent for treatment. These individuals should still undergo a comprehensive assessment, as described below.
Similar to SOC 7, SOC 8 continues to stress the importance of a comprehensive, multidisciplinary evaluation of those adolescents who seek medical therapy as part of their transition. This allows for the exploration of additional coexisting causes of gender dysphoria, such as anxiety, depression, or other mental health conditions. If these exist, then they must be appropriately treated before any gender-affirming medical treatment is initiated. Assessments should be performed by clinicians who have training and expertise with the developmental trajectory of adolescents, as well as with common mental health conditions. These assessments are also critical, as SOC 8 acknowledges a rise in the number of adolescents who may not have had gender-diverse expression in childhood.
SOC 8 and the Endocrine Society Guidelines (see references) provide physicians and other health care professionals with a road map for addressing the needs of transgender and gender-diverse persons. By referencing these guidelines when taking care of these patients, physicians and other health care professionals will know that they are providing the most up-to-date, evidence-based care.
Dr. M. Brett Cooper is an assistant professor of pediatrics at University of Texas Southwestern, Dallas, and an adolescent medicine specialist at Children’s Medical Center Dallas.
References
SOC 8: https://www.tandfonline.com/doi/pdf/10.1080/26895269.2022.2100644
SOC 7: https://www.wpath.org/media/cms/Documents/SOC%20v7/SOC%20V7_English2012.pdf?_t=1613669341
Endocrine Society Gender Affirming Care Guidelines: https://academic.oup.com/jcem/article/102/11/3869/4157558?login=false
The World Professional Association for Transgender Health (WPATH) is an interdisciplinary professional and educational organization devoted to transgender health. One of their activities is to produce the Standards of Care (SOC) for treatment of individuals with gender dysphoria. According to WPATH, the SOC “articulate a professional consensus about the psychiatric, psychological, medical, and surgical management of gender dysphoria and help professionals understand the parameters within which they may offer assistance to those with these conditions.” Many clinicians around the world use these guidelines to help them care for patients with gender dysphoria and diverse gender expressions.
The most recent SOC, version 8, were released on Sept. 15, 2022, after a 2-year postponement because of the pandemic. These new standards represent the first update to the SOC since version 7, which was released in 2012. Given how recent this update is, this column will attempt to summarize the changes in the new guidelines that affect children and adolescents.
One of the major differences between SOC versions 7 and 8 is that version 8 now includes a chapter specifically dedicated to the care of adolescents. Version 7 lumped children and adolescents together into one chapter. This is an important distinction for SOC 8, as it highlights that care for prepubertal youth is simply social in nature and distinct from that of pubertal adolescents. Social transition includes things such as using an affirmed name/pronouns and changing hair style and clothes. It does not include medications of any kind. Allowing these youth the time and space to explore the natural gender diversity of childhood leads to improved psychological outcomes over time and reduces adversity. Psychological support, where indicated, should be offered to gender-diverse children and their families to explore the persistence, consistence, and insistence of that child’s gender identity.
Once a child reaches puberty, medications may come into play as part of an adolescent’s transition. SOC 7 had established a minimum age of 16 before any partially reversible medications (testosterone, estrogen) were started as part of a patient’s medical transition. Starting with SOC 8, a minimum age has been removed for the initiation of gender-affirming hormone therapy. However, a patient must still have begun their natal puberty before any medication is started. A specific age was removed to acknowledge that maturity in adolescents occurs on a continuum and at different ages. SOC 8 guidelines continue to recommend that the individual’s emotional, cognitive, and psychosocial development be taken into account when determining their ability to provide consent for treatment. These individuals should still undergo a comprehensive assessment, as described below.
Similar to SOC 7, SOC 8 continues to stress the importance of a comprehensive, multidisciplinary evaluation of those adolescents who seek medical therapy as part of their transition. This allows for the exploration of additional coexisting causes of gender dysphoria, such as anxiety, depression, or other mental health conditions. If these exist, then they must be appropriately treated before any gender-affirming medical treatment is initiated. Assessments should be performed by clinicians who have training and expertise with the developmental trajectory of adolescents, as well as with common mental health conditions. These assessments are also critical, as SOC 8 acknowledges a rise in the number of adolescents who may not have had gender-diverse expression in childhood.
SOC 8 and the Endocrine Society Guidelines (see references) provide physicians and other health care professionals with a road map for addressing the needs of transgender and gender-diverse persons. By referencing these guidelines when taking care of these patients, physicians and other health care professionals will know that they are providing the most up-to-date, evidence-based care.
Dr. M. Brett Cooper is an assistant professor of pediatrics at University of Texas Southwestern, Dallas, and an adolescent medicine specialist at Children’s Medical Center Dallas.
References
SOC 8: https://www.tandfonline.com/doi/pdf/10.1080/26895269.2022.2100644
SOC 7: https://www.wpath.org/media/cms/Documents/SOC%20v7/SOC%20V7_English2012.pdf?_t=1613669341
Endocrine Society Gender Affirming Care Guidelines: https://academic.oup.com/jcem/article/102/11/3869/4157558?login=false
Climate change: Commentary in four dermatology journals calls for emergency action
“moving beyond merely discussing skin-related impacts” and toward prioritizing both patient and planetary health.
Dermatologists must make emissions-saving changes in everyday practice, for instance, and the specialty must enlist key stakeholders in public health, nonprofits, and industry – that is, pharmaceutical and medical supply companies – in finding solutions to help mitigate and adapt to climate change, wrote Eva Rawlings Parker, MD, and Markus D. Boos, MD, PhD.
“We have an ethical imperative to act,” they wrote. “The time is now for dermatologists and our medical societies to collectively rise to meet this crisis.”
Their commentary was published online in the International Journal of Dermatology , Journal of the European Academy of Dermatology and Venereology, British Journal of Dermatology, and Pediatric Dermatology.
In an interview, Dr. Parker, assistant professor of dermatology at Vanderbilt University, Nashville, Tenn., said that she and Dr. Boos, associate professor in the division of dermatology and department of pediatrics at the University of Washington, Seattle, were motivated to write the editorial upon finding that dermatology was not represented among more than 230 medical journals that published an editorial in September 2021 calling for emergency action to limit global warming and protect health. In addition to the New England Journal of Medicine and The Lancet, the copublishing journals represented numerous specialties, from nursing and pediatrics, to cardiology, rheumatology, and gastroenterology.
The editorial was not published in any dermatology journals, Dr. Parker said. “It was incredibly disappointing for me along with many of my colleagues who advocate for climate action because we realized it was a missed opportunity for dermatology to align with other medical specialties and be on the forefront of leading climate action to protect health.”
‘A threat multiplier’
The impact of climate change on skin disease is “an incredibly important part of our conversation as dermatologists because many cutaneous diseases are climate sensitive and we’re often seeing the effects of climate change every day in our clinical practices,” Dr. Parker said.
In fact, the impact on skin disease needs to be explored much further through more robust research funding, so that dermatology can better understand not only the incidence and severity of climate-induced changes in skin diseases – including and beyond atopic dermatitis, acne, and psoriasis – but also the mechanisms and pathophysiology involved, she said.
However, the impacts are much broader, she and Dr. Boos, a pediatric dermatologist at Seattle Children’s Hospital, maintain in their commentary. “An essential concept to broker among dermatologists is that the impacts of climate change extend well beyond skin disease by also placing broad pressure” on infrastructure, the economy, financial markets, global supply chains, food and water insecurity, and more, they wrote, noting the deep inequities of climate change.
Climate change is a “threat multiplier for public health, equity, and health systems,” the commentary says. “The confluence of these climate-related pressures should sound alarm bells as they place enormous jeopardy on the practice of dermatology across all scales and regions.”
Health care is among the most carbon-intensive service sectors worldwide, contributing to almost 5% of greenhouse gas emissions globally, the commentary says. And nationally, of the estimated greenhouse gas emissions from the United States, the health care sector contributes 10%, Dr. Parker said in the interview, referring to a 2016 report.
In addition, according to a 2019 report, the United States is the top contributor to health care’s global climate footprint, contributing 27% of health care’s global emissions, Dr. Parker noted.
In their commentary, she and Dr. Boos wrote that individually and practice wide, dermatologists can impact decarbonization through measures such as virtual attendance at medical meetings and greater utilization of telehealth services. Reductions in carbon emissions were demonstrated for virtual isotretinoin follow-up visits in a recent study, and these savings could be extrapolated to other routine follow-up visits for conditions such as rosacea, monitoring of biologics in patients with well-controlled disease, and postoperative wound checks, they said.
But when it comes to measures such as significantly reducing packaging and waste and “curating supply chains to make them more sustainable,” it is medical societies that have the “larger voice and broader relationship with the pharmaceutical industry” and with medical supply manufacturers and distributors, Dr. Parker explained in the interview, noting the potential for reducing the extensive amount of packaging used for drug samples.
Dr. Parker cochairs the American Academy of Dermatology’s Expert Resource Group for Climate Change and Environmental Issues, which was established several years ago, and Dr. Boos is a member of the group’s executive committee.
AAD actions
In its 2018 Position Statement on Climate and Health, the American Academy of Dermatology resolved to raise awareness of the effects of climate change on the skin and educate patients about this, and to “work with other medical societies in ongoing and future efforts to educate the public and mitigate the effects of climate change on global health.”
Asked about the commentary’s call for more collaboration with industry and other stakeholders – and the impact that organized dermatology can have on planetary health – Mark D. Kaufmann, MD, president of the AAD, said in an email that the AAD is “first and foremost an organization focused on providing gold-standard educational resources for dermatologists.”
The academy recognizes that “there are many dermatologic consequences of climate change that will increasingly affect our patients and challenge our membership,” and it has provided education on climate change in forums such as articles, podcasts, and sessions at AAD meetings, said Dr. Kaufmann, clinical professor in the department of dermatology, Icahn School of Medicine at Mount Sinai, New York.
Regarding collaboration with other societies, he said that the AAD’s “focus to date has been on how to provide our members with educational resources to understand and prepare for how climate change may impact their practices and the dermatologic health of their patients,” he said.
The AAD has also sought to address its own carbon footprint and improve sustainability of its operations, including taking steps to reduce plastic and paper waste at its educational events, and to eliminate plastic waste associated with mailing resources like its member magazine, Dr. Kaufmann noted.
And in keeping with the Academy pledge – also articulated in the 2018 position statement – to support and facilitate dermatologists’ efforts to decrease their carbon footprint “in a cost effective (or cost-saving) manner,” Dr. Kaufmann said that the AAD has been offering a program called My Green Doctor as a free benefit of membership.
