MDedge Neurology

Tramadol is increasingly used to manage chronic noncancer pain, but as compared with opioids, it appears to be linked to a higher risk for adverse outcomes, according to new data.

Among a cohort of patients who received a prescription for either tramadol or codeine for orthopedic-related pain, tramadol was significantly associated with a higher risk of mortality, cardiovascular events, and fractures.

However, there was no significant difference in the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders between the two drugs.

“However, this is a retrospective cohort study, and despite it providing information that would otherwise be impossible to gather – such as from randomized controlled trials – clinicians should not solely base their decision on this study,” cautioned lead author Carlen Reyes, MD, PhD, of the Institut Universitari d’Investigació en Atenció Primària (IDIAP Jordi Gol), Barcelona.

Dr. Reyes noted that the intake of tramadol and codeine was analyzed using the number of “packages” that were dispensed, as an approximation of the real intake. “Logically we could think that the more packages dispensed of one drug, the more dose the patient is taking, but this is not always true given the availability of different doses commercialized of tramadol and different doses prescribed,” she said. “Given that we did not account for the real dose prescribed, we can only suspect an increased risk of these outcomes and reinforce the need for further prospective studies with more specific dose-response analysis comparing tramadol and codeine.”

The paper was published Oct. 19 in JAMA.

Tramadol has been considered to be a relatively safe opioid and was even strongly recommended by the American Academy of Orthopaedic Surgeons for patients experiencing symptomatic knee osteoarthritis. The authors point out that studies looking at opioid use from 2019 to 2020 show that tramadol was the most prescribed opioid in England, the Netherlands, and Spain.

In the United States, the age-adjusted rate of drug overdose deaths from synthetic opioids rose from 1.0 per 100 000 in 2013 to 11.4 in 2019. Most of these deaths were attributable to fentanyl but some were also related to tramadol.

But despite its wide use in managing chronic noncancer pain, results of recent studies suggest adverse outcomes as compared with other agents. Last year, one study found that older patients who received tramadol had a significant increase in the risk of hip fracture vs. those using NSAIDs or codeine. Another study, also published in 2020, showed that patients with osteoarthritis who were treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs.

In the current paper, Dr. Reyes and colleagues evaluated the association of tramadol with mortality and other adverse clinical outcomes in outpatient settings, compared with codeine.

They conducted a retrospective, population-based, propensity score–matched cohort study using a primary care database that routinely collects medical records and pharmacy dispensations for more than 80% of the population of Catalonia, Spain. The cohort included people 18 years or older who had been prescribed tramadol or codeine from 2007 to 2017 and were followed up to Dec. 31, 2017.

After propensity score matching, the final analysis included 368,960 participants: 184,480 in the tramadol arm and 184,480 in the codeine arm.

The mean age of patients was 52.7 years in the tramadol arm and 53.5 years in the codeine arm, and the prevalence of cancer was 3.2% and 3.3%, respectively. The most common diagnoses in this cohort were back pain (47.5% vs. 48.5%), neck/shoulder pain (28.6% vs. 29.5%), and osteoarthritis (15.3% vs. 15.5%). The most commonly used drugs were ibuprofen (34.4% vs. 34.3%) and paracetamol/acetaminophen (37.1% vs. 36.8%)

Higher risk of adverse outcomes

As compared with codeine, tramadol use was significantly associated with a higher risk of mortality (13.00 vs. 5.61 per 1,000 person-years; hazard ratio, 2.31; 95% confidence interval, 2.08-2.56); absolute rate differences (7.37 per 1,000 person-years; 95% CI, 6.09-8.78), cardiovascular events (10.03 vs. 8.67 per 1,000 person-years; HR, 1.15; 95% CI, 1.05-1.27; ARD, 1.36 per 1,000 person-years; 95% CI, 0.45-2.36), and fractures (12.26 vs. 8.13 per 1,000 person-years; HR, 1.50; 95% CI, 1.37-1.65; ARD, 4.10 per 1,000 person-years; 95% CI, 3.02-5.29).

A subgroup and sensitivity analysis showed that the increased mortality risk associated with tramadol was significantly higher in younger persons vs. older ones (HR, 3.14; 95% CI, 1.82-5.41 vs. 2.39; 95% CI, 2.20-2.60]; P < .001 for interaction). In addition, women had a significantly greater risk of cardiovascular events versus men (HR, 1.32; 95% CI, 1.19-1.46] vs. 1.03; 95% CI, 0.9-1.13]; P < .001 for interaction).
 

Potential for confounding

Weighing in on the data, Daniel Solomon, MD, MPH, chief of clinical sciences, division of rheumatology, Brigham and Women’s Hospital, and professor of medicine, Harvard Medical School, Boston, noted that because it is extremely unlikely that anyone will ever conduct a large, head-to-head safety trial comparing different opioids, the results of this paper are important to consider.

“However, as the authors appropriately caution, this type of analysis is limited by the strong potential for residual confounding,” he said. “In other words, even though the authors used state-of-the-art methods to limit imbalances between the patients initiating tramadol versus codeine, there is strong reason to believe that imbalances that may account for the differences in adverse events exist.”

For example, he noted that if one looks at the distribution of comorbid conditions in the before-matching group, tramadol initiators demonstrate a higher frequency of chronic kidney disease, diabetes, and overall chronic comorbid diseases. “This suggests to me that prescribers apply selection criteria when choosing who to prescribe which opioid,” Dr. Solomon explained.

“While the authors’ use of propensity score matching limits confounding, it only can improve balance for measured confounders,” he said. “Other factors not measured in this type of data set – blood pressure, pain, physical activity, tobacco use, body mass index – may still demonstrate imbalances even after matching.”

But after these limitations are taken into consideration, the results remain concerning, Dr. Solomon emphasized, particularly the all-cause mortality excess of tramadol versus codeine users. “This study did not include cause of death, which would help the reader understand why users of tramadol were dying more frequently,” he added. “It also might help in understanding whether this is a true biologic effect or residual confounding.”

Perceived safety

In an accompanying editorial, Howard S. Kim, MD, MS, and colleagues from Northwestern University, Chicago, write that the greatest risk of tramadol may involve the perception that it is “inherently safer than other opioids.”

“In actuality, the mechanisms of action and variable metabolism of tramadol in a given population create considerable therapeutic uncertainty and introduce additional risk exposure,” they say, as demonstrated in the current study.

Therefore, when clinicians determine that an opioid is needed for pain relief, it may be a better option to select a pure opioid agonist that has a more predictable therapeutic effect and known adverse effect profile, such as morphine or hydrocodone. “This would allow clinicians and patients to more properly weigh the risks and benefits of initiating opioid therapy through shared decision-making and prompt the level of counseling on safe use, storage, and disposal practices that all opioids deserve,” write the editorialists.

The study was funded by the Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina. The research was supported by the National Institute for Health Research Oxford Biomedical Research Centre. Dr. Reyes has disclosed no relevant financial relationships. Dr. Solomon disclosed salary support from research contracts to his hospital from Amgen, AbbVie, Moderna, the Rheumatology Research Foundation, and National Institutes of Health; and royalties from UpToDate. Dr. Kim reported unrelated grant support from the Agency for Healthcare Research and Quality.
 

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

Tramadol is increasingly used to manage chronic noncancer pain, but as compared with opioids, it appears to be linked to a higher risk for adverse outcomes, according to new data.

Among a cohort of patients who received a prescription for either tramadol or codeine for orthopedic-related pain, tramadol was significantly associated with a higher risk of mortality, cardiovascular events, and fractures.

However, there was no significant difference in the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders between the two drugs.

“However, this is a retrospective cohort study, and despite it providing information that would otherwise be impossible to gather – such as from randomized controlled trials – clinicians should not solely base their decision on this study,” cautioned lead author Carlen Reyes, MD, PhD, of the Institut Universitari d’Investigació en Atenció Primària (IDIAP Jordi Gol), Barcelona.

Dr. Reyes noted that the intake of tramadol and codeine was analyzed using the number of “packages” that were dispensed, as an approximation of the real intake. “Logically we could think that the more packages dispensed of one drug, the more dose the patient is taking, but this is not always true given the availability of different doses commercialized of tramadol and different doses prescribed,” she said. “Given that we did not account for the real dose prescribed, we can only suspect an increased risk of these outcomes and reinforce the need for further prospective studies with more specific dose-response analysis comparing tramadol and codeine.”

The paper was published Oct. 19 in JAMA.

Tramadol has been considered to be a relatively safe opioid and was even strongly recommended by the American Academy of Orthopaedic Surgeons for patients experiencing symptomatic knee osteoarthritis. The authors point out that studies looking at opioid use from 2019 to 2020 show that tramadol was the most prescribed opioid in England, the Netherlands, and Spain.

In the United States, the age-adjusted rate of drug overdose deaths from synthetic opioids rose from 1.0 per 100 000 in 2013 to 11.4 in 2019. Most of these deaths were attributable to fentanyl but some were also related to tramadol.

But despite its wide use in managing chronic noncancer pain, results of recent studies suggest adverse outcomes as compared with other agents. Last year, one study found that older patients who received tramadol had a significant increase in the risk of hip fracture vs. those using NSAIDs or codeine. Another study, also published in 2020, showed that patients with osteoarthritis who were treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs.

In the current paper, Dr. Reyes and colleagues evaluated the association of tramadol with mortality and other adverse clinical outcomes in outpatient settings, compared with codeine.

They conducted a retrospective, population-based, propensity score–matched cohort study using a primary care database that routinely collects medical records and pharmacy dispensations for more than 80% of the population of Catalonia, Spain. The cohort included people 18 years or older who had been prescribed tramadol or codeine from 2007 to 2017 and were followed up to Dec. 31, 2017.

After propensity score matching, the final analysis included 368,960 participants: 184,480 in the tramadol arm and 184,480 in the codeine arm.

The mean age of patients was 52.7 years in the tramadol arm and 53.5 years in the codeine arm, and the prevalence of cancer was 3.2% and 3.3%, respectively. The most common diagnoses in this cohort were back pain (47.5% vs. 48.5%), neck/shoulder pain (28.6% vs. 29.5%), and osteoarthritis (15.3% vs. 15.5%). The most commonly used drugs were ibuprofen (34.4% vs. 34.3%) and paracetamol/acetaminophen (37.1% vs. 36.8%)

Higher risk of adverse outcomes

As compared with codeine, tramadol use was significantly associated with a higher risk of mortality (13.00 vs. 5.61 per 1,000 person-years; hazard ratio, 2.31; 95% confidence interval, 2.08-2.56); absolute rate differences (7.37 per 1,000 person-years; 95% CI, 6.09-8.78), cardiovascular events (10.03 vs. 8.67 per 1,000 person-years; HR, 1.15; 95% CI, 1.05-1.27; ARD, 1.36 per 1,000 person-years; 95% CI, 0.45-2.36), and fractures (12.26 vs. 8.13 per 1,000 person-years; HR, 1.50; 95% CI, 1.37-1.65; ARD, 4.10 per 1,000 person-years; 95% CI, 3.02-5.29).

A subgroup and sensitivity analysis showed that the increased mortality risk associated with tramadol was significantly higher in younger persons vs. older ones (HR, 3.14; 95% CI, 1.82-5.41 vs. 2.39; 95% CI, 2.20-2.60]; P < .001 for interaction). In addition, women had a significantly greater risk of cardiovascular events versus men (HR, 1.32; 95% CI, 1.19-1.46] vs. 1.03; 95% CI, 0.9-1.13]; P < .001 for interaction).
 

Potential for confounding

Weighing in on the data, Daniel Solomon, MD, MPH, chief of clinical sciences, division of rheumatology, Brigham and Women’s Hospital, and professor of medicine, Harvard Medical School, Boston, noted that because it is extremely unlikely that anyone will ever conduct a large, head-to-head safety trial comparing different opioids, the results of this paper are important to consider.

“However, as the authors appropriately caution, this type of analysis is limited by the strong potential for residual confounding,” he said. “In other words, even though the authors used state-of-the-art methods to limit imbalances between the patients initiating tramadol versus codeine, there is strong reason to believe that imbalances that may account for the differences in adverse events exist.”

For example, he noted that if one looks at the distribution of comorbid conditions in the before-matching group, tramadol initiators demonstrate a higher frequency of chronic kidney disease, diabetes, and overall chronic comorbid diseases. “This suggests to me that prescribers apply selection criteria when choosing who to prescribe which opioid,” Dr. Solomon explained.

“While the authors’ use of propensity score matching limits confounding, it only can improve balance for measured confounders,” he said. “Other factors not measured in this type of data set – blood pressure, pain, physical activity, tobacco use, body mass index – may still demonstrate imbalances even after matching.”

But after these limitations are taken into consideration, the results remain concerning, Dr. Solomon emphasized, particularly the all-cause mortality excess of tramadol versus codeine users. “This study did not include cause of death, which would help the reader understand why users of tramadol were dying more frequently,” he added. “It also might help in understanding whether this is a true biologic effect or residual confounding.”

Perceived safety

In an accompanying editorial, Howard S. Kim, MD, MS, and colleagues from Northwestern University, Chicago, write that the greatest risk of tramadol may involve the perception that it is “inherently safer than other opioids.”

“In actuality, the mechanisms of action and variable metabolism of tramadol in a given population create considerable therapeutic uncertainty and introduce additional risk exposure,” they say, as demonstrated in the current study.

Therefore, when clinicians determine that an opioid is needed for pain relief, it may be a better option to select a pure opioid agonist that has a more predictable therapeutic effect and known adverse effect profile, such as morphine or hydrocodone. “This would allow clinicians and patients to more properly weigh the risks and benefits of initiating opioid therapy through shared decision-making and prompt the level of counseling on safe use, storage, and disposal practices that all opioids deserve,” write the editorialists.

The study was funded by the Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina. The research was supported by the National Institute for Health Research Oxford Biomedical Research Centre. Dr. Reyes has disclosed no relevant financial relationships. Dr. Solomon disclosed salary support from research contracts to his hospital from Amgen, AbbVie, Moderna, the Rheumatology Research Foundation, and National Institutes of Health; and royalties from UpToDate. Dr. Kim reported unrelated grant support from the Agency for Healthcare Research and Quality.
 

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

Tramadol is increasingly used to manage chronic noncancer pain, but as compared with opioids, it appears to be linked to a higher risk for adverse outcomes, according to new data.

Among a cohort of patients who received a prescription for either tramadol or codeine for orthopedic-related pain, tramadol was significantly associated with a higher risk of mortality, cardiovascular events, and fractures.