‘Be part of the solution’
In an interview, Mary E. Maloney, MD, professor of medicine and director of dermatologic surgery at the University of Massachusetts, Worcester, said her practice did an audit of their surgical area and found ways to increase the use of paper-packaged gauze – and decrease use of gauze in hard plastic containers – and otherwise decrease the amount of disposables, all of which take “huge amounts of resources” to create.
In the process, “we found significant savings,” she said. “Little things can turn out, in the long run, to be big things.”
Asked about the commentary, Dr. Maloney, who is involved in the AAD’s climate change resource group, said “the message is that yes, we need to be aware of the diseases affected by climate change. But our greater imperative is to be part of the solution and not part of the problem as far as doing things that affect climate change.”
Organized dermatology needs to broaden its advocacy, she said. “I don’t want us to stop advocating for things for our patients, but I do want us to start advocating for the world ... If we don’t try to [mitigate] climate change, we won’t have patients to advocate for.”
Dr. Parker, an associate editor of The Journal of Climate Change and Health, and Dr. Boos declared no conflicts of interest and no funding source for their commentary. Dr. Maloney said she has no conflicts of interest.
“moving beyond merely discussing skin-related impacts” and toward prioritizing both patient and planetary health.
Dermatologists must make emissions-saving changes in everyday practice, for instance, and the specialty must enlist key stakeholders in public health, nonprofits, and industry – that is, pharmaceutical and medical supply companies – in finding solutions to help mitigate and adapt to climate change, wrote Eva Rawlings Parker, MD, and Markus D. Boos, MD, PhD.
“We have an ethical imperative to act,” they wrote. “The time is now for dermatologists and our medical societies to collectively rise to meet this crisis.”
Their commentary was published online in the International Journal of Dermatology , Journal of the European Academy of Dermatology and Venereology, British Journal of Dermatology, and Pediatric Dermatology.
In an interview, Dr. Parker, assistant professor of dermatology at Vanderbilt University, Nashville, Tenn., said that she and Dr. Boos, associate professor in the division of dermatology and department of pediatrics at the University of Washington, Seattle, were motivated to write the editorial upon finding that dermatology was not represented among more than 230 medical journals that published an editorial in September 2021 calling for emergency action to limit global warming and protect health. In addition to the New England Journal of Medicine and The Lancet, the copublishing journals represented numerous specialties, from nursing and pediatrics, to cardiology, rheumatology, and gastroenterology.
The editorial was not published in any dermatology journals, Dr. Parker said. “It was incredibly disappointing for me along with many of my colleagues who advocate for climate action because we realized it was a missed opportunity for dermatology to align with other medical specialties and be on the forefront of leading climate action to protect health.”
‘A threat multiplier’
The impact of climate change on skin disease is “an incredibly important part of our conversation as dermatologists because many cutaneous diseases are climate sensitive and we’re often seeing the effects of climate change every day in our clinical practices,” Dr. Parker said.
In fact, the impact on skin disease needs to be explored much further through more robust research funding, so that dermatology can better understand not only the incidence and severity of climate-induced changes in skin diseases – including and beyond atopic dermatitis, acne, and psoriasis – but also the mechanisms and pathophysiology involved, she said.
However, the impacts are much broader, she and Dr. Boos, a pediatric dermatologist at Seattle Children’s Hospital, maintain in their commentary. “An essential concept to broker among dermatologists is that the impacts of climate change extend well beyond skin disease by also placing broad pressure” on infrastructure, the economy, financial markets, global supply chains, food and water insecurity, and more, they wrote, noting the deep inequities of climate change.
Climate change is a “threat multiplier for public health, equity, and health systems,” the commentary says. “The confluence of these climate-related pressures should sound alarm bells as they place enormous jeopardy on the practice of dermatology across all scales and regions.”
Health care is among the most carbon-intensive service sectors worldwide, contributing to almost 5% of greenhouse gas emissions globally, the commentary says. And nationally, of the estimated greenhouse gas emissions from the United States, the health care sector contributes 10%, Dr. Parker said in the interview, referring to a 2016 report.
In addition, according to a 2019 report, the United States is the top contributor to health care’s global climate footprint, contributing 27% of health care’s global emissions, Dr. Parker noted.
In their commentary, she and Dr. Boos wrote that individually and practice wide, dermatologists can impact decarbonization through measures such as virtual attendance at medical meetings and greater utilization of telehealth services. Reductions in carbon emissions were demonstrated for virtual isotretinoin follow-up visits in a recent study, and these savings could be extrapolated to other routine follow-up visits for conditions such as rosacea, monitoring of biologics in patients with well-controlled disease, and postoperative wound checks, they said.
But when it comes to measures such as significantly reducing packaging and waste and “curating supply chains to make them more sustainable,” it is medical societies that have the “larger voice and broader relationship with the pharmaceutical industry” and with medical supply manufacturers and distributors, Dr. Parker explained in the interview, noting the potential for reducing the extensive amount of packaging used for drug samples.
Dr. Parker cochairs the American Academy of Dermatology’s Expert Resource Group for Climate Change and Environmental Issues, which was established several years ago, and Dr. Boos is a member of the group’s executive committee.
AAD actions
In its 2018 Position Statement on Climate and Health, the American Academy of Dermatology resolved to raise awareness of the effects of climate change on the skin and educate patients about this, and to “work with other medical societies in ongoing and future efforts to educate the public and mitigate the effects of climate change on global health.”
Asked about the commentary’s call for more collaboration with industry and other stakeholders – and the impact that organized dermatology can have on planetary health – Mark D. Kaufmann, MD, president of the AAD, said in an email that the AAD is “first and foremost an organization focused on providing gold-standard educational resources for dermatologists.”
The academy recognizes that “there are many dermatologic consequences of climate change that will increasingly affect our patients and challenge our membership,” and it has provided education on climate change in forums such as articles, podcasts, and sessions at AAD meetings, said Dr. Kaufmann, clinical professor in the department of dermatology, Icahn School of Medicine at Mount Sinai, New York.
Regarding collaboration with other societies, he said that the AAD’s “focus to date has been on how to provide our members with educational resources to understand and prepare for how climate change may impact their practices and the dermatologic health of their patients,” he said.
The AAD has also sought to address its own carbon footprint and improve sustainability of its operations, including taking steps to reduce plastic and paper waste at its educational events, and to eliminate plastic waste associated with mailing resources like its member magazine, Dr. Kaufmann noted.
And in keeping with the Academy pledge – also articulated in the 2018 position statement – to support and facilitate dermatologists’ efforts to decrease their carbon footprint “in a cost effective (or cost-saving) manner,” Dr. Kaufmann said that the AAD has been offering a program called My Green Doctor as a free benefit of membership.
‘Be part of the solution’
In an interview, Mary E. Maloney, MD, professor of medicine and director of dermatologic surgery at the University of Massachusetts, Worcester, said her practice did an audit of their surgical area and found ways to increase the use of paper-packaged gauze – and decrease use of gauze in hard plastic containers – and otherwise decrease the amount of disposables, all of which take “huge amounts of resources” to create.
In the process, “we found significant savings,” she said. “Little things can turn out, in the long run, to be big things.”
Asked about the commentary, Dr. Maloney, who is involved in the AAD’s climate change resource group, said “the message is that yes, we need to be aware of the diseases affected by climate change. But our greater imperative is to be part of the solution and not part of the problem as far as doing things that affect climate change.”
Organized dermatology needs to broaden its advocacy, she said. “I don’t want us to stop advocating for things for our patients, but I do want us to start advocating for the world ... If we don’t try to [mitigate] climate change, we won’t have patients to advocate for.”
Dr. Parker, an associate editor of The Journal of Climate Change and Health, and Dr. Boos declared no conflicts of interest and no funding source for their commentary. Dr. Maloney said she has no conflicts of interest.
“moving beyond merely discussing skin-related impacts” and toward prioritizing both patient and planetary health.
Dermatologists must make emissions-saving changes in everyday practice, for instance, and the specialty must enlist key stakeholders in public health, nonprofits, and industry – that is, pharmaceutical and medical supply companies – in finding solutions to help mitigate and adapt to climate change, wrote Eva Rawlings Parker, MD, and Markus D. Boos, MD, PhD.
“We have an ethical imperative to act,” they wrote. “The time is now for dermatologists and our medical societies to collectively rise to meet this crisis.”
Their commentary was published online in the International Journal of Dermatology , Journal of the European Academy of Dermatology and Venereology, British Journal of Dermatology, and Pediatric Dermatology.
In an interview, Dr. Parker, assistant professor of dermatology at Vanderbilt University, Nashville, Tenn., said that she and Dr. Boos, associate professor in the division of dermatology and department of pediatrics at the University of Washington, Seattle, were motivated to write the editorial upon finding that dermatology was not represented among more than 230 medical journals that published an editorial in September 2021 calling for emergency action to limit global warming and protect health. In addition to the New England Journal of Medicine and The Lancet, the copublishing journals represented numerous specialties, from nursing and pediatrics, to cardiology, rheumatology, and gastroenterology.
The editorial was not published in any dermatology journals, Dr. Parker said. “It was incredibly disappointing for me along with many of my colleagues who advocate for climate action because we realized it was a missed opportunity for dermatology to align with other medical specialties and be on the forefront of leading climate action to protect health.”
‘A threat multiplier’
The impact of climate change on skin disease is “an incredibly important part of our conversation as dermatologists because many cutaneous diseases are climate sensitive and we’re often seeing the effects of climate change every day in our clinical practices,” Dr. Parker said.
In fact, the impact on skin disease needs to be explored much further through more robust research funding, so that dermatology can better understand not only the incidence and severity of climate-induced changes in skin diseases – including and beyond atopic dermatitis, acne, and psoriasis – but also the mechanisms and pathophysiology involved, she said.
However, the impacts are much broader, she and Dr. Boos, a pediatric dermatologist at Seattle Children’s Hospital, maintain in their commentary. “An essential concept to broker among dermatologists is that the impacts of climate change extend well beyond skin disease by also placing broad pressure” on infrastructure, the economy, financial markets, global supply chains, food and water insecurity, and more, they wrote, noting the deep inequities of climate change.
Climate change is a “threat multiplier for public health, equity, and health systems,” the commentary says. “The confluence of these climate-related pressures should sound alarm bells as they place enormous jeopardy on the practice of dermatology across all scales and regions.”
Health care is among the most carbon-intensive service sectors worldwide, contributing to almost 5% of greenhouse gas emissions globally, the commentary says. And nationally, of the estimated greenhouse gas emissions from the United States, the health care sector contributes 10%, Dr. Parker said in the interview, referring to a 2016 report.
In addition, according to a 2019 report, the United States is the top contributor to health care’s global climate footprint, contributing 27% of health care’s global emissions, Dr. Parker noted.
In their commentary, she and Dr. Boos wrote that individually and practice wide, dermatologists can impact decarbonization through measures such as virtual attendance at medical meetings and greater utilization of telehealth services. Reductions in carbon emissions were demonstrated for virtual isotretinoin follow-up visits in a recent study, and these savings could be extrapolated to other routine follow-up visits for conditions such as rosacea, monitoring of biologics in patients with well-controlled disease, and postoperative wound checks, they said.
But when it comes to measures such as significantly reducing packaging and waste and “curating supply chains to make them more sustainable,” it is medical societies that have the “larger voice and broader relationship with the pharmaceutical industry” and with medical supply manufacturers and distributors, Dr. Parker explained in the interview, noting the potential for reducing the extensive amount of packaging used for drug samples.
Dr. Parker cochairs the American Academy of Dermatology’s Expert Resource Group for Climate Change and Environmental Issues, which was established several years ago, and Dr. Boos is a member of the group’s executive committee.
AAD actions
In its 2018 Position Statement on Climate and Health, the American Academy of Dermatology resolved to raise awareness of the effects of climate change on the skin and educate patients about this, and to “work with other medical societies in ongoing and future efforts to educate the public and mitigate the effects of climate change on global health.”
Asked about the commentary’s call for more collaboration with industry and other stakeholders – and the impact that organized dermatology can have on planetary health – Mark D. Kaufmann, MD, president of the AAD, said in an email that the AAD is “first and foremost an organization focused on providing gold-standard educational resources for dermatologists.”
The academy recognizes that “there are many dermatologic consequences of climate change that will increasingly affect our patients and challenge our membership,” and it has provided education on climate change in forums such as articles, podcasts, and sessions at AAD meetings, said Dr. Kaufmann, clinical professor in the department of dermatology, Icahn School of Medicine at Mount Sinai, New York.
Regarding collaboration with other societies, he said that the AAD’s “focus to date has been on how to provide our members with educational resources to understand and prepare for how climate change may impact their practices and the dermatologic health of their patients,” he said.
The AAD has also sought to address its own carbon footprint and improve sustainability of its operations, including taking steps to reduce plastic and paper waste at its educational events, and to eliminate plastic waste associated with mailing resources like its member magazine, Dr. Kaufmann noted.
And in keeping with the Academy pledge – also articulated in the 2018 position statement – to support and facilitate dermatologists’ efforts to decrease their carbon footprint “in a cost effective (or cost-saving) manner,” Dr. Kaufmann said that the AAD has been offering a program called My Green Doctor as a free benefit of membership.
‘Be part of the solution’
In an interview, Mary E. Maloney, MD, professor of medicine and director of dermatologic surgery at the University of Massachusetts, Worcester, said her practice did an audit of their surgical area and found ways to increase the use of paper-packaged gauze – and decrease use of gauze in hard plastic containers – and otherwise decrease the amount of disposables, all of which take “huge amounts of resources” to create.
In the process, “we found significant savings,” she said. “Little things can turn out, in the long run, to be big things.”
Asked about the commentary, Dr. Maloney, who is involved in the AAD’s climate change resource group, said “the message is that yes, we need to be aware of the diseases affected by climate change. But our greater imperative is to be part of the solution and not part of the problem as far as doing things that affect climate change.”
Organized dermatology needs to broaden its advocacy, she said. “I don’t want us to stop advocating for things for our patients, but I do want us to start advocating for the world ... If we don’t try to [mitigate] climate change, we won’t have patients to advocate for.”
Dr. Parker, an associate editor of The Journal of Climate Change and Health, and Dr. Boos declared no conflicts of interest and no funding source for their commentary. Dr. Maloney said she has no conflicts of interest.
The urgent need to diagnose Sanfilippo syndrome at an early age
Sanfilippo syndrome is a rare inherited neurodegenerative metabolic disorder for which there are no approved therapies. Symptoms of the more severe subtypes typically begin within the first years of life, rapidly producing serious and progressive physical and cognitive deficits. The underlying pathophysiology is targetable, but the delay in diagnosis of this as well as other lysosomal storage disorders (LSDs) is slowing progress toward effective therapies.
“Lack of awareness and the delays to diagnosis have been a real challenge for us. There is reason for cautious optimism about treatments now in or approaching clinical studies, but to evaluate efficacy on cognitive outcomes we need to enroll more children at a very young age, before loss of milestones,” according to Cara O’Neill, MD, a co-founder and chief science officer of Cure Sanfilippo Foundation.
Epidemiology and description
Sanfilippo syndrome, like the more than 50 other LSDs, is caused by a gene mutation that leads to an enzyme deficiency in the lysosome.1 In the case of Sanfilippo syndrome, also known as mucopolysaccharidosis (MPS III), there are hundreds of mutations that can lead to Sanfilippo by altering the function of one of the four genes essential to degradation of heparan sulfate.2 Lysosomal accumulation of heparan sulfate drives a broad spectrum of progressive and largely irreversible symptoms that typically begin with somatic manifestations, such as bowel dysfunction and recurrent ear and upper respiratory infections.
Impairment of the central nervous system (CNS) usually occurs early in life, halting physical and mental development. As it progresses, accumulation of heparan sulfate in a variety of cells leads to a cascade of abnormal cellular signaling and dysfunction. Disruption of these processes, which are critical for normal neurodevelopment, result in loss of the developmental skills already gained and eventually loss of brain tissue.3 Although life expectancy has improved with supportive care, survival into adulthood is typically limited to milder forms.4
Over the past several years, progress in this and other LSDs has yielded therapeutic targets, including those involving gene repair and enzyme replacement. Already approved for use in some LSDs, these therapies have also shown promise in the experimental setting for Sanfilippo syndrome, leading to several completed clinical trials.5
So far, none of these treatments has advanced beyond clinical trials in Sanfilippo syndrome, but there have been favorable changes in the markers of disease, suggesting that better methods of treatment delivery and/or more sensitive tools to measure clinical change might lead to evidence of disease attenuation. However, the promise of treatment in all cases has been to prevent, slow, or halt progression, not to reverse it. This point is important, because it indicates that degree of benefit will depend on enrolling patients early in life. Even if effective therapies are identified, few patients will benefit without strategies to accelerate diagnosis.
In fact, “one study6 reported that the average age of diagnosis for Sanfilippo syndrome has not improved over the past 30 years,” according to Dr. O’Neill. She indicated that this has been frustrating, given the availability of clinical trials on which progress is dependent. There is no widely accepted protocol for who and when to test for Sanfilippo syndrome or other LSDs, but Dr. O’Neill’s organization is among those advocating for strategies to detect these diseases earlier, including screening at birth.
Almost by definition, the clinical diagnosis of rare diseases poses a challenge. With nonspecific symptoms and a broad range of potential diagnoses, diseases with a low incidence are not the first ones that are typically considered. In the case of Sanfilippo syndrome, published studies indicate incidence rates at or below 1 per 70,000 live births.7 However, the incidence rates have been highly variable not only by geographical regions but even across neighboring countries where genetic risk would be expected to be similar.
In Europe, for example, epidemiologic studies suggest the lifetime risk of MPS IIIA is approximately two times greater in Germany and the Netherlands relative to France and Sweden.7 It is possible that the methodology for identifying cases might be a more important factor than differences in genetic risk to explain this variability. Many experts, including Dr. O’Neill, believe that prevalence figures for Sanfilippo syndrome are typically underestimates because of the frequency with which LSDs are attributed to other pathology.
“For these types of rare disorders, a clinician might only see a single case over a career, and the symptoms can vary in presentation and severity with many alternatives to consider in the differential diagnosis,” Dr. O’Neill explained. She cited case reports in which symptoms of Sanfilippo syndrome after a period of initial normal development has been initially attributed to autism, which is a comorbid feature of the disease, idiopathic developmental delay, or other nonprogressive disorders until further clinical deterioration leads to additional testing. The implication is that LSDs must be considered far earlier despite their rarity.
For the least common of the four clinical subtypes, MPS IIIC and MPS IIID, the median ages of diagnosis have ranged from 4.5 to 19 years of age.7 This is likely a reflection of a slower progression and a later onset of clinical manifestations.
For the more rapidly progressing and typically more severe subtypes, MPS IIIA and MPS IIIB, the diagnosis is typically made earlier. In one review of epidemiologic studies in different countries, the earliest reported median age at diagnosis was 2.5 years,7 a point at which significant disease progression is likely to have already occurred. If the promise of treatments in development is prevention of disease progression, disability in many patients might be substantial if the time to diagnosis is not reduced.
Screening and testing
Independent of the potential to enroll children in clinical trials, early diagnosis also advances the opportunities for supportive care to lessen the burden of the disease on patients and families. Perhaps even more important, early diagnosis is vital to family planning. Since the American pediatrician Sylvester Sanfilippo, MD, first described this syndrome in 1963,7 the genetic profile and many of the features of the disease have become well characterized.8
“One reason to emphasize the importance of early diagnosis is the heritability of this disorder. With prompt diagnosis, genetic counseling can be offered to families to provide them with critical information for future family planning and for cascade testing of other potentially affected siblings,” Dr. O’Neill reported. The inheritance pattern of Sanfilippo syndrome is autosomal recessive.3 In families with an affected child, the risk for any subsequent child to have the same disorder is 25%. The chance of a sibling to be unaffected and not a carrier is also 25%. There is a 50% chance of a sibling to be a carrier but asymptomatic. Of priorities, spreading awareness has been a critical mission of the Cure Sanfilippo Foundation since it was founded 8 years ago, according to Glenn O’Neill, the president. He and his wife, Dr. O’Neill, who is a pediatrician, founded the organization after their own child’s diagnosis of Sanfilippo syndrome. Creating awareness is fundamental to the mission of attracting funds for research, but support to patients and their families as well as early enrollment in clinical trials are among other initiatives being pursued by the foundation to improve care and prognosis.
These strategies include some novel ideas, including an algorithm based on artificial intelligence (AI) that can accelerate suspicion of Sanfilippo syndrome in advance of laboratory or genetic testing, according to Dr. O’Neill. She reported that the facial phenotype, which is observed in a high proportion of but not in all Sanfilippo patients, includes coarse facial features such as puffiness around the eyes, heavy eyebrows, full lips, and macrocephaly.9 Interpretation of photos for AI-based analysis is enhanced when combined with other clinical symptoms.
“The Foundation was involved in honing such a tool by submitting the photos that were used to teach the AI to recognize the Sanfilippo syndrome phenotype,” Dr. O’Neill said. The AI-based tool (Face2Gene.com) is available from FDNA, a company that has been involved in analyzing complex phenotypic and genomic information to guide diagnosis and therapeutic strategies for an array of diseases, not just Sanfilippo syndrome.