However, there was no significant difference in the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders between the two drugs.

“However, this is a retrospective cohort study, and despite it providing information that would otherwise be impossible to gather – such as from randomized controlled trials – clinicians should not solely base their decision on this study,” cautioned lead author Carlen Reyes, MD, PhD, of the Institut Universitari d’Investigació en Atenció Primària (IDIAP Jordi Gol), Barcelona.

Dr. Reyes noted that the intake of tramadol and codeine was analyzed using the number of “packages” that were dispensed, as an approximation of the real intake. “Logically we could think that the more packages dispensed of one drug, the more dose the patient is taking, but this is not always true given the availability of different doses commercialized of tramadol and different doses prescribed,” she said. “Given that we did not account for the real dose prescribed, we can only suspect an increased risk of these outcomes and reinforce the need for further prospective studies with more specific dose-response analysis comparing tramadol and codeine.”

The paper was published Oct. 19 in JAMA.

Tramadol has been considered to be a relatively safe opioid and was even strongly recommended by the American Academy of Orthopaedic Surgeons for patients experiencing symptomatic knee osteoarthritis. The authors point out that studies looking at opioid use from 2019 to 2020 show that tramadol was the most prescribed opioid in England, the Netherlands, and Spain.

In the United States, the age-adjusted rate of drug overdose deaths from synthetic opioids rose from 1.0 per 100 000 in 2013 to 11.4 in 2019. Most of these deaths were attributable to fentanyl but some were also related to tramadol.

But despite its wide use in managing chronic noncancer pain, results of recent studies suggest adverse outcomes as compared with other agents. Last year, one study found that older patients who received tramadol had a significant increase in the risk of hip fracture vs. those using NSAIDs or codeine. Another study, also published in 2020, showed that patients with osteoarthritis who were treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs.

In the current paper, Dr. Reyes and colleagues evaluated the association of tramadol with mortality and other adverse clinical outcomes in outpatient settings, compared with codeine.

They conducted a retrospective, population-based, propensity score–matched cohort study using a primary care database that routinely collects medical records and pharmacy dispensations for more than 80% of the population of Catalonia, Spain. The cohort included people 18 years or older who had been prescribed tramadol or codeine from 2007 to 2017 and were followed up to Dec. 31, 2017.

After propensity score matching, the final analysis included 368,960 participants: 184,480 in the tramadol arm and 184,480 in the codeine arm.

The mean age of patients was 52.7 years in the tramadol arm and 53.5 years in the codeine arm, and the prevalence of cancer was 3.2% and 3.3%, respectively. The most common diagnoses in this cohort were back pain (47.5% vs. 48.5%), neck/shoulder pain (28.6% vs. 29.5%), and osteoarthritis (15.3% vs. 15.5%). The most commonly used drugs were ibuprofen (34.4% vs. 34.3%) and paracetamol/acetaminophen (37.1% vs. 36.8%)

Higher risk of adverse outcomes

As compared with codeine, tramadol use was significantly associated with a higher risk of mortality (13.00 vs. 5.61 per 1,000 person-years; hazard ratio, 2.31; 95% confidence interval, 2.08-2.56); absolute rate differences (7.37 per 1,000 person-years; 95% CI, 6.09-8.78), cardiovascular events (10.03 vs. 8.67 per 1,000 person-years; HR, 1.15; 95% CI, 1.05-1.27; ARD, 1.36 per 1,000 person-years; 95% CI, 0.45-2.36), and fractures (12.26 vs. 8.13 per 1,000 person-years; HR, 1.50; 95% CI, 1.37-1.65; ARD, 4.10 per 1,000 person-years; 95% CI, 3.02-5.29).

A subgroup and sensitivity analysis showed that the increased mortality risk associated with tramadol was significantly higher in younger persons vs. older ones (HR, 3.14; 95% CI, 1.82-5.41 vs. 2.39; 95% CI, 2.20-2.60]; P < .001 for interaction). In addition, women had a significantly greater risk of cardiovascular events versus men (HR, 1.32; 95% CI, 1.19-1.46] vs. 1.03; 95% CI, 0.9-1.13]; P < .001 for interaction).
 

Potential for confounding

Weighing in on the data, Daniel Solomon, MD, MPH, chief of clinical sciences, division of rheumatology, Brigham and Women’s Hospital, and professor of medicine, Harvard Medical School, Boston, noted that because it is extremely unlikely that anyone will ever conduct a large, head-to-head safety trial comparing different opioids, the results of this paper are important to consider.

“However, as the authors appropriately caution, this type of analysis is limited by the strong potential for residual confounding,” he said. “In other words, even though the authors used state-of-the-art methods to limit imbalances between the patients initiating tramadol versus codeine, there is strong reason to believe that imbalances that may account for the differences in adverse events exist.”

For example, he noted that if one looks at the distribution of comorbid conditions in the before-matching group, tramadol initiators demonstrate a higher frequency of chronic kidney disease, diabetes, and overall chronic comorbid diseases. “This suggests to me that prescribers apply selection criteria when choosing who to prescribe which opioid,” Dr. Solomon explained.

“While the authors’ use of propensity score matching limits confounding, it only can improve balance for measured confounders,” he said. “Other factors not measured in this type of data set – blood pressure, pain, physical activity, tobacco use, body mass index – may still demonstrate imbalances even after matching.”

But after these limitations are taken into consideration, the results remain concerning, Dr. Solomon emphasized, particularly the all-cause mortality excess of tramadol versus codeine users. “This study did not include cause of death, which would help the reader understand why users of tramadol were dying more frequently,” he added. “It also might help in understanding whether this is a true biologic effect or residual confounding.”

Perceived safety

In an accompanying editorial, Howard S. Kim, MD, MS, and colleagues from Northwestern University, Chicago, write that the greatest risk of tramadol may involve the perception that it is “inherently safer than other opioids.”

“In actuality, the mechanisms of action and variable metabolism of tramadol in a given population create considerable therapeutic uncertainty and introduce additional risk exposure,” they say, as demonstrated in the current study.

Therefore, when clinicians determine that an opioid is needed for pain relief, it may be a better option to select a pure opioid agonist that has a more predictable therapeutic effect and known adverse effect profile, such as morphine or hydrocodone. “This would allow clinicians and patients to more properly weigh the risks and benefits of initiating opioid therapy through shared decision-making and prompt the level of counseling on safe use, storage, and disposal practices that all opioids deserve,” write the editorialists.

The study was funded by the Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina. The research was supported by the National Institute for Health Research Oxford Biomedical Research Centre. Dr. Reyes has disclosed no relevant financial relationships. Dr. Solomon disclosed salary support from research contracts to his hospital from Amgen, AbbVie, Moderna, the Rheumatology Research Foundation, and National Institutes of Health; and royalties from UpToDate. Dr. Kim reported unrelated grant support from the Agency for Healthcare Research and Quality.
 

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

The first European consensus on vaccination in patients with multiple sclerosis (MS) has been developed by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN).

The document, announced at the annual ECTRIMS meeting, proposes a standard for vaccination in patients with MS, including a global vaccination strategy for the general MS patient population and selected subpopulations.

The document does not include any recommendations regarding vaccination against COVID-19, which is the subject of a separate report, announced at the annual meeting. 

The main conclusions in the new report are as follows:

• Vaccinations in general are considered safe for patients with MS and do not modify disease activity/progression.
• Live attenuated vaccines, however, are contraindicated with immunosuppressants.
• Inactivated vaccines can be used safely, but their efficacy may be decreased with immunosuppressants.
• Vaccinations should be considered early in MS management before using immunosuppressants whenever possible.

Presenting the vaccination consensus document, Susana Otero-Romero, MD, from the Multiple Sclerosis Center of Catalonia, Spain, explained that vaccination has become an important part of the risk management strategy in patients with MS treated with highly active drugs but that questions remain as to when and whether to introduce a particular vaccine and which disease-modifying treatments affect vaccine response. 

“The current reference tool has been developed to help professionals to decide on the best vaccination strategy for their patients,” she said.  

The consensus document recommends that, in general, vaccination should be performed at the time of diagnosis of MS or in the early stages of the disease to prevent future delays in starting therapies.

“Ideally, vaccination should take place before the onset of disease-modifying treatment,” Dr. Otero-Romero said. The consensus document recommends inactivated vaccines to be given 2-3 weeks before immunosuppressive therapy is started, and live attenuated vaccines at least 4 weeks beforehand.

In the case of relapse, vaccination should be delayed until clinical resolution or stabilization if possible, the consensus statement recommends.

Serological testing for vaccine-induced antibody titers can be performed 1-2 months after the last dose of the vaccine (suggested for hepatitis B, measles, mumps, and varicella). For attenuated live vaccines, serological tests should be done before starting immunosuppressive therapy. In the case of insufficient response, consideration should be given to administering a booster dose of the vaccine, except for hepatitis B, in which a complete revaccination is recommended, according to the document.

As for vaccination during immunosuppressive therapy, this is considered safe for patients on interferon or glatiramer acetate when indicated, the report says. 

Vaccination should ideally be avoided in patients on dimethyl fumarate, teriflunomide (Aubagio) or natalizumab (Tysabri), although it can be considered in exceptional cases when the potential risk of acquiring the infection is greater than the risk of developing vaccine-related infections (unless the absolute lymphocyte count is below 800/mm³), it adds.

Vaccination should be avoided in patients on S1P modulators (for example, fingolimod [Gilenya]), anti-CD20 therapies, and before immune restoration for cladribine (Leustatin) and alemtuzumab (Lemtrada).

In the case of patients stopping immunosuppressive therapy, inactivated vaccines can be given any time after the discontinuation of therapy but preferably after immune restoration. Live attenuated vaccines should only be administered after a safety interval ensures immune restoration has been met.
 

Which vaccines?

On which vaccines are needed in patients with MS, the consensus document recommends the same routine vaccination schedule as for the general population. In addition, it advises influenza and pneumococcal vaccination if patients are immunosuppressed or have significant disability.

It also recommends human papillomavirus vaccine in women and men independent of their age if they are to be treated with alemtuzumab, fingolimod, cladribine, or anti-CD20 drugs. Hepatitis B vaccination is also advised in patients treated with anti-CD20 drugs.
 

Special populations: pregnancy/elderly

In patients with MS who are pregnant, inactivated flu vaccine can be given in any trimester at the start of the flu season, and vaccination against diphtheria, tetanus, and pertussis can be given during the third trimester, the report says. Live attenuated vaccines should be completed at least 1 month before pregnancy or after delivery and 4-6 weeks prior to the initiation of immunosuppressive therapy.

Elderly patients with MS should receive flu and pneumococcal vaccines annually and would also benefit from the inactivated herpes zoster vaccine.
 

Travel vaccines

On vaccinations needed for travel, the report recommends that patients with MS consult a specialized travel clinic or vaccination expert and start immunizations 2-3 months before departure. Patients with MS with or without immunosuppressive therapy can receive hepatitis A, rabies, Japanese encephalitis, tic-borne encephalitis, polio, and inactivated typhoid vaccine. But yellow fever and oral typhoid are contraindicated in patients on immunosuppressive therapies.

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

The first European consensus on vaccination in patients with multiple sclerosis (MS) has been developed by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN).

The document, announced at the annual ECTRIMS meeting, proposes a standard for vaccination in patients with MS, including a global vaccination strategy for the general MS patient population and selected subpopulations.

The document does not include any recommendations regarding vaccination against COVID-19, which is the subject of a separate report, announced at the annual meeting. 

The main conclusions in the new report are as follows:

• Vaccinations in general are considered safe for patients with MS and do not modify disease activity/progression.
• Live attenuated vaccines, however, are contraindicated with immunosuppressants.
• Inactivated vaccines can be used safely, but their efficacy may be decreased with immunosuppressants.
• Vaccinations should be considered early in MS management before using immunosuppressants whenever possible.

Presenting the vaccination consensus document, Susana Otero-Romero, MD, from the Multiple Sclerosis Center of Catalonia, Spain, explained that vaccination has become an important part of the risk management strategy in patients with MS treated with highly active drugs but that questions remain as to when and whether to introduce a particular vaccine and which disease-modifying treatments affect vaccine response. 

“The current reference tool has been developed to help professionals to decide on the best vaccination strategy for their patients,” she said.  

The consensus document recommends that, in general, vaccination should be performed at the time of diagnosis of MS or in the early stages of the disease to prevent future delays in starting therapies.

“Ideally, vaccination should take place before the onset of disease-modifying treatment,” Dr. Otero-Romero said. The consensus document recommends inactivated vaccines to be given 2-3 weeks before immunosuppressive therapy is started, and live attenuated vaccines at least 4 weeks beforehand.

In the case of relapse, vaccination should be delayed until clinical resolution or stabilization if possible, the consensus statement recommends.

Serological testing for vaccine-induced antibody titers can be performed 1-2 months after the last dose of the vaccine (suggested for hepatitis B, measles, mumps, and varicella). For attenuated live vaccines, serological tests should be done before starting immunosuppressive therapy. In the case of insufficient response, consideration should be given to administering a booster dose of the vaccine, except for hepatitis B, in which a complete revaccination is recommended, according to the document.

As for vaccination during immunosuppressive therapy, this is considered safe for patients on interferon or glatiramer acetate when indicated, the report says. 

Vaccination should ideally be avoided in patients on dimethyl fumarate, teriflunomide (Aubagio) or natalizumab (Tysabri), although it can be considered in exceptional cases when the potential risk of acquiring the infection is greater than the risk of developing vaccine-related infections (unless the absolute lymphocyte count is below 800/mm³), it adds.

Vaccination should be avoided in patients on S1P modulators (for example, fingolimod [Gilenya]), anti-CD20 therapies, and before immune restoration for cladribine (Leustatin) and alemtuzumab (Lemtrada).

In the case of patients stopping immunosuppressive therapy, inactivated vaccines can be given any time after the discontinuation of therapy but preferably after immune restoration. Live attenuated vaccines should only be administered after a safety interval ensures immune restoration has been met.
 

Which vaccines?

On which vaccines are needed in patients with MS, the consensus document recommends the same routine vaccination schedule as for the general population. In addition, it advises influenza and pneumococcal vaccination if patients are immunosuppressed or have significant disability.

It also recommends human papillomavirus vaccine in women and men independent of their age if they are to be treated with alemtuzumab, fingolimod, cladribine, or anti-CD20 drugs. Hepatitis B vaccination is also advised in patients treated with anti-CD20 drugs.
 