The preferred method for diagnosis is biochemical or genetic testing. Of these, urine testing for elevated levels of heparan sulfate glycosaminoglycans (GAG) can be useful for screening, although false-negative tests occur. Analysis of the blood can be performed to detect abnormal levels or activity of the enzymes that break down this GAG. In addition, genetic testing can be performed on blood, fibroblast, buccal swab, or saliva samples. Genetic testing of the blood is the most frequently performed.
For the four MPS III subtypes – MPS IIIA, IIIB, IIIC, and IIID – the presence of two pathogenic mutations in the SGSH (17q25.3), NAGLU (17q21.2), HGSNAT (8p11.21), and GNS (12q14.3) genes, respectively, are likely diagnostic, but enzymatic testing or GAG analysis should be performed to confirm disease status, according to Dr. O’Neill, who said that global consensus based clinical care guidelines led by the Foundation were recently accepted for publication and also include a section on the approach to diagnosis.
While laboratory testing is sensitive, urinary excretion of GAG can be variable, with the potential for ambiguous results. Typically, biochemical and genetic testing provide more reliable results for the diagnosis. They can be readily performed in utero or at the time of birth. In addition, gene panels can permit the diagnosis of multiple types of LSDs, not just Sanfilippo, making screening a cost-effective strategy to consider multiple diseases with overlapping symptoms when an LSD is suspected. Dr. O’Neill said clinical guidelines recommend confirmation of enzyme deficiency or evidence of GAG substrate accumulation as confirmatory tests when genetic testing is positive.
“Ultimately, our goal is to promote universal screening at birth for these serious genetic disorders affecting children,” Dr. O’Neill said.
“We are in a catch-22 when it comes to newborn screening. Currently our federal system requires there be an available treatment before recommending routine screening for a disease. However, it is extremely difficult to power trials with patients who are most likely to show benefit in a trial setting without that very early diagnosis. Universal newborn screening would pave the way for accelerated drug development for children,” she added.
In the meantime, Dr. O’Neill suggests that clinicians should employ a low threshold of suspicion to pursue diagnostic studies of LSDs in infants and children with developmental delays or otherwise unexplained progressive disorders.
Importantly, clinicians can now act quickly on their suspicions and order testing without concern for delays or denial by insurers through a special program, according to Dr. O’Neill. Free genetic testing, offered by the Invitae Corporation, evaluates a panel of 58 genes associated with lysosomal disorders, permitting detection of Sanfilippo syndrome and other LSDs, according to Dr. O’Neill. The Invitae testing is typically performed on 3 mL of whole blood delivered to a central testing facility.
“Results can be obtained within a few weeks or sooner. This can seem like a long wait for families, but it is much more efficient than ordering tests sequentially,” Dr. O’Neill said.
Diagnosis: Signs and symptoms
Despite the differences in progression of the MPS III subtypes, the clinical characteristics are more similar than different. In all patients, prenatal and infant development are typically normal. The initial signs of disease can be found in the newborn, such as neonatal tachypnea, through the early infancy period, such as macrocephaly. However, these are not commonly recognized until about age 1 or soon after in those with MPS IIIA and IIIB.3 Speech delay is the first developmental delay seen in most patients. In those with MPS IIIC, initial symptoms are typically detected at age 3 or later and progress more slowly.10,11 The same is likely to be true of MPS IIID, although this subtype is less well characterized than the other three.7
Although many organs can be involved, degeneration of the CNS is regarded as the most characteristic.3 In aggressive disease, this includes slower acquisition of and failure to meet developmental milestones with progressive intellectual disability, while behavioral difficulties are a more common initial compliant in children with milder disease.13,14 These behavioral changes include hyperactivity, inattention, autistic behaviors, worsening safety awareness, and in some cases aggressive behavior that can be destructive. Sleep disturbances are common.15Because of variability inherent in descriptions of relatively small numbers of patients, the characterization of each of the MPS III subgroups is based on a limited number of small studies, but most patients demonstrate behavior disorders, have coarse facial features, and develop speech delay, according to a survey conducted of published studies.7 Collectively, abnormal behavior was identified as an early symptom in 77% of those with MPS IIIA, 69% of those with IIIB, and 77% of those with IIIC.
For MPS IIIA, loss of speech was observed at a median age of 3.8 years and loss of walking ability at 10.4 years. The median survival has been reported to range between 13 and 18 years. In children with MPS IIIB, the median age of speech loss was reported to about the same age, while loss of walking ability occurred at 11 years. In one study of MPS IIIB, 24% of patients had developed dementia by age 6 years, and the reported median survival has ranged between 17 and 19 years. For MPS IIIC, the onset of clinical symptoms has been observed at a median age of 3.5 years with evidence of cognitive loss observed in 33% of children by the age of 6 years. The median survival has ranged from 19 to 34 years in three studies tracing the natural history of this MPS III subtype.
The differential diagnosis reasonably includes other types of mucopolysaccharidosis disorders with cognitive impairment, including Hurler, Hunter, or Sly syndromes, other neurodevelopmental disorders, and inborn errors of metabolism. The heterogeneity of the features makes definitive laboratory or genetic testing, rather than the effort to differentiate clinical features, appropriate for a definitive diagnosis.
Once the diagnosis is made, other examinations for the common complications of Sanfilippo syndrome are appropriate. Abdominal imaging is appropriate for detecting complications in the gastrointestinal tract, including hepatomegaly, which has been reported in more than half of patients with MPS IIIA and IIIB and in 39% of patients with IIIC.7 In patients with breathing concerns at night and/or sleep disturbance, polysomnography can be useful for identifying sleep apnea and nocturnal seizure activity. In children suspected of seizures, EEG is appropriate. In one study, 66% of patients with MPS IIIA developed seizure activity.16 This has been less commonly reported in MPS IIIB and IIIC, ranging from 8% to 13%.15
Formal hearing evaluation is indicated for any child with speech delays. Hearing loss typically develops after the newborn period in Sanfilippo and may affect peak language acquisition if not treated, according to Dr. O’Neill.
Radiographic studies for dysostosis multiplex or other skeletal abnormalities are also appropriate based on clinical presentation.
Treatment: Present and future
In the absence of treatments to improve the prognosis of Sanfilippo syndrome, current management is based on supportive care and managing organ-specific complications. However, several strategies have proven viable in experimental models and led to clinical trials. None of these therapies has reached approval yet, but several have been associated with attenuation of biomarkers of MPS III disease activity.
Of nearly 30 Sanfilippo clinical trials conducted over the past 20 years, at least 9 have now been completed.5 In addition to studying gene therapy and enzyme replacement therapy, these trials have included stem cell transplantation and substrate reduction therapy, for which the goal is to reduce synthesis of the heparan sulfate GAG to prevent accumulation.5 Of this latter approach, promising initial results with genistein, an isoflavone that breaks down heparan sulfate, reached a phase 3 evaluation.18 Although heparan sulfate levels in the CNS were non-significantly reduced over the course of the trial, the reduction was not sufficient to attenuate cognitive decline.
In other LSDs, several forms of enzyme replacement therapy are now approved. In Fabry disease, for example, recombinant alpha-galactosidase A has now been used for more than 15 years.19 Clinical benefit has not yet been demonstrated in patients with Sanfilippo syndrome because of the difficulty of delivering these therapies past the blood-brain barrier. Several strategies have been pursued. For example, intrathecal delivery of recombinant heparan-N-sulfatase reduced CNS levels of GAG heparan sulfate in one phase 2B study, but it approached but fell short of the statistical significance for the primary endpoint of predefined cognitive stabilization.20 The signal of activity and generally acceptable tolerability has encouraged further study, including an ongoing study with promising interim results of intracerebroventricular enzyme replacement in MPS IIIB, according to Dr. O’Neill.
Acceptable safety and promising activity on disease biomarkers have also been seen with gene therapy in clinical trials. In one study that showed attenuation of brain atrophy, there was moderate improvement in behavior and sleep in three of the four patients enrolled.21 Other studies using various strategies for gene delivery have also produced signals of activity against the underlying pathology, generating persistent interest in ongoing and planned clinical studies with this form of treatment.22Unmodified hematopoietic stem cell transplantation (HSCT), an approach that has demonstrated efficacy when delivered early in the course of other LSDs, such as Hurler syndrome,23 has not yet been associated with significant activity in clinical studies of MPS III, including those that initiated treatment prior to the onset of neurological symptoms.24 However, promising early results have been reported in a study of gene-modified HSCT, which overexpresses the MPS IIIA enzyme.
“The clinical trial landscape fluctuates quite a bit, so I always encourage clinicians and families to check back often for updates. Patient organizations can also be helpful for understanding the most up-to-date and emerging trial options,” Dr. O’Neill reported.
Although it is expected that the greatest benefit would be derived from treatments initiated before or very early after the onset of symptoms, based on the limited potential for reversing cognitive loss, Dr. O’Neill said that she and others are also striving to offer treatments for individuals now living with Sanfilippo syndrome.
“We have to be willing to test treatments that are symptomatic in nature. To that aim, the Cure Sanfilippo Foundation has sponsored a study of a CNS-penetrating anti-inflammatory agent in advanced-disease patients more than 4 years of age,” Dr. O’Neill said. This group of patients typically been ineligible for clinical trials in the past. Dr. O’Neill hopes to change this orientation.
“It is important to highlight that all patients deserve our efforts to improve their quality of life and alleviate suffering, regardless of how old they are or how progressed in the disease they happen to be,” she said.
However, whether the goal is enrollment before or early in disease or later in disease progression, the challenge of enrolling sufficient numbers of patients to confirm clinical activity has been and continues to be a hurdle to progress.
“Clinical studies in Sanfilippo enroll relatively small numbers of patients, often 20 or less,” said Dr. O’Neill, explaining one of the reasons why her organization has been so active in raising awareness and funding such studies. For patients and families, the Cure Sanfilippo Foundation can offer a variety of guidance and support, but information about opportunities for clinical trial participation is a key resource they provide for families and their physicians.
Conclusion
For most children with Sanfilippo syndrome, life expectancy is limited. However, the characterization of the genetic causes and the biochemistry of the subtypes has led to several viable therapeutic approaches under development. There has been progress in delivery of therapeutic enzymes to the CNS, and there is substantial optimism that more progress is coming. One issue for treatment development, is the last of a clear regulatory pathway addressing important biomarkers of pathology, such as heparan sulfate burden. Developing treatments that address this issue or impaired enzyme activity levels have promise for preventing progression, particularly if started in infancy. However, the effort to draw awareness to this disease is the first step toward accelerating the time to an early diagnosis and subsequent opportunities to enroll in clinical trials.
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14. Bax MC, Colville GA. Behaviour in mucopolysaccharide disorders. Arch Dis Child. 1995 Jul;73(1):77-81. doi: 10.1136/adc.73.1.77.
15. Fraser J et al. Sleep disturbance in mucopolysaccharidosis type III (Sanfilippo syndrome): A survey of managing clinicians. Clin Genet. 2002 Nov;62(5):418-21. doi: 10.1034/j.1399-0004.2002.620512.x.
16. Valstar MJ et al. Mucopolysaccharidosis type IIIA: Clinical spectrum and genotype-phenotype correlations. Ann Neurol. 2010 Dec;68(6):876-87. doi: 10.1002/ana.22092.
17. Heron B et al. Incidence and natural history of mucopolysaccharidosis type III in France and comparison with United Kingdom and Greece. Am J Med Genet A. 2011 Jan;155A(1):58-68. doi: 10.1002/ajmg.a.33779.
18. Delgadillo V et al. Genistein supplementation in patients affected by Sanfilippo disease. J Inherit Metab Dis. 2011 Oct;34(5):1039-44. doi: 10.1007/s10545-011-9342-4.
19. van der Veen SJ et al. Developments in the treatment of Fabry disease. J Inherit Metab Dis. 2020 Sep;43(5):908-21. doi: 10.1002/jimd.12228.
20. Wijburg FA et al. Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial. Mol Genet Metab. 2019 Feb;126(2):121-30. doi: 10.1016/j.ymgme.2018.10.006.
21. Tardieu M et al. Intracerebral administration of adeno-associated viral vector serotype rh.10 carrying human SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA disease: Results of a phase I/II trial. Hum Gene Ther. 2014 Jun;25(6):506-16. doi: 10.1089/hum.2013.238.
22. Marco S et al. In vivo gene therapy for mucopolysaccharidosis type III (Sanfilippo syndrome): A new treatment horizon. Hum Gene Ther. 2019 Oct;30(10):1211-1121. doi: 10.1089/hum.2019.217.
23. Taylor M et al. Hematopoietic stem cell transplantation for mucopolysaccharidoses: Past, present, and future. Biol Blood Marrow Transplant. 2019 Jul;25(7):e226-e246. doi: 10.1016/j.bbmt.2019.02.012.
24. Sivakumur P, Wraith JE. Bone marrow transplantation in mucopolysaccharidosis type IIIA: A comparison of an early treated patient with his untreated sibling. J Inherit Metab Dis. 1999 Oct;22(7):849-50. doi: 10.1023/a:1005526628598.
Sanfilippo syndrome is a rare inherited neurodegenerative metabolic disorder for which there are no approved therapies. Symptoms of the more severe subtypes typically begin within the first years of life, rapidly producing serious and progressive physical and cognitive deficits. The underlying pathophysiology is targetable, but the delay in diagnosis of this as well as other lysosomal storage disorders (LSDs) is slowing progress toward effective therapies.
“Lack of awareness and the delays to diagnosis have been a real challenge for us. There is reason for cautious optimism about treatments now in or approaching clinical studies, but to evaluate efficacy on cognitive outcomes we need to enroll more children at a very young age, before loss of milestones,” according to Cara O’Neill, MD, a co-founder and chief science officer of Cure Sanfilippo Foundation.
Epidemiology and description
Sanfilippo syndrome, like the more than 50 other LSDs, is caused by a gene mutation that leads to an enzyme deficiency in the lysosome.1 In the case of Sanfilippo syndrome, also known as mucopolysaccharidosis (MPS III), there are hundreds of mutations that can lead to Sanfilippo by altering the function of one of the four genes essential to degradation of heparan sulfate.2 Lysosomal accumulation of heparan sulfate drives a broad spectrum of progressive and largely irreversible symptoms that typically begin with somatic manifestations, such as bowel dysfunction and recurrent ear and upper respiratory infections.
Impairment of the central nervous system (CNS) usually occurs early in life, halting physical and mental development. As it progresses, accumulation of heparan sulfate in a variety of cells leads to a cascade of abnormal cellular signaling and dysfunction. Disruption of these processes, which are critical for normal neurodevelopment, result in loss of the developmental skills already gained and eventually loss of brain tissue.3 Although life expectancy has improved with supportive care, survival into adulthood is typically limited to milder forms.4
Over the past several years, progress in this and other LSDs has yielded therapeutic targets, including those involving gene repair and enzyme replacement. Already approved for use in some LSDs, these therapies have also shown promise in the experimental setting for Sanfilippo syndrome, leading to several completed clinical trials.5
So far, none of these treatments has advanced beyond clinical trials in Sanfilippo syndrome, but there have been favorable changes in the markers of disease, suggesting that better methods of treatment delivery and/or more sensitive tools to measure clinical change might lead to evidence of disease attenuation. However, the promise of treatment in all cases has been to prevent, slow, or halt progression, not to reverse it. This point is important, because it indicates that degree of benefit will depend on enrolling patients early in life. Even if effective therapies are identified, few patients will benefit without strategies to accelerate diagnosis.
In fact, “one study6 reported that the average age of diagnosis for Sanfilippo syndrome has not improved over the past 30 years,” according to Dr. O’Neill. She indicated that this has been frustrating, given the availability of clinical trials on which progress is dependent. There is no widely accepted protocol for who and when to test for Sanfilippo syndrome or other LSDs, but Dr. O’Neill’s organization is among those advocating for strategies to detect these diseases earlier, including screening at birth.
Almost by definition, the clinical diagnosis of rare diseases poses a challenge. With nonspecific symptoms and a broad range of potential diagnoses, diseases with a low incidence are not the first ones that are typically considered. In the case of Sanfilippo syndrome, published studies indicate incidence rates at or below 1 per 70,000 live births.7 However, the incidence rates have been highly variable not only by geographical regions but even across neighboring countries where genetic risk would be expected to be similar.
In Europe, for example, epidemiologic studies suggest the lifetime risk of MPS IIIA is approximately two times greater in Germany and the Netherlands relative to France and Sweden.7 It is possible that the methodology for identifying cases might be a more important factor than differences in genetic risk to explain this variability. Many experts, including Dr. O’Neill, believe that prevalence figures for Sanfilippo syndrome are typically underestimates because of the frequency with which LSDs are attributed to other pathology.
“For these types of rare disorders, a clinician might only see a single case over a career, and the symptoms can vary in presentation and severity with many alternatives to consider in the differential diagnosis,” Dr. O’Neill explained. She cited case reports in which symptoms of Sanfilippo syndrome after a period of initial normal development has been initially attributed to autism, which is a comorbid feature of the disease, idiopathic developmental delay, or other nonprogressive disorders until further clinical deterioration leads to additional testing. The implication is that LSDs must be considered far earlier despite their rarity.
For the least common of the four clinical subtypes, MPS IIIC and MPS IIID, the median ages of diagnosis have ranged from 4.5 to 19 years of age.7 This is likely a reflection of a slower progression and a later onset of clinical manifestations.
For the more rapidly progressing and typically more severe subtypes, MPS IIIA and MPS IIIB, the diagnosis is typically made earlier. In one review of epidemiologic studies in different countries, the earliest reported median age at diagnosis was 2.5 years,7 a point at which significant disease progression is likely to have already occurred. If the promise of treatments in development is prevention of disease progression, disability in many patients might be substantial if the time to diagnosis is not reduced.
Screening and testing
Independent of the potential to enroll children in clinical trials, early diagnosis also advances the opportunities for supportive care to lessen the burden of the disease on patients and families. Perhaps even more important, early diagnosis is vital to family planning. Since the American pediatrician Sylvester Sanfilippo, MD, first described this syndrome in 1963,7 the genetic profile and many of the features of the disease have become well characterized.8
“One reason to emphasize the importance of early diagnosis is the heritability of this disorder. With prompt diagnosis, genetic counseling can be offered to families to provide them with critical information for future family planning and for cascade testing of other potentially affected siblings,” Dr. O’Neill reported. The inheritance pattern of Sanfilippo syndrome is autosomal recessive.3 In families with an affected child, the risk for any subsequent child to have the same disorder is 25%. The chance of a sibling to be unaffected and not a carrier is also 25%. There is a 50% chance of a sibling to be a carrier but asymptomatic. Of priorities, spreading awareness has been a critical mission of the Cure Sanfilippo Foundation since it was founded 8 years ago, according to Glenn O’Neill, the president. He and his wife, Dr. O’Neill, who is a pediatrician, founded the organization after their own child’s diagnosis of Sanfilippo syndrome. Creating awareness is fundamental to the mission of attracting funds for research, but support to patients and their families as well as early enrollment in clinical trials are among other initiatives being pursued by the foundation to improve care and prognosis.
These strategies include some novel ideas, including an algorithm based on artificial intelligence (AI) that can accelerate suspicion of Sanfilippo syndrome in advance of laboratory or genetic testing, according to Dr. O’Neill. She reported that the facial phenotype, which is observed in a high proportion of but not in all Sanfilippo patients, includes coarse facial features such as puffiness around the eyes, heavy eyebrows, full lips, and macrocephaly.9 Interpretation of photos for AI-based analysis is enhanced when combined with other clinical symptoms.
“The Foundation was involved in honing such a tool by submitting the photos that were used to teach the AI to recognize the Sanfilippo syndrome phenotype,” Dr. O’Neill said. The AI-based tool (Face2Gene.com) is available from FDNA, a company that has been involved in analyzing complex phenotypic and genomic information to guide diagnosis and therapeutic strategies for an array of diseases, not just Sanfilippo syndrome.
The preferred method for diagnosis is biochemical or genetic testing. Of these, urine testing for elevated levels of heparan sulfate glycosaminoglycans (GAG) can be useful for screening, although false-negative tests occur. Analysis of the blood can be performed to detect abnormal levels or activity of the enzymes that break down this GAG. In addition, genetic testing can be performed on blood, fibroblast, buccal swab, or saliva samples. Genetic testing of the blood is the most frequently performed.
For the four MPS III subtypes – MPS IIIA, IIIB, IIIC, and IIID – the presence of two pathogenic mutations in the SGSH (17q25.3), NAGLU (17q21.2), HGSNAT (8p11.21), and GNS (12q14.3) genes, respectively, are likely diagnostic, but enzymatic testing or GAG analysis should be performed to confirm disease status, according to Dr. O’Neill, who said that global consensus based clinical care guidelines led by the Foundation were recently accepted for publication and also include a section on the approach to diagnosis.
While laboratory testing is sensitive, urinary excretion of GAG can be variable, with the potential for ambiguous results. Typically, biochemical and genetic testing provide more reliable results for the diagnosis. They can be readily performed in utero or at the time of birth. In addition, gene panels can permit the diagnosis of multiple types of LSDs, not just Sanfilippo, making screening a cost-effective strategy to consider multiple diseases with overlapping symptoms when an LSD is suspected. Dr. O’Neill said clinical guidelines recommend confirmation of enzyme deficiency or evidence of GAG substrate accumulation as confirmatory tests when genetic testing is positive.