Special populations: pregnancy/elderly

In patients with MS who are pregnant, inactivated flu vaccine can be given in any trimester at the start of the flu season, and vaccination against diphtheria, tetanus, and pertussis can be given during the third trimester, the report says. Live attenuated vaccines should be completed at least 1 month before pregnancy or after delivery and 4-6 weeks prior to the initiation of immunosuppressive therapy.

Elderly patients with MS should receive flu and pneumococcal vaccines annually and would also benefit from the inactivated herpes zoster vaccine.
 

Travel vaccines

On vaccinations needed for travel, the report recommends that patients with MS consult a specialized travel clinic or vaccination expert and start immunizations 2-3 months before departure. Patients with MS with or without immunosuppressive therapy can receive hepatitis A, rabies, Japanese encephalitis, tic-borne encephalitis, polio, and inactivated typhoid vaccine. But yellow fever and oral typhoid are contraindicated in patients on immunosuppressive therapies.

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

The first European consensus on vaccination in patients with multiple sclerosis (MS) has been developed by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN).

The document, announced at the annual ECTRIMS meeting, proposes a standard for vaccination in patients with MS, including a global vaccination strategy for the general MS patient population and selected subpopulations.

The document does not include any recommendations regarding vaccination against COVID-19, which is the subject of a separate report, announced at the annual meeting. 

The main conclusions in the new report are as follows:

• Vaccinations in general are considered safe for patients with MS and do not modify disease activity/progression.
• Live attenuated vaccines, however, are contraindicated with immunosuppressants.
• Inactivated vaccines can be used safely, but their efficacy may be decreased with immunosuppressants.
• Vaccinations should be considered early in MS management before using immunosuppressants whenever possible.

Presenting the vaccination consensus document, Susana Otero-Romero, MD, from the Multiple Sclerosis Center of Catalonia, Spain, explained that vaccination has become an important part of the risk management strategy in patients with MS treated with highly active drugs but that questions remain as to when and whether to introduce a particular vaccine and which disease-modifying treatments affect vaccine response. 

“The current reference tool has been developed to help professionals to decide on the best vaccination strategy for their patients,” she said.  

The consensus document recommends that, in general, vaccination should be performed at the time of diagnosis of MS or in the early stages of the disease to prevent future delays in starting therapies.

“Ideally, vaccination should take place before the onset of disease-modifying treatment,” Dr. Otero-Romero said. The consensus document recommends inactivated vaccines to be given 2-3 weeks before immunosuppressive therapy is started, and live attenuated vaccines at least 4 weeks beforehand.

In the case of relapse, vaccination should be delayed until clinical resolution or stabilization if possible, the consensus statement recommends.

Serological testing for vaccine-induced antibody titers can be performed 1-2 months after the last dose of the vaccine (suggested for hepatitis B, measles, mumps, and varicella). For attenuated live vaccines, serological tests should be done before starting immunosuppressive therapy. In the case of insufficient response, consideration should be given to administering a booster dose of the vaccine, except for hepatitis B, in which a complete revaccination is recommended, according to the document.

As for vaccination during immunosuppressive therapy, this is considered safe for patients on interferon or glatiramer acetate when indicated, the report says. 

Vaccination should ideally be avoided in patients on dimethyl fumarate, teriflunomide (Aubagio) or natalizumab (Tysabri), although it can be considered in exceptional cases when the potential risk of acquiring the infection is greater than the risk of developing vaccine-related infections (unless the absolute lymphocyte count is below 800/mm³), it adds.

Vaccination should be avoided in patients on S1P modulators (for example, fingolimod [Gilenya]), anti-CD20 therapies, and before immune restoration for cladribine (Leustatin) and alemtuzumab (Lemtrada).

In the case of patients stopping immunosuppressive therapy, inactivated vaccines can be given any time after the discontinuation of therapy but preferably after immune restoration. Live attenuated vaccines should only be administered after a safety interval ensures immune restoration has been met.
 

Which vaccines?

On which vaccines are needed in patients with MS, the consensus document recommends the same routine vaccination schedule as for the general population. In addition, it advises influenza and pneumococcal vaccination if patients are immunosuppressed or have significant disability.

It also recommends human papillomavirus vaccine in women and men independent of their age if they are to be treated with alemtuzumab, fingolimod, cladribine, or anti-CD20 drugs. Hepatitis B vaccination is also advised in patients treated with anti-CD20 drugs.
 

Special populations: pregnancy/elderly

In patients with MS who are pregnant, inactivated flu vaccine can be given in any trimester at the start of the flu season, and vaccination against diphtheria, tetanus, and pertussis can be given during the third trimester, the report says. Live attenuated vaccines should be completed at least 1 month before pregnancy or after delivery and 4-6 weeks prior to the initiation of immunosuppressive therapy.

Elderly patients with MS should receive flu and pneumococcal vaccines annually and would also benefit from the inactivated herpes zoster vaccine.
 

Travel vaccines

On vaccinations needed for travel, the report recommends that patients with MS consult a specialized travel clinic or vaccination expert and start immunizations 2-3 months before departure. Patients with MS with or without immunosuppressive therapy can receive hepatitis A, rabies, Japanese encephalitis, tic-borne encephalitis, polio, and inactivated typhoid vaccine. But yellow fever and oral typhoid are contraindicated in patients on immunosuppressive therapies.

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

Rituximab reduces relapses and MRI activity in patients with relapsing-remitting multiple sclerosis (MS) more effectively than dimethyl fumarate, natalizumab, and injectable drugs, according to new research.

The risk for a first relapse was 6 times higher in patients receiving interferon beta or glatiramer acetate, compared with those receiving rituximab. But the level of disability at 3 years was only marginally different between the drugs studied.

The small differences in Expanded Disability Status Scale (EDSS) score are surprising, said investigator Peter Alping, a clinical assistant and doctoral student in the Department of Clinical Neuroscience at the Karolinska Institutet, Stockholm, as he presented the data. “It could be that we have too-short follow-up, so that EDSS doesn’t have time to diverge between therapies.”

He presented the findings at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

COMBAT-MS study

Direct comparisons of disease-modifying therapies (DMTs) for MS can help neurologists choose the most appropriate treatment for a given patient. To compare the effectiveness of the most common initial DMTs administered in Sweden, the researchers examined data from the COMBAT-MS study.

They identified all patients who initiated an injectable therapy (interferon beta or glatiramer acetate), dimethyl fumarate, natalizumab, or rituximab as a first treatment between Jan. 1, 2011, and Dec. 14, 2020. Eligible participants had prospectively recorded outcome data in the Swedish MS Register. Follow-up for a participant continued even if the participant stopped receiving therapy.

The investigators replaced missing data using multiple imputation. They adjusted for potential confounders using stabilized inverse probability of treatment weighting with baseline variables. These variables included age, sex, disease duration, geographical region, EDSS score, and relapses.
 

Rituximab reduced relapses

The researchers included 1,938 first-ever treatment episodes in their analysis. Of this group, 858 were associated with injectables, 339 with dimethyl fumarate, 269 with natalizumab, and 472 with rituximab.

Participants’ baseline characteristics differed by the DMT that they used. Patients who initiated natalizumab were the youngest, had the shortest disease duration, and had the most previous relapses.

For each outcome, the investigators compared all other therapies with rituximab. After they adjusted the data, they found that the hazard ratio for first relapse was 6.0 for injectables, 2.9 for dimethyl fumarate, and 1.8 for natalizumab.

In the adjusted model, the MRI lesion rate ratio for injectables, compared with rituximab, was 4.5. The rate ratio was 4.8 for dimethyl fumarate and 1.9 for natalizumab.

But differences in EDSS score at 3 years from treatment initiation were small. EDSS score in patients who received injectables was 0.24 points higher, compared with those receiving rituximab. EDSS score was 0.05 points higher in patients receiving dimethyl fumarate and 0.01 points lower in patients receiving natalizumab.

The risk for treatment discontinuation, however, differed significantly between therapies. The HR for treatment discontinuation was 32.7 for injectables, 20.3 for dimethyl fumarate, and 16.3 for natalizumab, compared with rituximab.

Among patients receiving dimethyl fumarate and injectables, the main reasons for discontinuing therapy were inadequate effect and adverse events. The main reason for discontinuation among patients receiving natalizumab was categorized as “other reason,” which mostly reflected John Cunningham virus positivity and concern for developing progressive multifocal leukoencephalopathy.
 

‘The uncertainty continues’

“These differences that we see in the effectiveness can be somewhat surprising, especially when it comes to natalizumab,” which is considered very effective, said Mr. Alping. The vulnerable period that occurs after switching from natalizumab may partly explain the difference. “This is something to keep in mind when starting patients on natalizumab treatment in the clinic,” Mr. Alping added.

Although rituximab is not indicated for MS, many clinics are using it in this population, said Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research at the Neurological Institute of Cleveland Clinic, both in Cleveland, Ohio. Dr. Fox was not involved in the study.

“Assessing the generalizability of the study outside Sweden will be important,” he added, “but I would be surprised if their findings did not hold up to external validation.”

The way that the researchers addressed missing data could affect the interpretation of the findings. “Depending upon how much data was missing, their imputation methods may have a high level of uncertainty,” said Dr. Fox.

The researchers’ adjustments for baseline differences also raise questions. “Even though MRI was an outcome, it doesn’t appear they adjusted for baseline differences in MRI between the groups,” Dr. Fox observed.

Moreover, the study was conducted over a long period of time. “We know there are time effects in MS, with a very different disease activity expected from patients over time,” said Dr. Fox. For example, relapse rates in placebo groups of MS trials tend to decline over time. “This time effect likely impacted their results.”

But the disability findings may be the most important part of the study, according to Dr. Fox. The lack of significant difference in disability progression between therapies “highlights that a couple relapses or lesions on MRI may be too small to translate into long-term differences in disability progression,” he said.

“The long-term implications of small differences in relapse and MRI outcomes may be very small,” Dr. Fox went on. “Thus, the uncertainty continues around escalation treatment versus initial highly effective treatment paradigms.”

The Patient-Centered Outcomes Research Institute, the Swedish Research Council, and NEURO Sweden funded this study. Mr. Alping disclosed no relevant financial relationships. Dr. Fox receives consulting fees from the companies that manufacture all the therapies analyzed in the study.

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

Rituximab reduces relapses and MRI activity in patients with relapsing-remitting multiple sclerosis (MS) more effectively than dimethyl fumarate, natalizumab, and injectable drugs, according to new research.

The risk for a first relapse was 6 times higher in patients receiving interferon beta or glatiramer acetate, compared with those receiving rituximab. But the level of disability at 3 years was only marginally different between the drugs studied.

The small differences in Expanded Disability Status Scale (EDSS) score are surprising, said investigator Peter Alping, a clinical assistant and doctoral student in the Department of Clinical Neuroscience at the Karolinska Institutet, Stockholm, as he presented the data. “It could be that we have too-short follow-up, so that EDSS doesn’t have time to diverge between therapies.”

He presented the findings at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

COMBAT-MS study

Direct comparisons of disease-modifying therapies (DMTs) for MS can help neurologists choose the most appropriate treatment for a given patient. To compare the effectiveness of the most common initial DMTs administered in Sweden, the researchers examined data from the COMBAT-MS study.

They identified all patients who initiated an injectable therapy (interferon beta or glatiramer acetate), dimethyl fumarate, natalizumab, or rituximab as a first treatment between Jan. 1, 2011, and Dec. 14, 2020. Eligible participants had prospectively recorded outcome data in the Swedish MS Register. Follow-up for a participant continued even if the participant stopped receiving therapy.

The investigators replaced missing data using multiple imputation. They adjusted for potential confounders using stabilized inverse probability of treatment weighting with baseline variables. These variables included age, sex, disease duration, geographical region, EDSS score, and relapses.
 

Rituximab reduced relapses

The researchers included 1,938 first-ever treatment episodes in their analysis. Of this group, 858 were associated with injectables, 339 with dimethyl fumarate, 269 with natalizumab, and 472 with rituximab.

Participants’ baseline characteristics differed by the DMT that they used. Patients who initiated natalizumab were the youngest, had the shortest disease duration, and had the most previous relapses.

For each outcome, the investigators compared all other therapies with rituximab. After they adjusted the data, they found that the hazard ratio for first relapse was 6.0 for injectables, 2.9 for dimethyl fumarate, and 1.8 for natalizumab.

In the adjusted model, the MRI lesion rate ratio for injectables, compared with rituximab, was 4.5. The rate ratio was 4.8 for dimethyl fumarate and 1.9 for natalizumab.

But differences in EDSS score at 3 years from treatment initiation were small. EDSS score in patients who received injectables was 0.24 points higher, compared with those receiving rituximab. EDSS score was 0.05 points higher in patients receiving dimethyl fumarate and 0.01 points lower in patients receiving natalizumab.

The risk for treatment discontinuation, however, differed significantly between therapies. The HR for treatment discontinuation was 32.7 for injectables, 20.3 for dimethyl fumarate, and 16.3 for natalizumab, compared with rituximab.

Among patients receiving dimethyl fumarate and injectables, the main reasons for discontinuing therapy were inadequate effect and adverse events. The main reason for discontinuation among patients receiving natalizumab was categorized as “other reason,” which mostly reflected John Cunningham virus positivity and concern for developing progressive multifocal leukoencephalopathy.
 

‘The uncertainty continues’

“These differences that we see in the effectiveness can be somewhat surprising, especially when it comes to natalizumab,” which is considered very effective, said Mr. Alping. The vulnerable period that occurs after switching from natalizumab may partly explain the difference. “This is something to keep in mind when starting patients on natalizumab treatment in the clinic,” Mr. Alping added.

Although rituximab is not indicated for MS, many clinics are using it in this population, said Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research at the Neurological Institute of Cleveland Clinic, both in Cleveland, Ohio. Dr. Fox was not involved in the study.

“Assessing the generalizability of the study outside Sweden will be important,” he added, “but I would be surprised if their findings did not hold up to external validation.”

The way that the researchers addressed missing data could affect the interpretation of the findings. “Depending upon how much data was missing, their imputation methods may have a high level of uncertainty,” said Dr. Fox.

The researchers’ adjustments for baseline differences also raise questions. “Even though MRI was an outcome, it doesn’t appear they adjusted for baseline differences in MRI between the groups,” Dr. Fox observed.

Moreover, the study was conducted over a long period of time. “We know there are time effects in MS, with a very different disease activity expected from patients over time,” said Dr. Fox. For example, relapse rates in placebo groups of MS trials tend to decline over time. “This time effect likely impacted their results.”

But the disability findings may be the most important part of the study, according to Dr. Fox. The lack of significant difference in disability progression between therapies “highlights that a couple relapses or lesions on MRI may be too small to translate into long-term differences in disability progression,” he said.

“The long-term implications of small differences in relapse and MRI outcomes may be very small,” Dr. Fox went on. “Thus, the uncertainty continues around escalation treatment versus initial highly effective treatment paradigms.”

The Patient-Centered Outcomes Research Institute, the Swedish Research Council, and NEURO Sweden funded this study. Mr. Alping disclosed no relevant financial relationships. Dr. Fox receives consulting fees from the companies that manufacture all the therapies analyzed in the study.

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

Rituximab reduces relapses and MRI activity in patients with relapsing-remitting multiple sclerosis (MS) more effectively than dimethyl fumarate, natalizumab, and injectable drugs, according to new research.

The risk for a first relapse was 6 times higher in patients receiving interferon beta or glatiramer acetate, compared with those receiving rituximab. But the level of disability at 3 years was only marginally different between the drugs studied.

The small differences in Expanded Disability Status Scale (EDSS) score are surprising, said investigator Peter Alping, a clinical assistant and doctoral student in the Department of Clinical Neuroscience at the Karolinska Institutet, Stockholm, as he presented the data. “It could be that we have too-short follow-up, so that EDSS doesn’t have time to diverge between therapies.”

He presented the findings at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

COMBAT-MS study

Direct comparisons of disease-modifying therapies (DMTs) for MS can help neurologists choose the most appropriate treatment for a given patient. To compare the effectiveness of the most common initial DMTs administered in Sweden, the researchers examined data from the COMBAT-MS study.

They identified all patients who initiated an injectable therapy (interferon beta or glatiramer acetate), dimethyl fumarate, natalizumab, or rituximab as a first treatment between Jan. 1, 2011, and Dec. 14, 2020. Eligible participants had prospectively recorded outcome data in the Swedish MS Register. Follow-up for a participant continued even if the participant stopped receiving therapy.

The investigators replaced missing data using multiple imputation. They adjusted for potential confounders using stabilized inverse probability of treatment weighting with baseline variables. These variables included age, sex, disease duration, geographical region, EDSS score, and relapses.
 

Rituximab reduced relapses

The researchers included 1,938 first-ever treatment episodes in their analysis. Of this group, 858 were associated with injectables, 339 with dimethyl fumarate, 269 with natalizumab, and 472 with rituximab.

Participants’ baseline characteristics differed by the DMT that they used. Patients who initiated natalizumab were the youngest, had the shortest disease duration, and had the most previous relapses.

For each outcome, the investigators compared all other therapies with rituximab. After they adjusted the data, they found that the hazard ratio for first relapse was 6.0 for injectables, 2.9 for dimethyl fumarate, and 1.8 for natalizumab.

In the adjusted model, the MRI lesion rate ratio for injectables, compared with rituximab, was 4.5. The rate ratio was 4.8 for dimethyl fumarate and 1.9 for natalizumab.

But differences in EDSS score at 3 years from treatment initiation were small. EDSS score in patients who received injectables was 0.24 points higher, compared with those receiving rituximab. EDSS score was 0.05 points higher in patients receiving dimethyl fumarate and 0.01 points lower in patients receiving natalizumab.

The risk for treatment discontinuation, however, differed significantly between therapies. The HR for treatment discontinuation was 32.7 for injectables, 20.3 for dimethyl fumarate, and 16.3 for natalizumab, compared with rituximab.

Among patients receiving dimethyl fumarate and injectables, the main reasons for discontinuing therapy were inadequate effect and adverse events. The main reason for discontinuation among patients receiving natalizumab was categorized as “other reason,” which mostly reflected John Cunningham virus positivity and concern for developing progressive multifocal leukoencephalopathy.
 

‘The uncertainty continues’

“These differences that we see in the effectiveness can be somewhat surprising, especially when it comes to natalizumab,” which is considered very effective, said Mr. Alping. The vulnerable period that occurs after switching from natalizumab may partly explain the difference. “This is something to keep in mind when starting patients on natalizumab treatment in the clinic,” Mr. Alping added.

Although rituximab is not indicated for MS, many clinics are using it in this population, said Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research at the Neurological Institute of Cleveland Clinic, both in Cleveland, Ohio. Dr. Fox was not involved in the study.

“Assessing the generalizability of the study outside Sweden will be important,” he added, “but I would be surprised if their findings did not hold up to external validation.”

The way that the researchers addressed missing data could affect the interpretation of the findings. “Depending upon how much data was missing, their imputation methods may have a high level of uncertainty,” said Dr. Fox.

The researchers’ adjustments for baseline differences also raise questions. “Even though MRI was an outcome, it doesn’t appear they adjusted for baseline differences in MRI between the groups,” Dr. Fox observed.

Moreover, the study was conducted over a long period of time. “We know there are time effects in MS, with a very different disease activity expected from patients over time,” said Dr. Fox. For example, relapse rates in placebo groups of MS trials tend to decline over time. “This time effect likely impacted their results.”

But the disability findings may be the most important part of the study, according to Dr. Fox. The lack of significant difference in disability progression between therapies “highlights that a couple relapses or lesions on MRI may be too small to translate into long-term differences in disability progression,” he said.

“The long-term implications of small differences in relapse and MRI outcomes may be very small,” Dr. Fox went on. “Thus, the uncertainty continues around escalation treatment versus initial highly effective treatment paradigms.”

The Patient-Centered Outcomes Research Institute, the Swedish Research Council, and NEURO Sweden funded this study. Mr. Alping disclosed no relevant financial relationships. Dr. Fox receives consulting fees from the companies that manufacture all the therapies analyzed in the study.

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

An inpatient psychiatric diagnosis at some point over a lifetime is significantly associated with a range of sleep problems, results from the largest study of its kind show.

A prior diagnosis of major depression, schizophrenia, anxiety, or bipolar disorder was associated with a later bedtime, earlier waking time, and significantly poorer sleep quality that included frequent awakenings during the night and shorter sleep bouts.

“We were struck by the pervasiveness of sleep problems across all the diagnoses of mental illness and sleep parameters we looked at,” study investigator Michael Wainberg, PhD, a postdoctoral fellow at the Krembil Centre for Neuroinformatics at the Center for Addiction and Mental Health (CAMH), Toronto, told this news organization. “This suggests there may need to be even more of an emphasis on sleep in these patients than there already is.”

The study, which includes data from nearly 90,000 adults in the United Kingdom, was published online October 12 in PLoS Medicine.

Wavebreak Media/Thinkstockphotos

Trove of data

Data for the analysis comes from the UK Biobank, a large-scale biomedical database launched in 2006 that has collected biological and medical data on more than 500,000 individuals who consented to provide blood, urine, and saliva samples and detailed lifestyle information that is matched to their medical records.

Between 2013 and 2015, more than 103,000 of these participants agreed to wear accelerometers on their wrists for 24 hours a day for 7 days, collecting a trove of data for researchers to mine.

“This allows us to get at objectively derived sleep measures and to measure them in greater numbers of people who have experienced mental illness,” said senior author Shreejoy Tripathy, PhD, assistant professor at the University of Toronto and independent scientist for CAMH. “You can study multiple disorders at once and the influence of other variables that might not be possible in the context of other studies.”

The research is the first known large-scale transdiagnostic study of objectively measured sleep and mental health. Insomnia and other sleep disorders are common among people with mental illness, as shown in prior research, including at least one study that used the same dataset the team employed for this project.

The new findings add to that body of work, Dr. Wainberg said, and look beyond just how long a person sleeps to the quality of the sleep they get.

“We found that the metrics of sleep quality seem to be affected more than mere sleep duration,” he said.
 

Unexpected finding

After excluding participants with faulty accelerometers and those who didn’t wear them for the entire 7-day study period, data from 89,205 participants (aged 43-79, 56% female, 97% self-reported White) was included. Lifetime inpatient psychiatric diagnoses were reported in 2.5% of the entire cohort.

Researchers looked at 10 sleep measures: bedtime, wake-up time, sleep duration, wake after sleep onset, sleep efficiency, number of awakenings, duration of longest sleep bout, number of naps, and variability in bedtime and sleep duration.

Although the effect sizes were small, having any psychiatric diagnosis was associated with significantly lower scores on every sleep measure except sleep duration.

Compared with those with no inpatient psychiatric diagnosis, those with any psychiatric diagnosis were significantly more likely to:

• have a later bedtime (beta = 0.07; 95% confidence interval, 0.06-0.09)
• have later wake-up time (beta = 0.10; 95% CI, 0.09-0.11)
• wake after sleep onset (beta = 0.10; 95% CI, 0.09-0.12)
• have poorer sleep efficiency (beta = –0.12; 95% CI, −0.14 to −0.11)
• have more awakenings (beta = 0.10; 95% CI, 0.09-0.11)
• have shorter duration of their longest sleep bout (beta = –0.09; 95% CI, −0.11 to −0.08)
• take more naps (beta = 0.11; 95% CI, 0.09-0.12)
• have greater variability in their bedtime (beta = 0.08; 95% CI, 0.06-0.09)
• have greater variability in their sleep duration (beta = 0.10; 95% CI, 0.09-0.12)

The only significant differences in sleep duration were found in those with lifetime major depressive disorder, who slept significantly less (beta = −0.02; P = .003), and in those with lifetime schizophrenia, who slept significantly longer (beta = 0.02; P = .0008).

Researchers found similar results when they examined patient-reported sleep measures collected when participants enrolled in the biobank, long before they agreed to wear an accelerometer.

“Everyone with a lifetime mental illness diagnosis trended toward worse sleep quality, regardless of their diagnosis,” Dr. Tripathy said. “We didn’t expect to see that.”

Limitations of the biobank data prohibited analysis by age and past or current use of psychiatric medications. In addition, investigators were unable to determine whether mental illness was active or controlled at the time of the study. Information on these, and other factors, is needed to truly begin to understand the real-world status of sleep patterns in people with mental illness, the researchers note.

However, the biobank data demonstrates how this type of information can be collected, helping Dr. Tripathy and others to design a new study that will launch next year with patients at CAMH. This effort is part of the BrainHealth Databank, a project that aims to develop a patient data bank similar to the one in the UK that was used for this study.

“We’ve shown that you can use wearable devices to measure correlates of sleep and derive insights about the objective measurements of sleep and associate them with mental illness diagnosis,” Dr. Tripathy said.

The study received no outside funding. Dr. Wainberg and Dr. Tripathy report receiving funding from Kavli Foundation, Krembil Foundation, CAMH Discovery Fund, the McLaughlin Foundation, NSERC, and CIHR. Disclosures for other authors are fully listed in the original article.

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

An inpatient psychiatric diagnosis at some point over a lifetime is significantly associated with a range of sleep problems, results from the largest study of its kind show.

A prior diagnosis of major depression, schizophrenia, anxiety, or bipolar disorder was associated with a later bedtime, earlier waking time, and significantly poorer sleep quality that included frequent awakenings during the night and shorter sleep bouts.

“We were struck by the pervasiveness of sleep problems across all the diagnoses of mental illness and sleep parameters we looked at,” study investigator Michael Wainberg, PhD, a postdoctoral fellow at the Krembil Centre for Neuroinformatics at the Center for Addiction and Mental Health (CAMH), Toronto, told this news organization. “This suggests there may need to be even more of an emphasis on sleep in these patients than there already is.”

The study, which includes data from nearly 90,000 adults in the United Kingdom, was published online October 12 in PLoS Medicine.

Wavebreak Media/Thinkstockphotos

Trove of data

Data for the analysis comes from the UK Biobank, a large-scale biomedical database launched in 2006 that has collected biological and medical data on more than 500,000 individuals who consented to provide blood, urine, and saliva samples and detailed lifestyle information that is matched to their medical records.

Between 2013 and 2015, more than 103,000 of these participants agreed to wear accelerometers on their wrists for 24 hours a day for 7 days, collecting a trove of data for researchers to mine.

“This allows us to get at objectively derived sleep measures and to measure them in greater numbers of people who have experienced mental illness,” said senior author Shreejoy Tripathy, PhD, assistant professor at the University of Toronto and independent scientist for CAMH. “You can study multiple disorders at once and the influence of other variables that might not be possible in the context of other studies.”

The research is the first known large-scale transdiagnostic study of objectively measured sleep and mental health. Insomnia and other sleep disorders are common among people with mental illness, as shown in prior research, including at least one study that used the same dataset the team employed for this project.

The new findings add to that body of work, Dr. Wainberg said, and look beyond just how long a person sleeps to the quality of the sleep they get.

“We found that the metrics of sleep quality seem to be affected more than mere sleep duration,” he said.
 

Unexpected finding

After excluding participants with faulty accelerometers and those who didn’t wear them for the entire 7-day study period, data from 89,205 participants (aged 43-79, 56% female, 97% self-reported White) was included. Lifetime inpatient psychiatric diagnoses were reported in 2.5% of the entire cohort.

Researchers looked at 10 sleep measures: bedtime, wake-up time, sleep duration, wake after sleep onset, sleep efficiency, number of awakenings, duration of longest sleep bout, number of naps, and variability in bedtime and sleep duration.

Although the effect sizes were small, having any psychiatric diagnosis was associated with significantly lower scores on every sleep measure except sleep duration.

Compared with those with no inpatient psychiatric diagnosis, those with any psychiatric diagnosis were significantly more likely to:

• have a later bedtime (beta = 0.07; 95% confidence interval, 0.06-0.09)
• have later wake-up time (beta = 0.10; 95% CI, 0.09-0.11)
• wake after sleep onset (beta = 0.10; 95% CI, 0.09-0.12)
• have poorer sleep efficiency (beta = –0.12; 95% CI, −0.14 to −0.11)
• have more awakenings (beta = 0.10; 95% CI, 0.09-0.11)
• have shorter duration of their longest sleep bout (beta = –0.09; 95% CI, −0.11 to −0.08)
• take more naps (beta = 0.11; 95% CI, 0.09-0.12)
• have greater variability in their bedtime (beta = 0.08; 95% CI, 0.06-0.09)
• have greater variability in their sleep duration (beta = 0.10; 95% CI, 0.09-0.12)

The only significant differences in sleep duration were found in those with lifetime major depressive disorder, who slept significantly less (beta = −0.02; P = .003), and in those with lifetime schizophrenia, who slept significantly longer (beta = 0.02; P = .0008).

Researchers found similar results when they examined patient-reported sleep measures collected when participants enrolled in the biobank, long before they agreed to wear an accelerometer.