“Ultimately, our goal is to promote universal screening at birth for these serious genetic disorders affecting children,” Dr. O’Neill said.
“We are in a catch-22 when it comes to newborn screening. Currently our federal system requires there be an available treatment before recommending routine screening for a disease. However, it is extremely difficult to power trials with patients who are most likely to show benefit in a trial setting without that very early diagnosis. Universal newborn screening would pave the way for accelerated drug development for children,” she added.
In the meantime, Dr. O’Neill suggests that clinicians should employ a low threshold of suspicion to pursue diagnostic studies of LSDs in infants and children with developmental delays or otherwise unexplained progressive disorders.
Importantly, clinicians can now act quickly on their suspicions and order testing without concern for delays or denial by insurers through a special program, according to Dr. O’Neill. Free genetic testing, offered by the Invitae Corporation, evaluates a panel of 58 genes associated with lysosomal disorders, permitting detection of Sanfilippo syndrome and other LSDs, according to Dr. O’Neill. The Invitae testing is typically performed on 3 mL of whole blood delivered to a central testing facility.
“Results can be obtained within a few weeks or sooner. This can seem like a long wait for families, but it is much more efficient than ordering tests sequentially,” Dr. O’Neill said.
Diagnosis: Signs and symptoms
Despite the differences in progression of the MPS III subtypes, the clinical characteristics are more similar than different. In all patients, prenatal and infant development are typically normal. The initial signs of disease can be found in the newborn, such as neonatal tachypnea, through the early infancy period, such as macrocephaly. However, these are not commonly recognized until about age 1 or soon after in those with MPS IIIA and IIIB.3 Speech delay is the first developmental delay seen in most patients. In those with MPS IIIC, initial symptoms are typically detected at age 3 or later and progress more slowly.10,11 The same is likely to be true of MPS IIID, although this subtype is less well characterized than the other three.7
Although many organs can be involved, degeneration of the CNS is regarded as the most characteristic.3 In aggressive disease, this includes slower acquisition of and failure to meet developmental milestones with progressive intellectual disability, while behavioral difficulties are a more common initial compliant in children with milder disease.13,14 These behavioral changes include hyperactivity, inattention, autistic behaviors, worsening safety awareness, and in some cases aggressive behavior that can be destructive. Sleep disturbances are common.15Because of variability inherent in descriptions of relatively small numbers of patients, the characterization of each of the MPS III subgroups is based on a limited number of small studies, but most patients demonstrate behavior disorders, have coarse facial features, and develop speech delay, according to a survey conducted of published studies.7 Collectively, abnormal behavior was identified as an early symptom in 77% of those with MPS IIIA, 69% of those with IIIB, and 77% of those with IIIC.
For MPS IIIA, loss of speech was observed at a median age of 3.8 years and loss of walking ability at 10.4 years. The median survival has been reported to range between 13 and 18 years. In children with MPS IIIB, the median age of speech loss was reported to about the same age, while loss of walking ability occurred at 11 years. In one study of MPS IIIB, 24% of patients had developed dementia by age 6 years, and the reported median survival has ranged between 17 and 19 years. For MPS IIIC, the onset of clinical symptoms has been observed at a median age of 3.5 years with evidence of cognitive loss observed in 33% of children by the age of 6 years. The median survival has ranged from 19 to 34 years in three studies tracing the natural history of this MPS III subtype.
The differential diagnosis reasonably includes other types of mucopolysaccharidosis disorders with cognitive impairment, including Hurler, Hunter, or Sly syndromes, other neurodevelopmental disorders, and inborn errors of metabolism. The heterogeneity of the features makes definitive laboratory or genetic testing, rather than the effort to differentiate clinical features, appropriate for a definitive diagnosis.
Once the diagnosis is made, other examinations for the common complications of Sanfilippo syndrome are appropriate. Abdominal imaging is appropriate for detecting complications in the gastrointestinal tract, including hepatomegaly, which has been reported in more than half of patients with MPS IIIA and IIIB and in 39% of patients with IIIC.7 In patients with breathing concerns at night and/or sleep disturbance, polysomnography can be useful for identifying sleep apnea and nocturnal seizure activity. In children suspected of seizures, EEG is appropriate. In one study, 66% of patients with MPS IIIA developed seizure activity.16 This has been less commonly reported in MPS IIIB and IIIC, ranging from 8% to 13%.15
Formal hearing evaluation is indicated for any child with speech delays. Hearing loss typically develops after the newborn period in Sanfilippo and may affect peak language acquisition if not treated, according to Dr. O’Neill.
Radiographic studies for dysostosis multiplex or other skeletal abnormalities are also appropriate based on clinical presentation.
Treatment: Present and future
In the absence of treatments to improve the prognosis of Sanfilippo syndrome, current management is based on supportive care and managing organ-specific complications. However, several strategies have proven viable in experimental models and led to clinical trials. None of these therapies has reached approval yet, but several have been associated with attenuation of biomarkers of MPS III disease activity.
Of nearly 30 Sanfilippo clinical trials conducted over the past 20 years, at least 9 have now been completed.5 In addition to studying gene therapy and enzyme replacement therapy, these trials have included stem cell transplantation and substrate reduction therapy, for which the goal is to reduce synthesis of the heparan sulfate GAG to prevent accumulation.5 Of this latter approach, promising initial results with genistein, an isoflavone that breaks down heparan sulfate, reached a phase 3 evaluation.18 Although heparan sulfate levels in the CNS were non-significantly reduced over the course of the trial, the reduction was not sufficient to attenuate cognitive decline.
In other LSDs, several forms of enzyme replacement therapy are now approved. In Fabry disease, for example, recombinant alpha-galactosidase A has now been used for more than 15 years.19 Clinical benefit has not yet been demonstrated in patients with Sanfilippo syndrome because of the difficulty of delivering these therapies past the blood-brain barrier. Several strategies have been pursued. For example, intrathecal delivery of recombinant heparan-N-sulfatase reduced CNS levels of GAG heparan sulfate in one phase 2B study, but it approached but fell short of the statistical significance for the primary endpoint of predefined cognitive stabilization.20 The signal of activity and generally acceptable tolerability has encouraged further study, including an ongoing study with promising interim results of intracerebroventricular enzyme replacement in MPS IIIB, according to Dr. O’Neill.
Acceptable safety and promising activity on disease biomarkers have also been seen with gene therapy in clinical trials. In one study that showed attenuation of brain atrophy, there was moderate improvement in behavior and sleep in three of the four patients enrolled.21 Other studies using various strategies for gene delivery have also produced signals of activity against the underlying pathology, generating persistent interest in ongoing and planned clinical studies with this form of treatment.22Unmodified hematopoietic stem cell transplantation (HSCT), an approach that has demonstrated efficacy when delivered early in the course of other LSDs, such as Hurler syndrome,23 has not yet been associated with significant activity in clinical studies of MPS III, including those that initiated treatment prior to the onset of neurological symptoms.24 However, promising early results have been reported in a study of gene-modified HSCT, which overexpresses the MPS IIIA enzyme.
“The clinical trial landscape fluctuates quite a bit, so I always encourage clinicians and families to check back often for updates. Patient organizations can also be helpful for understanding the most up-to-date and emerging trial options,” Dr. O’Neill reported.
Although it is expected that the greatest benefit would be derived from treatments initiated before or very early after the onset of symptoms, based on the limited potential for reversing cognitive loss, Dr. O’Neill said that she and others are also striving to offer treatments for individuals now living with Sanfilippo syndrome.
“We have to be willing to test treatments that are symptomatic in nature. To that aim, the Cure Sanfilippo Foundation has sponsored a study of a CNS-penetrating anti-inflammatory agent in advanced-disease patients more than 4 years of age,” Dr. O’Neill said. This group of patients typically been ineligible for clinical trials in the past. Dr. O’Neill hopes to change this orientation.
“It is important to highlight that all patients deserve our efforts to improve their quality of life and alleviate suffering, regardless of how old they are or how progressed in the disease they happen to be,” she said.
However, whether the goal is enrollment before or early in disease or later in disease progression, the challenge of enrolling sufficient numbers of patients to confirm clinical activity has been and continues to be a hurdle to progress.
“Clinical studies in Sanfilippo enroll relatively small numbers of patients, often 20 or less,” said Dr. O’Neill, explaining one of the reasons why her organization has been so active in raising awareness and funding such studies. For patients and families, the Cure Sanfilippo Foundation can offer a variety of guidance and support, but information about opportunities for clinical trial participation is a key resource they provide for families and their physicians.
Conclusion
For most children with Sanfilippo syndrome, life expectancy is limited. However, the characterization of the genetic causes and the biochemistry of the subtypes has led to several viable therapeutic approaches under development. There has been progress in delivery of therapeutic enzymes to the CNS, and there is substantial optimism that more progress is coming. One issue for treatment development, is the last of a clear regulatory pathway addressing important biomarkers of pathology, such as heparan sulfate burden. Developing treatments that address this issue or impaired enzyme activity levels have promise for preventing progression, particularly if started in infancy. However, the effort to draw awareness to this disease is the first step toward accelerating the time to an early diagnosis and subsequent opportunities to enroll in clinical trials.
References
1. Sun A. Lysosomal storage disease overview. Ann Transl Med. 2018 Dec;6(24):476. doi: 10.21037/atm.2018.11.39.
2. Andrade F et al. Sanfilippo syndrome: Overall review. Pediatr Int. 2015 Jun;57(3):331-8. doi: 10.1111/ped.12636.
3. Fedele AO. Sanfilippo syndrome: Causes, consequences, and treatments. Appl Clin Genet. 2015 Nov 25;8:269-81. doi: 10.2147/TACG.S57672.
4. Lavery C et al. Mortality in patients with Sanfilippo syndrome. Orphanet J Rare Dis. 2017 Oct 23;12(1):168. doi: 10.1186/s13023-017-0717-y.
5. Pearse Y et al. A cure for Sanfilippo syndrome? A summary of current therapeutic approaches and their promise. Med Res Arch. 2020 Feb 1;8(2). doi: 10.18103/mra.v8i2.2045.
6. Kuiper GA et al. Failure to shorten the diagnostic delay in two ultrao-rphan diseases (mucopolysaccharidosis types I and III): potential causes and implication. Orphanet J Rare Dis. 2018;13:2. Doi: 10.1186/s13023-017-0733-y.
7. Zelei T et al. Epidemiology of Sanfilippo syndrome: Results of a systematic literature review. Orphanet J Rare Dis. 2018 Apr 10;13(1):53. doi: 10.1186/s13023-018-0796-4.