“Everyone with a lifetime mental illness diagnosis trended toward worse sleep quality, regardless of their diagnosis,” Dr. Tripathy said. “We didn’t expect to see that.”

Limitations of the biobank data prohibited analysis by age and past or current use of psychiatric medications. In addition, investigators were unable to determine whether mental illness was active or controlled at the time of the study. Information on these, and other factors, is needed to truly begin to understand the real-world status of sleep patterns in people with mental illness, the researchers note.

However, the biobank data demonstrates how this type of information can be collected, helping Dr. Tripathy and others to design a new study that will launch next year with patients at CAMH. This effort is part of the BrainHealth Databank, a project that aims to develop a patient data bank similar to the one in the UK that was used for this study.

“We’ve shown that you can use wearable devices to measure correlates of sleep and derive insights about the objective measurements of sleep and associate them with mental illness diagnosis,” Dr. Tripathy said.

The study received no outside funding. Dr. Wainberg and Dr. Tripathy report receiving funding from Kavli Foundation, Krembil Foundation, CAMH Discovery Fund, the McLaughlin Foundation, NSERC, and CIHR. Disclosures for other authors are fully listed in the original article.

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

An inpatient psychiatric diagnosis at some point over a lifetime is significantly associated with a range of sleep problems, results from the largest study of its kind show.

A prior diagnosis of major depression, schizophrenia, anxiety, or bipolar disorder was associated with a later bedtime, earlier waking time, and significantly poorer sleep quality that included frequent awakenings during the night and shorter sleep bouts.

“We were struck by the pervasiveness of sleep problems across all the diagnoses of mental illness and sleep parameters we looked at,” study investigator Michael Wainberg, PhD, a postdoctoral fellow at the Krembil Centre for Neuroinformatics at the Center for Addiction and Mental Health (CAMH), Toronto, told this news organization. “This suggests there may need to be even more of an emphasis on sleep in these patients than there already is.”

The study, which includes data from nearly 90,000 adults in the United Kingdom, was published online October 12 in PLoS Medicine.

Wavebreak Media/Thinkstockphotos

Trove of data

Data for the analysis comes from the UK Biobank, a large-scale biomedical database launched in 2006 that has collected biological and medical data on more than 500,000 individuals who consented to provide blood, urine, and saliva samples and detailed lifestyle information that is matched to their medical records.

Between 2013 and 2015, more than 103,000 of these participants agreed to wear accelerometers on their wrists for 24 hours a day for 7 days, collecting a trove of data for researchers to mine.

“This allows us to get at objectively derived sleep measures and to measure them in greater numbers of people who have experienced mental illness,” said senior author Shreejoy Tripathy, PhD, assistant professor at the University of Toronto and independent scientist for CAMH. “You can study multiple disorders at once and the influence of other variables that might not be possible in the context of other studies.”

The research is the first known large-scale transdiagnostic study of objectively measured sleep and mental health. Insomnia and other sleep disorders are common among people with mental illness, as shown in prior research, including at least one study that used the same dataset the team employed for this project.

The new findings add to that body of work, Dr. Wainberg said, and look beyond just how long a person sleeps to the quality of the sleep they get.

“We found that the metrics of sleep quality seem to be affected more than mere sleep duration,” he said.
 

Unexpected finding

After excluding participants with faulty accelerometers and those who didn’t wear them for the entire 7-day study period, data from 89,205 participants (aged 43-79, 56% female, 97% self-reported White) was included. Lifetime inpatient psychiatric diagnoses were reported in 2.5% of the entire cohort.

Researchers looked at 10 sleep measures: bedtime, wake-up time, sleep duration, wake after sleep onset, sleep efficiency, number of awakenings, duration of longest sleep bout, number of naps, and variability in bedtime and sleep duration.

Although the effect sizes were small, having any psychiatric diagnosis was associated with significantly lower scores on every sleep measure except sleep duration.

Compared with those with no inpatient psychiatric diagnosis, those with any psychiatric diagnosis were significantly more likely to:

• have a later bedtime (beta = 0.07; 95% confidence interval, 0.06-0.09)
• have later wake-up time (beta = 0.10; 95% CI, 0.09-0.11)
• wake after sleep onset (beta = 0.10; 95% CI, 0.09-0.12)
• have poorer sleep efficiency (beta = –0.12; 95% CI, −0.14 to −0.11)
• have more awakenings (beta = 0.10; 95% CI, 0.09-0.11)
• have shorter duration of their longest sleep bout (beta = –0.09; 95% CI, −0.11 to −0.08)
• take more naps (beta = 0.11; 95% CI, 0.09-0.12)
• have greater variability in their bedtime (beta = 0.08; 95% CI, 0.06-0.09)
• have greater variability in their sleep duration (beta = 0.10; 95% CI, 0.09-0.12)

The only significant differences in sleep duration were found in those with lifetime major depressive disorder, who slept significantly less (beta = −0.02; P = .003), and in those with lifetime schizophrenia, who slept significantly longer (beta = 0.02; P = .0008).

Researchers found similar results when they examined patient-reported sleep measures collected when participants enrolled in the biobank, long before they agreed to wear an accelerometer.

“Everyone with a lifetime mental illness diagnosis trended toward worse sleep quality, regardless of their diagnosis,” Dr. Tripathy said. “We didn’t expect to see that.”

Limitations of the biobank data prohibited analysis by age and past or current use of psychiatric medications. In addition, investigators were unable to determine whether mental illness was active or controlled at the time of the study. Information on these, and other factors, is needed to truly begin to understand the real-world status of sleep patterns in people with mental illness, the researchers note.

However, the biobank data demonstrates how this type of information can be collected, helping Dr. Tripathy and others to design a new study that will launch next year with patients at CAMH. This effort is part of the BrainHealth Databank, a project that aims to develop a patient data bank similar to the one in the UK that was used for this study.

“We’ve shown that you can use wearable devices to measure correlates of sleep and derive insights about the objective measurements of sleep and associate them with mental illness diagnosis,” Dr. Tripathy said.

The study received no outside funding. Dr. Wainberg and Dr. Tripathy report receiving funding from Kavli Foundation, Krembil Foundation, CAMH Discovery Fund, the McLaughlin Foundation, NSERC, and CIHR. Disclosures for other authors are fully listed in the original article.

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

Adding art therapy to standard drug treatment in Parkinson’s disease (PD) not only improves severity of both motor and nonmotor symptoms, but also slows rates of disease progression, new research suggests.

TimothyOLeary/Thinkstock

Fifty PD patients were randomly assigned to receive either art therapy, including sculpting and drawing, plus drug therapy or drug therapy alone, and followed up over 12 months.

Patients receiving combined therapy experienced improvements in symptoms, depression, and cognitive scores, and had reduced tremor and daytime sleepiness. They were also substantially less likely to experience disease progression.

“The use of art therapy can reduce the severity of motor and nonmotor manifestations of Parkinson’s disease,” said study investigator Iryna Khubetova, MD, PhD, head of the neurology department, Odessa (Ukraine) Regional Clinical Hospital.

Crucially, the positive effects “persisted throughout the observation period,” she added.

The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
 

A promising approach

Dr. Khubetova told this news organization that offering art therapy to PD patients was “very affordable,” especially as professional artists “provided materials for painting and other art supplies free of charge.”

“We hope this approach is very promising and would be widely adopted.”

She suggested the positive effect of art therapy could be related to “activating the brain’s reward neural network.”

This may be via improved visual attention acting on visuospatial mechanisms and emotional drive, with “activation of the medial orbitofrontal cortex, ventral striatum, and other structures.”

The researchers note PD, a “multisystem progressive neurodegenerative disease,” is among the three most common neurological disorders, with an incidence of 100-150 cases per 100,000 people.

They also note that nonpharmacologic approaches are “widely used” as an adjunct to drug therapy and as part of an “integrated approach” to disease management.

To examine the clinical efficacy of art therapy, the team recruited patients with PD who had preserved facility for independent movement, defined as stages 1-2.5 on the Hoehn and Yahr scale.

Patients were randomly assigned to art therapy sessions alongside standard drug therapy or to standard drug therapy alone. The art therapy included sculpting, free drawing, and coloring patterns.
 

Multiple benefits

Participants were assessed at baseline and at 6 and 12 months with the Unified Parkinson Disease Rating Scale (UPDRS), the Beck Depression Inventory, the Montreal Cognitive Assessment, and the Pegboard Test of finger dexterity.

Fifty patients were included in the study, with 30 assigned to standard drug therapy alone and 20 to the combined intervention. Participants had a mean age of 57.8 years, and 46% were women.

Over the study period, investigators found patients assigned to art therapy plus drug treatment had improved mood, as well as decreased daytime sleeping, reduced tremor, and a decrease in anxiety and fear intensity.

Between baseline and the 6- and 12-month assessments, patients in the combined therapy group showed improvements in scores on all of the questionnaires, and on the Pegboard Test. In contrast, scores were either stable or worsened in the standard drug therapy–alone group.

The team notes that there was also a marked difference in rates of disease progression, defined as a change on the Hoehn and Yahr scale of at least 0.5 points, between the two groups.

Only two (10%) patients in the combined drug and art therapy progressed over the study period, compared with 10 (33%) in the control group (P = .05).

The findings complement those of a recent study conducted by Alberto Cucca, MD, of the Fresco Institute for Parkinson’s and Movement Disorders, New York University, and colleagues.

Eighteen patients took part in the prospective, open-label trial. They were assessed before and after 20 sessions of art therapy on a range of measures.

Results revealed that following the art therapy, patients had improvements in the Navon Test (which assesses visual neglect, eye tracking, and UPDRS scores), as well as significantly increased functional connectivity levels in the visual cortex on resting-state functional MRI.
 

Many benefits, no side effects

Rebecca Gilbert, MD, PhD, vice president and chief scientific officer of the American Parkinson Disease Association, who was not involved in either study, told this news organization that the idea of art therapy for patients with Parkinson’s is “very reasonable.”

She highlighted that “people with Parkinson’s have many issues with their visuospatial abilities,” as well as their depth and distance perception, and so “enhancing that aspect could potentially be very beneficial.”

“So I’m hopeful that it’s a really good avenue to explore, and the preliminary data are very exciting.”

Dr. Gilbert also highlighted that the “wonderful” aspect of art therapy is that there are “so many benefits and not really any side effects.” Patients can “take the meds … and then enhance that with various therapies, and this would be an additional option.”

Another notable aspect of art therapy is the “social element” and the sense of “camaraderie,” although that has “to be teased out from the benefits you would get from the actual art therapy.”

Finally, Dr. Gilbert pointed out that the difference between the current trial and Dr. Cucca’s trial is the presence of a control group.

“Of course, it’s not blinded, because you know whether you got therapy or not … but that extra element of being able to compare with a group that didn’t get the treatment gives it a little more weight in terms of the field.”

No funding was declared. The authors have disclosed no relevant financial relationships.

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

Adding art therapy to standard drug treatment in Parkinson’s disease (PD) not only improves severity of both motor and nonmotor symptoms, but also slows rates of disease progression, new research suggests.

TimothyOLeary/Thinkstock

Fifty PD patients were randomly assigned to receive either art therapy, including sculpting and drawing, plus drug therapy or drug therapy alone, and followed up over 12 months.

Patients receiving combined therapy experienced improvements in symptoms, depression, and cognitive scores, and had reduced tremor and daytime sleepiness. They were also substantially less likely to experience disease progression.

“The use of art therapy can reduce the severity of motor and nonmotor manifestations of Parkinson’s disease,” said study investigator Iryna Khubetova, MD, PhD, head of the neurology department, Odessa (Ukraine) Regional Clinical Hospital.

Crucially, the positive effects “persisted throughout the observation period,” she added.

The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
 

A promising approach

Dr. Khubetova told this news organization that offering art therapy to PD patients was “very affordable,” especially as professional artists “provided materials for painting and other art supplies free of charge.”

“We hope this approach is very promising and would be widely adopted.”

She suggested the positive effect of art therapy could be related to “activating the brain’s reward neural network.”

This may be via improved visual attention acting on visuospatial mechanisms and emotional drive, with “activation of the medial orbitofrontal cortex, ventral striatum, and other structures.”

The researchers note PD, a “multisystem progressive neurodegenerative disease,” is among the three most common neurological disorders, with an incidence of 100-150 cases per 100,000 people.

They also note that nonpharmacologic approaches are “widely used” as an adjunct to drug therapy and as part of an “integrated approach” to disease management.

To examine the clinical efficacy of art therapy, the team recruited patients with PD who had preserved facility for independent movement, defined as stages 1-2.5 on the Hoehn and Yahr scale.

Patients were randomly assigned to art therapy sessions alongside standard drug therapy or to standard drug therapy alone. The art therapy included sculpting, free drawing, and coloring patterns.
 

Multiple benefits

Participants were assessed at baseline and at 6 and 12 months with the Unified Parkinson Disease Rating Scale (UPDRS), the Beck Depression Inventory, the Montreal Cognitive Assessment, and the Pegboard Test of finger dexterity.

Fifty patients were included in the study, with 30 assigned to standard drug therapy alone and 20 to the combined intervention. Participants had a mean age of 57.8 years, and 46% were women.

Over the study period, investigators found patients assigned to art therapy plus drug treatment had improved mood, as well as decreased daytime sleeping, reduced tremor, and a decrease in anxiety and fear intensity.

Between baseline and the 6- and 12-month assessments, patients in the combined therapy group showed improvements in scores on all of the questionnaires, and on the Pegboard Test. In contrast, scores were either stable or worsened in the standard drug therapy–alone group.

The team notes that there was also a marked difference in rates of disease progression, defined as a change on the Hoehn and Yahr scale of at least 0.5 points, between the two groups.

Only two (10%) patients in the combined drug and art therapy progressed over the study period, compared with 10 (33%) in the control group (P = .05).

The findings complement those of a recent study conducted by Alberto Cucca, MD, of the Fresco Institute for Parkinson’s and Movement Disorders, New York University, and colleagues.

Eighteen patients took part in the prospective, open-label trial. They were assessed before and after 20 sessions of art therapy on a range of measures.

Results revealed that following the art therapy, patients had improvements in the Navon Test (which assesses visual neglect, eye tracking, and UPDRS scores), as well as significantly increased functional connectivity levels in the visual cortex on resting-state functional MRI.
 

Many benefits, no side effects

Rebecca Gilbert, MD, PhD, vice president and chief scientific officer of the American Parkinson Disease Association, who was not involved in either study, told this news organization that the idea of art therapy for patients with Parkinson’s is “very reasonable.”