8. Wagner VF, Northrup H. Mucopolysaccaharidosis type III. Gene Reviews. 2019 Sep 19. University of Washington, Seattle. https://www.ncbi.nlm.nih.gov/books/NBK546574/8.
9. O’Neill C et al. Natural history of facial features observed in Sanfilippo syndrome (MPS IIIB) using a next generation phenotyping tool. Mol Genet Metab. 2019 Feb;126:S112.
10. Ruijter GJ et al. Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in the Netherlands. Mol Genet Metab. 2008 Feb;93(2):104-11. doi: 10.1016/j.ymgme.2007.09.011.
11. Valstar MJ et al. Mucopolysaccharidosis type IIID: 12 new patients and 15 novel mutations. Hum Mutat. 2010 May;31(5):E1348-60. doi: 10.1002/humu.21234.
12. Nijmeijer SCM. The attenuated end of phenotypic spectrum in MPS III: from late-onset stable cognitive impairment to non-neuronopathic phenotype. Orphanet J Rare Dis. 2019;14:249. Doi10.1186/s13023-019-1232-0.
13. Nidiffer FD, Kelly TE. Developmental and degenerative patterns associated with cognitive, behavioural and motor difficulties in the Sanfilippo syndrome: An epidemiological study. J Ment Defic Res. 1983 Sep;27 (Pt 3):185-203. doi: 10.1111/j.1365-2788.1983.tb00291.x.
14. Bax MC, Colville GA. Behaviour in mucopolysaccharide disorders. Arch Dis Child. 1995 Jul;73(1):77-81. doi: 10.1136/adc.73.1.77.
15. Fraser J et al. Sleep disturbance in mucopolysaccharidosis type III (Sanfilippo syndrome): A survey of managing clinicians. Clin Genet. 2002 Nov;62(5):418-21. doi: 10.1034/j.1399-0004.2002.620512.x.
16. Valstar MJ et al. Mucopolysaccharidosis type IIIA: Clinical spectrum and genotype-phenotype correlations. Ann Neurol. 2010 Dec;68(6):876-87. doi: 10.1002/ana.22092.
17. Heron B et al. Incidence and natural history of mucopolysaccharidosis type III in France and comparison with United Kingdom and Greece. Am J Med Genet A. 2011 Jan;155A(1):58-68. doi: 10.1002/ajmg.a.33779.
18. Delgadillo V et al. Genistein supplementation in patients affected by Sanfilippo disease. J Inherit Metab Dis. 2011 Oct;34(5):1039-44. doi: 10.1007/s10545-011-9342-4.
19. van der Veen SJ et al. Developments in the treatment of Fabry disease. J Inherit Metab Dis. 2020 Sep;43(5):908-21. doi: 10.1002/jimd.12228.
20. Wijburg FA et al. Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial. Mol Genet Metab. 2019 Feb;126(2):121-30. doi: 10.1016/j.ymgme.2018.10.006.
21. Tardieu M et al. Intracerebral administration of adeno-associated viral vector serotype rh.10 carrying human SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA disease: Results of a phase I/II trial. Hum Gene Ther. 2014 Jun;25(6):506-16. doi: 10.1089/hum.2013.238.
22. Marco S et al. In vivo gene therapy for mucopolysaccharidosis type III (Sanfilippo syndrome): A new treatment horizon. Hum Gene Ther. 2019 Oct;30(10):1211-1121. doi: 10.1089/hum.2019.217.
23. Taylor M et al. Hematopoietic stem cell transplantation for mucopolysaccharidoses: Past, present, and future. Biol Blood Marrow Transplant. 2019 Jul;25(7):e226-e246. doi: 10.1016/j.bbmt.2019.02.012.
24. Sivakumur P, Wraith JE. Bone marrow transplantation in mucopolysaccharidosis type IIIA: A comparison of an early treated patient with his untreated sibling. J Inherit Metab Dis. 1999 Oct;22(7):849-50. doi: 10.1023/a:1005526628598.
Sanfilippo syndrome is a rare inherited neurodegenerative metabolic disorder for which there are no approved therapies. Symptoms of the more severe subtypes typically begin within the first years of life, rapidly producing serious and progressive physical and cognitive deficits. The underlying pathophysiology is targetable, but the delay in diagnosis of this as well as other lysosomal storage disorders (LSDs) is slowing progress toward effective therapies.
“Lack of awareness and the delays to diagnosis have been a real challenge for us. There is reason for cautious optimism about treatments now in or approaching clinical studies, but to evaluate efficacy on cognitive outcomes we need to enroll more children at a very young age, before loss of milestones,” according to Cara O’Neill, MD, a co-founder and chief science officer of Cure Sanfilippo Foundation.
Epidemiology and description
Sanfilippo syndrome, like the more than 50 other LSDs, is caused by a gene mutation that leads to an enzyme deficiency in the lysosome.1 In the case of Sanfilippo syndrome, also known as mucopolysaccharidosis (MPS III), there are hundreds of mutations that can lead to Sanfilippo by altering the function of one of the four genes essential to degradation of heparan sulfate.2 Lysosomal accumulation of heparan sulfate drives a broad spectrum of progressive and largely irreversible symptoms that typically begin with somatic manifestations, such as bowel dysfunction and recurrent ear and upper respiratory infections.
Impairment of the central nervous system (CNS) usually occurs early in life, halting physical and mental development. As it progresses, accumulation of heparan sulfate in a variety of cells leads to a cascade of abnormal cellular signaling and dysfunction. Disruption of these processes, which are critical for normal neurodevelopment, result in loss of the developmental skills already gained and eventually loss of brain tissue.3 Although life expectancy has improved with supportive care, survival into adulthood is typically limited to milder forms.4
Over the past several years, progress in this and other LSDs has yielded therapeutic targets, including those involving gene repair and enzyme replacement. Already approved for use in some LSDs, these therapies have also shown promise in the experimental setting for Sanfilippo syndrome, leading to several completed clinical trials.5
So far, none of these treatments has advanced beyond clinical trials in Sanfilippo syndrome, but there have been favorable changes in the markers of disease, suggesting that better methods of treatment delivery and/or more sensitive tools to measure clinical change might lead to evidence of disease attenuation. However, the promise of treatment in all cases has been to prevent, slow, or halt progression, not to reverse it. This point is important, because it indicates that degree of benefit will depend on enrolling patients early in life. Even if effective therapies are identified, few patients will benefit without strategies to accelerate diagnosis.
In fact, “one study6 reported that the average age of diagnosis for Sanfilippo syndrome has not improved over the past 30 years,” according to Dr. O’Neill. She indicated that this has been frustrating, given the availability of clinical trials on which progress is dependent. There is no widely accepted protocol for who and when to test for Sanfilippo syndrome or other LSDs, but Dr. O’Neill’s organization is among those advocating for strategies to detect these diseases earlier, including screening at birth.
Almost by definition, the clinical diagnosis of rare diseases poses a challenge. With nonspecific symptoms and a broad range of potential diagnoses, diseases with a low incidence are not the first ones that are typically considered. In the case of Sanfilippo syndrome, published studies indicate incidence rates at or below 1 per 70,000 live births.7 However, the incidence rates have been highly variable not only by geographical regions but even across neighboring countries where genetic risk would be expected to be similar.
In Europe, for example, epidemiologic studies suggest the lifetime risk of MPS IIIA is approximately two times greater in Germany and the Netherlands relative to France and Sweden.7 It is possible that the methodology for identifying cases might be a more important factor than differences in genetic risk to explain this variability. Many experts, including Dr. O’Neill, believe that prevalence figures for Sanfilippo syndrome are typically underestimates because of the frequency with which LSDs are attributed to other pathology.
“For these types of rare disorders, a clinician might only see a single case over a career, and the symptoms can vary in presentation and severity with many alternatives to consider in the differential diagnosis,” Dr. O’Neill explained. She cited case reports in which symptoms of Sanfilippo syndrome after a period of initial normal development has been initially attributed to autism, which is a comorbid feature of the disease, idiopathic developmental delay, or other nonprogressive disorders until further clinical deterioration leads to additional testing. The implication is that LSDs must be considered far earlier despite their rarity.
For the least common of the four clinical subtypes, MPS IIIC and MPS IIID, the median ages of diagnosis have ranged from 4.5 to 19 years of age.7 This is likely a reflection of a slower progression and a later onset of clinical manifestations.
For the more rapidly progressing and typically more severe subtypes, MPS IIIA and MPS IIIB, the diagnosis is typically made earlier. In one review of epidemiologic studies in different countries, the earliest reported median age at diagnosis was 2.5 years,7 a point at which significant disease progression is likely to have already occurred. If the promise of treatments in development is prevention of disease progression, disability in many patients might be substantial if the time to diagnosis is not reduced.
Screening and testing
Independent of the potential to enroll children in clinical trials, early diagnosis also advances the opportunities for supportive care to lessen the burden of the disease on patients and families. Perhaps even more important, early diagnosis is vital to family planning. Since the American pediatrician Sylvester Sanfilippo, MD, first described this syndrome in 1963,7 the genetic profile and many of the features of the disease have become well characterized.8
“One reason to emphasize the importance of early diagnosis is the heritability of this disorder. With prompt diagnosis, genetic counseling can be offered to families to provide them with critical information for future family planning and for cascade testing of other potentially affected siblings,” Dr. O’Neill reported. The inheritance pattern of Sanfilippo syndrome is autosomal recessive.3 In families with an affected child, the risk for any subsequent child to have the same disorder is 25%. The chance of a sibling to be unaffected and not a carrier is also 25%. There is a 50% chance of a sibling to be a carrier but asymptomatic. Of priorities, spreading awareness has been a critical mission of the Cure Sanfilippo Foundation since it was founded 8 years ago, according to Glenn O’Neill, the president. He and his wife, Dr. O’Neill, who is a pediatrician, founded the organization after their own child’s diagnosis of Sanfilippo syndrome. Creating awareness is fundamental to the mission of attracting funds for research, but support to patients and their families as well as early enrollment in clinical trials are among other initiatives being pursued by the foundation to improve care and prognosis.
These strategies include some novel ideas, including an algorithm based on artificial intelligence (AI) that can accelerate suspicion of Sanfilippo syndrome in advance of laboratory or genetic testing, according to Dr. O’Neill. She reported that the facial phenotype, which is observed in a high proportion of but not in all Sanfilippo patients, includes coarse facial features such as puffiness around the eyes, heavy eyebrows, full lips, and macrocephaly.9 Interpretation of photos for AI-based analysis is enhanced when combined with other clinical symptoms.
“The Foundation was involved in honing such a tool by submitting the photos that were used to teach the AI to recognize the Sanfilippo syndrome phenotype,” Dr. O’Neill said. The AI-based tool (Face2Gene.com) is available from FDNA, a company that has been involved in analyzing complex phenotypic and genomic information to guide diagnosis and therapeutic strategies for an array of diseases, not just Sanfilippo syndrome.