She highlighted that “people with Parkinson’s have many issues with their visuospatial abilities,” as well as their depth and distance perception, and so “enhancing that aspect could potentially be very beneficial.”

“So I’m hopeful that it’s a really good avenue to explore, and the preliminary data are very exciting.”

Dr. Gilbert also highlighted that the “wonderful” aspect of art therapy is that there are “so many benefits and not really any side effects.” Patients can “take the meds … and then enhance that with various therapies, and this would be an additional option.”

Another notable aspect of art therapy is the “social element” and the sense of “camaraderie,” although that has “to be teased out from the benefits you would get from the actual art therapy.”

Finally, Dr. Gilbert pointed out that the difference between the current trial and Dr. Cucca’s trial is the presence of a control group.

“Of course, it’s not blinded, because you know whether you got therapy or not … but that extra element of being able to compare with a group that didn’t get the treatment gives it a little more weight in terms of the field.”

No funding was declared. The authors have disclosed no relevant financial relationships.

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

Adding art therapy to standard drug treatment in Parkinson’s disease (PD) not only improves severity of both motor and nonmotor symptoms, but also slows rates of disease progression, new research suggests.

TimothyOLeary/Thinkstock

Fifty PD patients were randomly assigned to receive either art therapy, including sculpting and drawing, plus drug therapy or drug therapy alone, and followed up over 12 months.

Patients receiving combined therapy experienced improvements in symptoms, depression, and cognitive scores, and had reduced tremor and daytime sleepiness. They were also substantially less likely to experience disease progression.

“The use of art therapy can reduce the severity of motor and nonmotor manifestations of Parkinson’s disease,” said study investigator Iryna Khubetova, MD, PhD, head of the neurology department, Odessa (Ukraine) Regional Clinical Hospital.

Crucially, the positive effects “persisted throughout the observation period,” she added.

The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
 

A promising approach

Dr. Khubetova told this news organization that offering art therapy to PD patients was “very affordable,” especially as professional artists “provided materials for painting and other art supplies free of charge.”

“We hope this approach is very promising and would be widely adopted.”

She suggested the positive effect of art therapy could be related to “activating the brain’s reward neural network.”

This may be via improved visual attention acting on visuospatial mechanisms and emotional drive, with “activation of the medial orbitofrontal cortex, ventral striatum, and other structures.”

The researchers note PD, a “multisystem progressive neurodegenerative disease,” is among the three most common neurological disorders, with an incidence of 100-150 cases per 100,000 people.

They also note that nonpharmacologic approaches are “widely used” as an adjunct to drug therapy and as part of an “integrated approach” to disease management.

To examine the clinical efficacy of art therapy, the team recruited patients with PD who had preserved facility for independent movement, defined as stages 1-2.5 on the Hoehn and Yahr scale.

Patients were randomly assigned to art therapy sessions alongside standard drug therapy or to standard drug therapy alone. The art therapy included sculpting, free drawing, and coloring patterns.
 

Multiple benefits

Participants were assessed at baseline and at 6 and 12 months with the Unified Parkinson Disease Rating Scale (UPDRS), the Beck Depression Inventory, the Montreal Cognitive Assessment, and the Pegboard Test of finger dexterity.

Fifty patients were included in the study, with 30 assigned to standard drug therapy alone and 20 to the combined intervention. Participants had a mean age of 57.8 years, and 46% were women.

Over the study period, investigators found patients assigned to art therapy plus drug treatment had improved mood, as well as decreased daytime sleeping, reduced tremor, and a decrease in anxiety and fear intensity.

Between baseline and the 6- and 12-month assessments, patients in the combined therapy group showed improvements in scores on all of the questionnaires, and on the Pegboard Test. In contrast, scores were either stable or worsened in the standard drug therapy–alone group.

The team notes that there was also a marked difference in rates of disease progression, defined as a change on the Hoehn and Yahr scale of at least 0.5 points, between the two groups.

Only two (10%) patients in the combined drug and art therapy progressed over the study period, compared with 10 (33%) in the control group (P = .05).

The findings complement those of a recent study conducted by Alberto Cucca, MD, of the Fresco Institute for Parkinson’s and Movement Disorders, New York University, and colleagues.

Eighteen patients took part in the prospective, open-label trial. They were assessed before and after 20 sessions of art therapy on a range of measures.

Results revealed that following the art therapy, patients had improvements in the Navon Test (which assesses visual neglect, eye tracking, and UPDRS scores), as well as significantly increased functional connectivity levels in the visual cortex on resting-state functional MRI.
 

Many benefits, no side effects

Rebecca Gilbert, MD, PhD, vice president and chief scientific officer of the American Parkinson Disease Association, who was not involved in either study, told this news organization that the idea of art therapy for patients with Parkinson’s is “very reasonable.”

She highlighted that “people with Parkinson’s have many issues with their visuospatial abilities,” as well as their depth and distance perception, and so “enhancing that aspect could potentially be very beneficial.”

“So I’m hopeful that it’s a really good avenue to explore, and the preliminary data are very exciting.”

Dr. Gilbert also highlighted that the “wonderful” aspect of art therapy is that there are “so many benefits and not really any side effects.” Patients can “take the meds … and then enhance that with various therapies, and this would be an additional option.”

Another notable aspect of art therapy is the “social element” and the sense of “camaraderie,” although that has “to be teased out from the benefits you would get from the actual art therapy.”

Finally, Dr. Gilbert pointed out that the difference between the current trial and Dr. Cucca’s trial is the presence of a control group.

“Of course, it’s not blinded, because you know whether you got therapy or not … but that extra element of being able to compare with a group that didn’t get the treatment gives it a little more weight in terms of the field.”

No funding was declared. The authors have disclosed no relevant financial relationships.

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

The U.S. Food and Drug Administration (FDA) has approved a high-dose naloxone injection product for the emergency treatment of opioid overdose.

ZIMHI from Adamis Pharmaceuticals is administered using a single-dose, prefilled syringe that delivers 5 mg of naloxone hydrochloride solution through intramuscular or subcutaneous injection.

Naloxone is an opioid antagonist that works by blocking or reversing the effects of the opioid, including extreme drowsiness, slowed breathing, or loss of consciousness.

Opioid-related overdose deaths — driven partly by prescription drug overdoses — remain a leading cause of death in the United States.

ZIMHI “provides an additional option in the treatment of opioid overdoses,” the FDA said in a statement announcing approval.

In a statement from Adamis Pharmaceuticals, Jeffrey Galinkin, MD, an anesthesiologist and former member of the FDA advisory committee for analgesics and addiction products, said he is “pleased to see this much-needed, high-dose naloxone product will become part of the treatment tool kit as a countermeasure to the continued surge in fentanyl related deaths.”

“The higher intramuscular doses of naloxone in ZIMHI should result in more rapid and higher levels of naloxone in the systemic circulation, which in turn, should result in more successful resuscitations,” Dr. Galinkin said.

Last spring the FDA approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of opioid overdose.

Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.

The FDA approved ZIMHI (and Kloxxado) through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.

The company plans to launch ZIMHI in the first quarter of 2022.

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

The U.S. Food and Drug Administration (FDA) has approved a high-dose naloxone injection product for the emergency treatment of opioid overdose.

ZIMHI from Adamis Pharmaceuticals is administered using a single-dose, prefilled syringe that delivers 5 mg of naloxone hydrochloride solution through intramuscular or subcutaneous injection.

Naloxone is an opioid antagonist that works by blocking or reversing the effects of the opioid, including extreme drowsiness, slowed breathing, or loss of consciousness.

Opioid-related overdose deaths — driven partly by prescription drug overdoses — remain a leading cause of death in the United States.

ZIMHI “provides an additional option in the treatment of opioid overdoses,” the FDA said in a statement announcing approval.

In a statement from Adamis Pharmaceuticals, Jeffrey Galinkin, MD, an anesthesiologist and former member of the FDA advisory committee for analgesics and addiction products, said he is “pleased to see this much-needed, high-dose naloxone product will become part of the treatment tool kit as a countermeasure to the continued surge in fentanyl related deaths.”

“The higher intramuscular doses of naloxone in ZIMHI should result in more rapid and higher levels of naloxone in the systemic circulation, which in turn, should result in more successful resuscitations,” Dr. Galinkin said.

Last spring the FDA approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of opioid overdose.

Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.

The FDA approved ZIMHI (and Kloxxado) through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.

The company plans to launch ZIMHI in the first quarter of 2022.

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

The U.S. Food and Drug Administration (FDA) has approved a high-dose naloxone injection product for the emergency treatment of opioid overdose.

ZIMHI from Adamis Pharmaceuticals is administered using a single-dose, prefilled syringe that delivers 5 mg of naloxone hydrochloride solution through intramuscular or subcutaneous injection.

Naloxone is an opioid antagonist that works by blocking or reversing the effects of the opioid, including extreme drowsiness, slowed breathing, or loss of consciousness.

Opioid-related overdose deaths — driven partly by prescription drug overdoses — remain a leading cause of death in the United States.

ZIMHI “provides an additional option in the treatment of opioid overdoses,” the FDA said in a statement announcing approval.

In a statement from Adamis Pharmaceuticals, Jeffrey Galinkin, MD, an anesthesiologist and former member of the FDA advisory committee for analgesics and addiction products, said he is “pleased to see this much-needed, high-dose naloxone product will become part of the treatment tool kit as a countermeasure to the continued surge in fentanyl related deaths.”

“The higher intramuscular doses of naloxone in ZIMHI should result in more rapid and higher levels of naloxone in the systemic circulation, which in turn, should result in more successful resuscitations,” Dr. Galinkin said.

Last spring the FDA approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of opioid overdose.

Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.

The FDA approved ZIMHI (and Kloxxado) through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.

The company plans to launch ZIMHI in the first quarter of 2022.

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

The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have produced a joint position statement on COVID-19 vaccination for patients with multiple sclerosis (MS).

The statement was released at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The statement concludes that the COVID-19 vaccines that are currently available are safe for patients with MS. Further, it states that the vaccines confer the same protection for patients with MS as they do for the general population. Exceptions may be patients taking the S1P modulator fingolimod and anti-CD20 drugs. For these patients, antibody responses have been shown to be reduced.

This position statement will be published on the ECTRIMS and EAN websites. Owing to the shifting, ongoing nature of evidence, the position statement will be updated periodically.

Presenting the statement, Mauricio Farez, MD, Fundacion FLENI, Buenos Aires, concluded: “Overall, MS patients do not seem to develop more severe forms of COVID-19 as compared with healthy controls, but patients with greater disability, anti-CD20 treatment, or those with recent steroid use have a higher risk of severe disease.”

“So far there are no specific contraindications for any COVID vaccines in MS patients reported,” he added. “We should work with our patients to keep them safe with vaccines while optimizing treatment strategies and MS management, in particular for those treated with anti-CD20 and S1P modulators.”
 

Risk for COVID-19 among patients with MS

On the issue of whether patients with MS are at higher risk for COVID-19 or for having a more severe form of the disease, Dr. Farez noted that studies published to date are reassuring and don’t suggest major problems regarding safety.

The main factors that are associated with more serious forms of COVID in patients with MS are similar to those in the general population. These include age, obesity, diabetes, male sex, and Black race.

As for any risk associated with MS therapies, interferons and glatiramer acetate do not increase the risk of getting COVID-19 or worsen the clinical course of the disease. Fingolimod, teriflunomide, natalizumab, and dimethyl fumarate also do not seem to negatively affect risk for COVID-19, according to the statement.

However, several studies have shown that anti-CD20 therapies, such as ocrelizumab, and steroid pulses can confer an increased risk for COVID-19.
 

COVID-19 vaccine safety

Four COVID-19 vaccines are licensed for use in the European Union. These include two mRNA vaccines – Spikevax (Moderna) and Comimaty (Pfizer) – and two adenovirus-based vaccines, one from Janssen (J&J) and the other from AstraZeneca. Five other COVID-19 vaccines are under review and may be available in the future.

All the currently available vaccines can be administered to patients with MS, including patients receiving immunosuppressant disease-modifying therapies, the statement notes.

In real-life clinical practice, no red flags have been observed for patients with MS who have received mRNA vaccines to date. Nevertheless, because immunocompromised patients and those taking immunomodulators were excluded from trials, continued surveillance for immune-mediated adverse effects is warranted, Dr. Farez said.

Regarding possible effects of vaccines on MS relapses/disability, no significant adverse effects occurred in a study conducted in Israel (by Achiron and colleagues) that involved 435 patients with MS who were fully vaccinated with the Pfizer mRNA vaccine. The relapse rate was 1.6%, similar to the rate among patients who did not have MS. A study by Di Filippo and colleagues showed no significant changes in relapse rate in the 2 months following immunization with the Pfizer vaccine among 324 patients with MS.

“There are no specific contraindications to any of the vaccines particularly for MS patients compared with the general population,” Dr. Farez noted.
 

Are there different recommendations for different MS therapies?

On the issue of vaccine effects in patients taking various disease-modifying treatments, the statement says that the data on this are limited. Patients taking interferons, glatiramer acetate, teriflunomide, and fumarates whose lymphocyte counts are normal will most likely be adequately protected. Patients with moderate to severe lymphopenia may not mount an adequate immune response to COVID-19 vaccination, so absolute lymphocyte count may be checked before vaccination.

Patients taking natalizumab will also likely be protected with COVID vaccination.

It is likely that for patients taking alemtuzumab, immune cellular and humoral response to COVID-10 vaccines will be attenuated, especially in the first 6 months during maximum lymphopenia. If possible, vaccination should be delayed until at least 6 months after treatment. It is thought that patients who have completed both courses of alemtuzumab with complete immune reconstitution will mount a full immune response.

In studies, all patients with MS who were treated with cladribine demonstrated a protective humoral immune response to the COVID-19 vaccine. In those studies, the antibody response was evident about 4 months after the last treatment dose, and the titer did not differ from that of healthy persons, Dr. Farez reported.
 

Low antibody level with fingolimod

The majority of patients treated with fingolimod have failed to show a protective level of antibodies following COVID-19 vaccination, the statement notes.

Asked whether patients taking fingolimod should receive a COVID vaccination, Dr. Farez said that that was a good question. “We have to think about what is an immune response. Antibodies are only a small fraction of all immune responses. So, until we have data to show otherwise, I think we should vaccinate – any immunity is better than no immunity,” he said.

Dr. Farez also suggested that patients with MS who are taking fingolimod should continue to do so. “Any treatment for MS is better than none. If fingolimod is stopped, MS may rebound. So, the most likely scenario would be to keep treating with fingolimod and to give the vaccination. But these patients may need a more aggressive booster approach – we will be looking at that,” he said.
 

Anti-CD20 antibody drugs

Patients taking ocrelizumab also do not mount an appropriate antibody response regardless of lymphocyte count or the time interval from the last ocrelizumab dose (3-9 months), the statement says. To optimize vaccine efficacy and to balance benefits and risks, the statement advises administering COVID vaccines at least 12 weeks after administering ocrelizumab and 4-6 weeks prior to the next dose, whenever possible.

A study by Apostolidis and colleagues provides strong evidence of immune priming by COVID vaccination in patients treated with anti-CD20 medications. Although for most of these patients, antibody responses are not optimal, T-cell priming is largely intact, Dr. Farez noted.
 

Booster doses/antibody tests

The need for and timing of COVID vaccine booster doses have not been established. “This is being discussed now for the general population. The recommendations for MS patients will not differ significantly from those for the general population, apart from perhaps for specific populations such as those on anti-CD20 drugs or fingolimod,” Dr. Farez said.

Antibody testing is not currently recommended for assessing immunity following COVID vaccination because the clinical utility and serologic correlates of protection after vaccination have not been established. Antibody testing does not evaluate the cellular immune response, which may play a role in vaccine-mediated protection, according to the statement.


Vaccination strategy after COVID

People should be offered vaccination regardless of their history of symptomatic or asymptomatic COVID-19, including people with prolonged post-COVID symptoms. Data from clinical trials indicate that the currently authorized vaccines can be given safely to people with evidence of prior SARS-CoV-2 infection. For people who are known to be currently infected with SARS-CoV-2, vaccination should be deferred until the acute illness has passed.

Pregnancy/children

Data on the safety of COVID vaccines during pregnancy are limited. On the basis of current knowledge, experts believe that it is unlikely that COVID vaccines pose a risk to the pregnant person or fetus, and thus pregnant people with MS are eligible for and can receive a COVID-19 vaccine, the statement notes.

Adolescents aged 12-17 are eligible to receive the authorized mRNA vaccine, but children younger than 12 are not authorized to receive any COVID vaccine at this time, it adds.

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

The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have produced a joint position statement on COVID-19 vaccination for patients with multiple sclerosis (MS).

The statement was released at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The statement concludes that the COVID-19 vaccines that are currently available are safe for patients with MS. Further, it states that the vaccines confer the same protection for patients with MS as they do for the general population. Exceptions may be patients taking the S1P modulator fingolimod and anti-CD20 drugs. For these patients, antibody responses have been shown to be reduced.

This position statement will be published on the ECTRIMS and EAN websites. Owing to the shifting, ongoing nature of evidence, the position statement will be updated periodically.

Presenting the statement, Mauricio Farez, MD, Fundacion FLENI, Buenos Aires, concluded: “Overall, MS patients do not seem to develop more severe forms of COVID-19 as compared with healthy controls, but patients with greater disability, anti-CD20 treatment, or those with recent steroid use have a higher risk of severe disease.”

“So far there are no specific contraindications for any COVID vaccines in MS patients reported,” he added. “We should work with our patients to keep them safe with vaccines while optimizing treatment strategies and MS management, in particular for those treated with anti-CD20 and S1P modulators.”
 

Risk for COVID-19 among patients with MS

On the issue of whether patients with MS are at higher risk for COVID-19 or for having a more severe form of the disease, Dr. Farez noted that studies published to date are reassuring and don’t suggest major problems regarding safety.

The main factors that are associated with more serious forms of COVID in patients with MS are similar to those in the general population. These include age, obesity, diabetes, male sex, and Black race.

As for any risk associated with MS therapies, interferons and glatiramer acetate do not increase the risk of getting COVID-19 or worsen the clinical course of the disease. Fingolimod, teriflunomide, natalizumab, and dimethyl fumarate also do not seem to negatively affect risk for COVID-19, according to the statement.

However, several studies have shown that anti-CD20 therapies, such as ocrelizumab, and steroid pulses can confer an increased risk for COVID-19.
 

COVID-19 vaccine safety

Four COVID-19 vaccines are licensed for use in the European Union. These include two mRNA vaccines – Spikevax (Moderna) and Comimaty (Pfizer) – and two adenovirus-based vaccines, one from Janssen (J&J) and the other from AstraZeneca. Five other COVID-19 vaccines are under review and may be available in the future.

All the currently available vaccines can be administered to patients with MS, including patients receiving immunosuppressant disease-modifying therapies, the statement notes.

In real-life clinical practice, no red flags have been observed for patients with MS who have received mRNA vaccines to date. Nevertheless, because immunocompromised patients and those taking immunomodulators were excluded from trials, continued surveillance for immune-mediated adverse effects is warranted, Dr. Farez said.

Regarding possible effects of vaccines on MS relapses/disability, no significant adverse effects occurred in a study conducted in Israel (by Achiron and colleagues) that involved 435 patients with MS who were fully vaccinated with the Pfizer mRNA vaccine. The relapse rate was 1.6%, similar to the rate among patients who did not have MS. A study by Di Filippo and colleagues showed no significant changes in relapse rate in the 2 months following immunization with the Pfizer vaccine among 324 patients with MS.

“There are no specific contraindications to any of the vaccines particularly for MS patients compared with the general population,” Dr. Farez noted.
 

Are there different recommendations for different MS therapies?

On the issue of vaccine effects in patients taking various disease-modifying treatments, the statement says that the data on this are limited. Patients taking interferons, glatiramer acetate, teriflunomide, and fumarates whose lymphocyte counts are normal will most likely be adequately protected. Patients with moderate to severe lymphopenia may not mount an adequate immune response to COVID-19 vaccination, so absolute lymphocyte count may be checked before vaccination.

Patients taking natalizumab will also likely be protected with COVID vaccination.

It is likely that for patients taking alemtuzumab, immune cellular and humoral response to COVID-10 vaccines will be attenuated, especially in the first 6 months during maximum lymphopenia. If possible, vaccination should be delayed until at least 6 months after treatment. It is thought that patients who have completed both courses of alemtuzumab with complete immune reconstitution will mount a full immune response.

In studies, all patients with MS who were treated with cladribine demonstrated a protective humoral immune response to the COVID-19 vaccine. In those studies, the antibody response was evident about 4 months after the last treatment dose, and the titer did not differ from that of healthy persons, Dr. Farez reported.
 

Low antibody level with fingolimod

The majority of patients treated with fingolimod have failed to show a protective level of antibodies following COVID-19 vaccination, the statement notes.

Asked whether patients taking fingolimod should receive a COVID vaccination, Dr. Farez said that that was a good question. “We have to think about what is an immune response. Antibodies are only a small fraction of all immune responses. So, until we have data to show otherwise, I think we should vaccinate – any immunity is better than no immunity,” he said.

Dr. Farez also suggested that patients with MS who are taking fingolimod should continue to do so. “Any treatment for MS is better than none. If fingolimod is stopped, MS may rebound. So, the most likely scenario would be to keep treating with fingolimod and to give the vaccination. But these patients may need a more aggressive booster approach – we will be looking at that,” he said.
 

Anti-CD20 antibody drugs

Patients taking ocrelizumab also do not mount an appropriate antibody response regardless of lymphocyte count or the time interval from the last ocrelizumab dose (3-9 months), the statement says. To optimize vaccine efficacy and to balance benefits and risks, the statement advises administering COVID vaccines at least 12 weeks after administering ocrelizumab and 4-6 weeks prior to the next dose, whenever possible.

A study by Apostolidis and colleagues provides strong evidence of immune priming by COVID vaccination in patients treated with anti-CD20 medications. Although for most of these patients, antibody responses are not optimal, T-cell priming is largely intact, Dr. Farez noted.
 

Booster doses/antibody tests

The need for and timing of COVID vaccine booster doses have not been established. “This is being discussed now for the general population. The recommendations for MS patients will not differ significantly from those for the general population, apart from perhaps for specific populations such as those on anti-CD20 drugs or fingolimod,” Dr. Farez said.

Antibody testing is not currently recommended for assessing immunity following COVID vaccination because the clinical utility and serologic correlates of protection after vaccination have not been established. Antibody testing does not evaluate the cellular immune response, which may play a role in vaccine-mediated protection, according to the statement.


Vaccination strategy after COVID

People should be offered vaccination regardless of their history of symptomatic or asymptomatic COVID-19, including people with prolonged post-COVID symptoms. Data from clinical trials indicate that the currently authorized vaccines can be given safely to people with evidence of prior SARS-CoV-2 infection. For people who are known to be currently infected with SARS-CoV-2, vaccination should be deferred until the acute illness has passed.

Pregnancy/children

Data on the safety of COVID vaccines during pregnancy are limited. On the basis of current knowledge, experts believe that it is unlikely that COVID vaccines pose a risk to the pregnant person or fetus, and thus pregnant people with MS are eligible for and can receive a COVID-19 vaccine, the statement notes.

Adolescents aged 12-17 are eligible to receive the authorized mRNA vaccine, but children younger than 12 are not authorized to receive any COVID vaccine at this time, it adds.

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

The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have produced a joint position statement on COVID-19 vaccination for patients with multiple sclerosis (MS).

The statement was released at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The statement concludes that the COVID-19 vaccines that are currently available are safe for patients with MS. Further, it states that the vaccines confer the same protection for patients with MS as they do for the general population. Exceptions may be patients taking the S1P modulator fingolimod and anti-CD20 drugs. For these patients, antibody responses have been shown to be reduced.

This position statement will be published on the ECTRIMS and EAN websites. Owing to the shifting, ongoing nature of evidence, the position statement will be updated periodically.

Presenting the statement, Mauricio Farez, MD, Fundacion FLENI, Buenos Aires, concluded: “Overall, MS patients do not seem to develop more severe forms of COVID-19 as compared with healthy controls, but patients with greater disability, anti-CD20 treatment, or those with recent steroid use have a higher risk of severe disease.”

“So far there are no specific contraindications for any COVID vaccines in MS patients reported,” he added. “We should work with our patients to keep them safe with vaccines while optimizing treatment strategies and MS management, in particular for those treated with anti-CD20 and S1P modulators.”
 

Risk for COVID-19 among patients with MS

On the issue of whether patients with MS are at higher risk for COVID-19 or for having a more severe form of the disease, Dr. Farez noted that studies published to date are reassuring and don’t suggest major problems regarding safety.

The main factors that are associated with more serious forms of COVID in patients with MS are similar to those in the general population. These include age, obesity, diabetes, male sex, and Black race.

As for any risk associated with MS therapies, interferons and glatiramer acetate do not increase the risk of getting COVID-19 or worsen the clinical course of the disease. Fingolimod, teriflunomide, natalizumab, and dimethyl fumarate also do not seem to negatively affect risk for COVID-19, according to the statement.

However, several studies have shown that anti-CD20 therapies, such as ocrelizumab, and steroid pulses can confer an increased risk for COVID-19.
 

COVID-19 vaccine safety

Four COVID-19 vaccines are licensed for use in the European Union. These include two mRNA vaccines – Spikevax (Moderna) and Comimaty (Pfizer) – and two adenovirus-based vaccines, one from Janssen (J&J) and the other from AstraZeneca. Five other COVID-19 vaccines are under review and may be available in the future.

All the currently available vaccines can be administered to patients with MS, including patients receiving immunosuppressant disease-modifying therapies, the statement notes.

In real-life clinical practice, no red flags have been observed for patients with MS who have received mRNA vaccines to date. Nevertheless, because immunocompromised patients and those taking immunomodulators were excluded from trials, continued surveillance for immune-mediated adverse effects is warranted, Dr. Farez said.

Regarding possible effects of vaccines on MS relapses/disability, no significant adverse effects occurred in a study conducted in Israel (by Achiron and colleagues) that involved 435 patients with MS who were fully vaccinated with the Pfizer mRNA vaccine. The relapse rate was 1.6%, similar to the rate among patients who did not have MS. A study by Di Filippo and colleagues showed no significant changes in relapse rate in the 2 months following immunization with the Pfizer vaccine among 324 patients with MS.

“There are no specific contraindications to any of the vaccines particularly for MS patients compared with the general population,” Dr. Farez noted.
 

Are there different recommendations for different MS therapies?

On the issue of vaccine effects in patients taking various disease-modifying treatments, the statement says that the data on this are limited. Patients taking interferons, glatiramer acetate, teriflunomide, and fumarates whose lymphocyte counts are normal will most likely be adequately protected. Patients with moderate to severe lymphopenia may not mount an adequate immune response to COVID-19 vaccination, so absolute lymphocyte count may be checked before vaccination.

Patients taking natalizumab will also likely be protected with COVID vaccination.

It is likely that for patients taking alemtuzumab, immune cellular and humoral response to COVID-10 vaccines will be attenuated, especially in the first 6 months during maximum lymphopenia. If possible, vaccination should be delayed until at least 6 months after treatment. It is thought that patients who have completed both courses of alemtuzumab with complete immune reconstitution will mount a full immune response.

In studies, all patients with MS who were treated with cladribine demonstrated a protective humoral immune response to the COVID-19 vaccine. In those studies, the antibody response was evident about 4 months after the last treatment dose, and the titer did not differ from that of healthy persons, Dr. Farez reported.
 

Low antibody level with fingolimod

The majority of patients treated with fingolimod have failed to show a protective level of antibodies following COVID-19 vaccination, the statement notes.

Asked whether patients taking fingolimod should receive a COVID vaccination, Dr. Farez said that that was a good question. “We have to think about what is an immune response. Antibodies are only a small fraction of all immune responses. So, until we have data to show otherwise, I think we should vaccinate – any immunity is better than no immunity,” he said.

Dr. Farez also suggested that patients with MS who are taking fingolimod should continue to do so. “Any treatment for MS is better than none. If fingolimod is stopped, MS may rebound. So, the most likely scenario would be to keep treating with fingolimod and to give the vaccination. But these patients may need a more aggressive booster approach – we will be looking at that,” he said.
 

Anti-CD20 antibody drugs

Patients taking ocrelizumab also do not mount an appropriate antibody response regardless of lymphocyte count or the time interval from the last ocrelizumab dose (3-9 months), the statement says. To optimize vaccine efficacy and to balance benefits and risks, the statement advises administering COVID vaccines at least 12 weeks after administering ocrelizumab and 4-6 weeks prior to the next dose, whenever possible.