The preferred method for diagnosis is biochemical or genetic testing. Of these, urine testing for elevated levels of heparan sulfate glycosaminoglycans (GAG) can be useful for screening, although false-negative tests occur. Analysis of the blood can be performed to detect abnormal levels or activity of the enzymes that break down this GAG. In addition, genetic testing can be performed on blood, fibroblast, buccal swab, or saliva samples. Genetic testing of the blood is the most frequently performed.
For the four MPS III subtypes – MPS IIIA, IIIB, IIIC, and IIID – the presence of two pathogenic mutations in the SGSH (17q25.3), NAGLU (17q21.2), HGSNAT (8p11.21), and GNS (12q14.3) genes, respectively, are likely diagnostic, but enzymatic testing or GAG analysis should be performed to confirm disease status, according to Dr. O’Neill, who said that global consensus based clinical care guidelines led by the Foundation were recently accepted for publication and also include a section on the approach to diagnosis.
While laboratory testing is sensitive, urinary excretion of GAG can be variable, with the potential for ambiguous results. Typically, biochemical and genetic testing provide more reliable results for the diagnosis. They can be readily performed in utero or at the time of birth. In addition, gene panels can permit the diagnosis of multiple types of LSDs, not just Sanfilippo, making screening a cost-effective strategy to consider multiple diseases with overlapping symptoms when an LSD is suspected. Dr. O’Neill said clinical guidelines recommend confirmation of enzyme deficiency or evidence of GAG substrate accumulation as confirmatory tests when genetic testing is positive.
“Ultimately, our goal is to promote universal screening at birth for these serious genetic disorders affecting children,” Dr. O’Neill said.
“We are in a catch-22 when it comes to newborn screening. Currently our federal system requires there be an available treatment before recommending routine screening for a disease. However, it is extremely difficult to power trials with patients who are most likely to show benefit in a trial setting without that very early diagnosis. Universal newborn screening would pave the way for accelerated drug development for children,” she added.
In the meantime, Dr. O’Neill suggests that clinicians should employ a low threshold of suspicion to pursue diagnostic studies of LSDs in infants and children with developmental delays or otherwise unexplained progressive disorders.
Importantly, clinicians can now act quickly on their suspicions and order testing without concern for delays or denial by insurers through a special program, according to Dr. O’Neill. Free genetic testing, offered by the Invitae Corporation, evaluates a panel of 58 genes associated with lysosomal disorders, permitting detection of Sanfilippo syndrome and other LSDs, according to Dr. O’Neill. The Invitae testing is typically performed on 3 mL of whole blood delivered to a central testing facility.
“Results can be obtained within a few weeks or sooner. This can seem like a long wait for families, but it is much more efficient than ordering tests sequentially,” Dr. O’Neill said.
Diagnosis: Signs and symptoms
Despite the differences in progression of the MPS III subtypes, the clinical characteristics are more similar than different. In all patients, prenatal and infant development are typically normal. The initial signs of disease can be found in the newborn, such as neonatal tachypnea, through the early infancy period, such as macrocephaly. However, these are not commonly recognized until about age 1 or soon after in those with MPS IIIA and IIIB.3 Speech delay is the first developmental delay seen in most patients. In those with MPS IIIC, initial symptoms are typically detected at age 3 or later and progress more slowly.10,11 The same is likely to be true of MPS IIID, although this subtype is less well characterized than the other three.7
Although many organs can be involved, degeneration of the CNS is regarded as the most characteristic.3 In aggressive disease, this includes slower acquisition of and failure to meet developmental milestones with progressive intellectual disability, while behavioral difficulties are a more common initial compliant in children with milder disease.13,14 These behavioral changes include hyperactivity, inattention, autistic behaviors, worsening safety awareness, and in some cases aggressive behavior that can be destructive. Sleep disturbances are common.15Because of variability inherent in descriptions of relatively small numbers of patients, the characterization of each of the MPS III subgroups is based on a limited number of small studies, but most patients demonstrate behavior disorders, have coarse facial features, and develop speech delay, according to a survey conducted of published studies.7 Collectively, abnormal behavior was identified as an early symptom in 77% of those with MPS IIIA, 69% of those with IIIB, and 77% of those with IIIC.
For MPS IIIA, loss of speech was observed at a median age of 3.8 years and loss of walking ability at 10.4 years. The median survival has been reported to range between 13 and 18 years. In children with MPS IIIB, the median age of speech loss was reported to about the same age, while loss of walking ability occurred at 11 years. In one study of MPS IIIB, 24% of patients had developed dementia by age 6 years, and the reported median survival has ranged between 17 and 19 years. For MPS IIIC, the onset of clinical symptoms has been observed at a median age of 3.5 years with evidence of cognitive loss observed in 33% of children by the age of 6 years. The median survival has ranged from 19 to 34 years in three studies tracing the natural history of this MPS III subtype.
The differential diagnosis reasonably includes other types of mucopolysaccharidosis disorders with cognitive impairment, including Hurler, Hunter, or Sly syndromes, other neurodevelopmental disorders, and inborn errors of metabolism. The heterogeneity of the features makes definitive laboratory or genetic testing, rather than the effort to differentiate clinical features, appropriate for a definitive diagnosis.
Once the diagnosis is made, other examinations for the common complications of Sanfilippo syndrome are appropriate. Abdominal imaging is appropriate for detecting complications in the gastrointestinal tract, including hepatomegaly, which has been reported in more than half of patients with MPS IIIA and IIIB and in 39% of patients with IIIC.7 In patients with breathing concerns at night and/or sleep disturbance, polysomnography can be useful for identifying sleep apnea and nocturnal seizure activity. In children suspected of seizures, EEG is appropriate. In one study, 66% of patients with MPS IIIA developed seizure activity.16 This has been less commonly reported in MPS IIIB and IIIC, ranging from 8% to 13%.15
Formal hearing evaluation is indicated for any child with speech delays. Hearing loss typically develops after the newborn period in Sanfilippo and may affect peak language acquisition if not treated, according to Dr. O’Neill.
Radiographic studies for dysostosis multiplex or other skeletal abnormalities are also appropriate based on clinical presentation.
Treatment: Present and future
In the absence of treatments to improve the prognosis of Sanfilippo syndrome, current management is based on supportive care and managing organ-specific complications. However, several strategies have proven viable in experimental models and led to clinical trials. None of these therapies has reached approval yet, but several have been associated with attenuation of biomarkers of MPS III disease activity.
Of nearly 30 Sanfilippo clinical trials conducted over the past 20 years, at least 9 have now been completed.5 In addition to studying gene therapy and enzyme replacement therapy, these trials have included stem cell transplantation and substrate reduction therapy, for which the goal is to reduce synthesis of the heparan sulfate GAG to prevent accumulation.5 Of this latter approach, promising initial results with genistein, an isoflavone that breaks down heparan sulfate, reached a phase 3 evaluation.18 Although heparan sulfate levels in the CNS were non-significantly reduced over the course of the trial, the reduction was not sufficient to attenuate cognitive decline.
In other LSDs, several forms of enzyme replacement therapy are now approved. In Fabry disease, for example, recombinant alpha-galactosidase A has now been used for more than 15 years.19 Clinical benefit has not yet been demonstrated in patients with Sanfilippo syndrome because of the difficulty of delivering these therapies past the blood-brain barrier. Several strategies have been pursued. For example, intrathecal delivery of recombinant heparan-N-sulfatase reduced CNS levels of GAG heparan sulfate in one phase 2B study, but it approached but fell short of the statistical significance for the primary endpoint of predefined cognitive stabilization.20 The signal of activity and generally acceptable tolerability has encouraged further study, including an ongoing study with promising interim results of intracerebroventricular enzyme replacement in MPS IIIB, according to Dr. O’Neill.
Acceptable safety and promising activity on disease biomarkers have also been seen with gene therapy in clinical trials. In one study that showed attenuation of brain atrophy, there was moderate improvement in behavior and sleep in three of the four patients enrolled.21 Other studies using various strategies for gene delivery have also produced signals of activity against the underlying pathology, generating persistent interest in ongoing and planned clinical studies with this form of treatment.22Unmodified hematopoietic stem cell transplantation (HSCT), an approach that has demonstrated efficacy when delivered early in the course of other LSDs, such as Hurler syndrome,23 has not yet been associated with significant activity in clinical studies of MPS III, including those that initiated treatment prior to the onset of neurological symptoms.24 However, promising early results have been reported in a study of gene-modified HSCT, which overexpresses the MPS IIIA enzyme.
“The clinical trial landscape fluctuates quite a bit, so I always encourage clinicians and families to check back often for updates. Patient organizations can also be helpful for understanding the most up-to-date and emerging trial options,” Dr. O’Neill reported.
Although it is expected that the greatest benefit would be derived from treatments initiated before or very early after the onset of symptoms, based on the limited potential for reversing cognitive loss, Dr. O’Neill said that she and others are also striving to offer treatments for individuals now living with Sanfilippo syndrome.
“We have to be willing to test treatments that are symptomatic in nature. To that aim, the Cure Sanfilippo Foundation has sponsored a study of a CNS-penetrating anti-inflammatory agent in advanced-disease patients more than 4 years of age,” Dr. O’Neill said. This group of patients typically been ineligible for clinical trials in the past. Dr. O’Neill hopes to change this orientation.
“It is important to highlight that all patients deserve our efforts to improve their quality of life and alleviate suffering, regardless of how old they are or how progressed in the disease they happen to be,” she said.
However, whether the goal is enrollment before or early in disease or later in disease progression, the challenge of enrolling sufficient numbers of patients to confirm clinical activity has been and continues to be a hurdle to progress.
“Clinical studies in Sanfilippo enroll relatively small numbers of patients, often 20 or less,” said Dr. O’Neill, explaining one of the reasons why her organization has been so active in raising awareness and funding such studies. For patients and families, the Cure Sanfilippo Foundation can offer a variety of guidance and support, but information about opportunities for clinical trial participation is a key resource they provide for families and their physicians.
Conclusion
For most children with Sanfilippo syndrome, life expectancy is limited. However, the characterization of the genetic causes and the biochemistry of the subtypes has led to several viable therapeutic approaches under development. There has been progress in delivery of therapeutic enzymes to the CNS, and there is substantial optimism that more progress is coming. One issue for treatment development, is the last of a clear regulatory pathway addressing important biomarkers of pathology, such as heparan sulfate burden. Developing treatments that address this issue or impaired enzyme activity levels have promise for preventing progression, particularly if started in infancy. However, the effort to draw awareness to this disease is the first step toward accelerating the time to an early diagnosis and subsequent opportunities to enroll in clinical trials.
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