A study by Apostolidis and colleagues provides strong evidence of immune priming by COVID vaccination in patients treated with anti-CD20 medications. Although for most of these patients, antibody responses are not optimal, T-cell priming is largely intact, Dr. Farez noted.
 

Booster doses/antibody tests

The need for and timing of COVID vaccine booster doses have not been established. “This is being discussed now for the general population. The recommendations for MS patients will not differ significantly from those for the general population, apart from perhaps for specific populations such as those on anti-CD20 drugs or fingolimod,” Dr. Farez said.

Antibody testing is not currently recommended for assessing immunity following COVID vaccination because the clinical utility and serologic correlates of protection after vaccination have not been established. Antibody testing does not evaluate the cellular immune response, which may play a role in vaccine-mediated protection, according to the statement.


Vaccination strategy after COVID

People should be offered vaccination regardless of their history of symptomatic or asymptomatic COVID-19, including people with prolonged post-COVID symptoms. Data from clinical trials indicate that the currently authorized vaccines can be given safely to people with evidence of prior SARS-CoV-2 infection. For people who are known to be currently infected with SARS-CoV-2, vaccination should be deferred until the acute illness has passed.

Pregnancy/children

Data on the safety of COVID vaccines during pregnancy are limited. On the basis of current knowledge, experts believe that it is unlikely that COVID vaccines pose a risk to the pregnant person or fetus, and thus pregnant people with MS are eligible for and can receive a COVID-19 vaccine, the statement notes.

Adolescents aged 12-17 are eligible to receive the authorized mRNA vaccine, but children younger than 12 are not authorized to receive any COVID vaccine at this time, it adds.

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

In June, Gerald Bock, MD, a dermatologist in central California, instituted a new office policy: He would not be seeing any more patients who remain unvaccinated against COVID-19 in his practice.

peterschreiber_media/iStock/Getty Images

“[It is] the height of self-centered and irresponsible behavior,” he told me. “People who come in unvaccinated, when vaccination is widely available, are stating that their personal preferences are more important than their health, and are more important than any risk that they may expose their friends and family to, and also to any risk they might present to my staff and me. We have gone to considerable effort and expense to diminish any risk that visiting our office might entail. I see no reason why we should tolerate this.”

Other doctors appear to be following in his footsteps. There is no question that physicians have the right to choose their patients, just as patients are free to choose their doctors, but is it ethical to treat unvaccinated patients differently than their vaccinated counterparts? That is a complicated question without a clear answer. In a statement on whether physicians can decline unvaccinated patients, the American Medical Association continues to maintain that “in general” a physician may not “ethically turn a patient away based solely on the individual’s infectious disease status,” but does concede that “the decision to accept or decline a patient must balance the urgency of the individual patient’s need; the risk the patient may pose to other patients in the physician’s practice; and the need for the physician and staff, to be available to provide care in the future.”

Medical ethics experts have offered varying opinions. Daniel Wikler, PhD, professor of ethics and population health at the Harvard School of Public Health, Boston, wrote in an op-ed in the Washington Post that “ignorance or other personal failing” should not be factors in the evaluation of patients for health care. He argues that “doctors and hospitals are not in the blame and punishment business. Nor should they be. That doctors treat sinners and responsible citizens alike is a noble tradition.”

Timothy Hoff, professor of management, healthcare systems, and health policy at Northeastern University, Boston, maintains that, in nonemergency situations, physicians are legally able to refuse patients for a variety of reasons, provided they are not doing so because of some aspect of the patient’s race, gender, sexuality, or religion. However, in the same Northeastern University news release,Robert Baginski, MD, the director of interdisciplinary affairs for the department of medical sciences at Northeastern, cautions that it is vital for health authorities to continue urging the public to get vaccinated, but not at the expense of care.

Arthur L. Caplan, PhD, the head of the division of medical ethics at New York University, said in a Medscape commentary, that the decision to refuse to see patients who can vaccinate, but choose not to, is justifiable. “If you’re trying to protect yourself, your staff, or other patients, I think you do have the right to not take on somebody who won’t vaccinate,” he writes. “This is somewhat similar to when pediatricians do not accept a family if they won’t give their kids the state-required shots to go to school. That’s been happening for many years now.

“I also think it is morally justified if they won’t take your advice,” he continues. “If they won’t follow what you think is the best healthcare for them [such as getting vaccinated], there’s not much point in building that relationship.”

The situation is different in ED and hospital settings, however. “It’s a little harder to use unvaccinated status when someone really is at death’s door,” Dr. Caplan pointed out. “When someone comes in very sick, or whatever the reason, I think we have to take care of them ethically, and legally we’re bound to get them stable in the emergency room. I do think different rules apply there.”

In the end, every private practitioner will have to make his or her own decision on this question. Dr. Bock feels he made the right one. “Since instituting the policy, we have written 55 refund checks for people who had paid for a series of cosmetic procedures. We have no idea how many people were deterred from making appointments. We’ve had several negative online reviews and one woman who wrote a letter to the Medical Board of California complaining that we were discriminating against her,” he said. He added, however, that “we’ve also had several patients who commented favorably about the policy. I have no regrets about instituting the policy, and would do it again.”

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 [email protected].

In June, Gerald Bock, MD, a dermatologist in central California, instituted a new office policy: He would not be seeing any more patients who remain unvaccinated against COVID-19 in his practice.

peterschreiber_media/iStock/Getty Images

“[It is] the height of self-centered and irresponsible behavior,” he told me. “People who come in unvaccinated, when vaccination is widely available, are stating that their personal preferences are more important than their health, and are more important than any risk that they may expose their friends and family to, and also to any risk they might present to my staff and me. We have gone to considerable effort and expense to diminish any risk that visiting our office might entail. I see no reason why we should tolerate this.”

Other doctors appear to be following in his footsteps. There is no question that physicians have the right to choose their patients, just as patients are free to choose their doctors, but is it ethical to treat unvaccinated patients differently than their vaccinated counterparts? That is a complicated question without a clear answer. In a statement on whether physicians can decline unvaccinated patients, the American Medical Association continues to maintain that “in general” a physician may not “ethically turn a patient away based solely on the individual’s infectious disease status,” but does concede that “the decision to accept or decline a patient must balance the urgency of the individual patient’s need; the risk the patient may pose to other patients in the physician’s practice; and the need for the physician and staff, to be available to provide care in the future.”

Medical ethics experts have offered varying opinions. Daniel Wikler, PhD, professor of ethics and population health at the Harvard School of Public Health, Boston, wrote in an op-ed in the Washington Post that “ignorance or other personal failing” should not be factors in the evaluation of patients for health care. He argues that “doctors and hospitals are not in the blame and punishment business. Nor should they be. That doctors treat sinners and responsible citizens alike is a noble tradition.”

Timothy Hoff, professor of management, healthcare systems, and health policy at Northeastern University, Boston, maintains that, in nonemergency situations, physicians are legally able to refuse patients for a variety of reasons, provided they are not doing so because of some aspect of the patient’s race, gender, sexuality, or religion. However, in the same Northeastern University news release,Robert Baginski, MD, the director of interdisciplinary affairs for the department of medical sciences at Northeastern, cautions that it is vital for health authorities to continue urging the public to get vaccinated, but not at the expense of care.

Arthur L. Caplan, PhD, the head of the division of medical ethics at New York University, said in a Medscape commentary, that the decision to refuse to see patients who can vaccinate, but choose not to, is justifiable. “If you’re trying to protect yourself, your staff, or other patients, I think you do have the right to not take on somebody who won’t vaccinate,” he writes. “This is somewhat similar to when pediatricians do not accept a family if they won’t give their kids the state-required shots to go to school. That’s been happening for many years now.

“I also think it is morally justified if they won’t take your advice,” he continues. “If they won’t follow what you think is the best healthcare for them [such as getting vaccinated], there’s not much point in building that relationship.”

The situation is different in ED and hospital settings, however. “It’s a little harder to use unvaccinated status when someone really is at death’s door,” Dr. Caplan pointed out. “When someone comes in very sick, or whatever the reason, I think we have to take care of them ethically, and legally we’re bound to get them stable in the emergency room. I do think different rules apply there.”

In the end, every private practitioner will have to make his or her own decision on this question. Dr. Bock feels he made the right one. “Since instituting the policy, we have written 55 refund checks for people who had paid for a series of cosmetic procedures. We have no idea how many people were deterred from making appointments. We’ve had several negative online reviews and one woman who wrote a letter to the Medical Board of California complaining that we were discriminating against her,” he said. He added, however, that “we’ve also had several patients who commented favorably about the policy. I have no regrets about instituting the policy, and would do it again.”

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 [email protected].

In June, Gerald Bock, MD, a dermatologist in central California, instituted a new office policy: He would not be seeing any more patients who remain unvaccinated against COVID-19 in his practice.

peterschreiber_media/iStock/Getty Images

“[It is] the height of self-centered and irresponsible behavior,” he told me. “People who come in unvaccinated, when vaccination is widely available, are stating that their personal preferences are more important than their health, and are more important than any risk that they may expose their friends and family to, and also to any risk they might present to my staff and me. We have gone to considerable effort and expense to diminish any risk that visiting our office might entail. I see no reason why we should tolerate this.”

Other doctors appear to be following in his footsteps. There is no question that physicians have the right to choose their patients, just as patients are free to choose their doctors, but is it ethical to treat unvaccinated patients differently than their vaccinated counterparts? That is a complicated question without a clear answer. In a statement on whether physicians can decline unvaccinated patients, the American Medical Association continues to maintain that “in general” a physician may not “ethically turn a patient away based solely on the individual’s infectious disease status,” but does concede that “the decision to accept or decline a patient must balance the urgency of the individual patient’s need; the risk the patient may pose to other patients in the physician’s practice; and the need for the physician and staff, to be available to provide care in the future.”

Medical ethics experts have offered varying opinions. Daniel Wikler, PhD, professor of ethics and population health at the Harvard School of Public Health, Boston, wrote in an op-ed in the Washington Post that “ignorance or other personal failing” should not be factors in the evaluation of patients for health care. He argues that “doctors and hospitals are not in the blame and punishment business. Nor should they be. That doctors treat sinners and responsible citizens alike is a noble tradition.”

Timothy Hoff, professor of management, healthcare systems, and health policy at Northeastern University, Boston, maintains that, in nonemergency situations, physicians are legally able to refuse patients for a variety of reasons, provided they are not doing so because of some aspect of the patient’s race, gender, sexuality, or religion. However, in the same Northeastern University news release,Robert Baginski, MD, the director of interdisciplinary affairs for the department of medical sciences at Northeastern, cautions that it is vital for health authorities to continue urging the public to get vaccinated, but not at the expense of care.

Arthur L. Caplan, PhD, the head of the division of medical ethics at New York University, said in a Medscape commentary, that the decision to refuse to see patients who can vaccinate, but choose not to, is justifiable. “If you’re trying to protect yourself, your staff, or other patients, I think you do have the right to not take on somebody who won’t vaccinate,” he writes. “This is somewhat similar to when pediatricians do not accept a family if they won’t give their kids the state-required shots to go to school. That’s been happening for many years now.

“I also think it is morally justified if they won’t take your advice,” he continues. “If they won’t follow what you think is the best healthcare for them [such as getting vaccinated], there’s not much point in building that relationship.”

The situation is different in ED and hospital settings, however. “It’s a little harder to use unvaccinated status when someone really is at death’s door,” Dr. Caplan pointed out. “When someone comes in very sick, or whatever the reason, I think we have to take care of them ethically, and legally we’re bound to get them stable in the emergency room. I do think different rules apply there.”

In the end, every private practitioner will have to make his or her own decision on this question. Dr. Bock feels he made the right one. “Since instituting the policy, we have written 55 refund checks for people who had paid for a series of cosmetic procedures. We have no idea how many people were deterred from making appointments. We’ve had several negative online reviews and one woman who wrote a letter to the Medical Board of California complaining that we were discriminating against her,” he said. He added, however, that “we’ve also had several patients who commented favorably about the policy. I have no regrets about instituting the policy, and would do it again.”

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 [email protected].

The Barcelona baseline risk score predicted progression of multiple sclerosis (MS) in patients by assigning them to low-, medium-, and high-risk groups. The high-risk group had the shortest time to progression to an Expanded Disability Status Score (EDSS) of 3.0, and were also more likely to progress by MRI and quality of life measures.

The ranking is based on sex, age at the first clinically isolated syndrome, CIS topography, the number of T2 lesions, and the presence of infratentorial and spinal cord lesions, contrast-enhancing lesions, and oligoclonal bands.

“What we wanted to do is merge all of the different prognostic variables for one single patient into one single score,” said Mar Tintoré, MD, PhD, in an interview. Dr. Tintoré is a professor of neurology at Vall d’Hebron University Hospital in Barcelona and a senior consultant at the Multiple Sclerosis Centre of Catalonia (Cemcat). Dr. Tintoré presented the results of the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

The three groups had different outcomes in MRI, clinical factors, and MRI scans, and quality of life outcomes over the course of their disease. “So this is a confirmation that this classification at baseline is really meaningful,” Dr. Tintoré said in an interview.

She attributed the success of the model to its reliance on multiple factors, but it is also designed to be simple to use. “We have been trying to use it with simple factors, [information] that you always have, like age, sex, gender, number of lesions, and topography of the region. Everybody has this information at their desk.”
 

Proof of concept

The study validates the approach that neurologists already utilize, according to Patricia Coyle, MD, who moderated the session. “I think the prospective study is a really unique and powerful concept,” said Dr. Coyle, who is a professor of neurology, vice chair of neurology, and director of the Stony Brook (N.Y.) Comprehensive Care Center.

The new study “kind of confirmed their concept of the initial rating, judging long-term disability progression measures in subsets. They also looked at brain atrophy, they looked at gray-matter atrophy, and that also traveled with these three different groups of severity. So it kind of gives value to looking at prognostic indicators at a first attack,” said Dr. Coyle.

The results also validate the Barcelona group’s heavy emphasis on MRI, which Dr. Coyle pointed out is common practice. “If the brain MRI looks very bad, if there are a lot of spinal cord lesions, then that’s somebody we’re much more worried about.”

Once the model is confirmed in other cohorts, the researchers plan to release the model as a generally available algorithm that clinicians could use to help manage patients. Dr. Tintoré pointed out the debate over when to begin a patient on high-efficacy disease-modifying therapies. That choice depends on a lot of factors, including patient choice, safety, and comorbidities. “But knowing that your patient is at risk of having a bad prognosis is something that is helpful” in that decision-making process, she said.
 

Predicting time to EDSS 3.0

The researchers used the Barcelona CIS cohort to build a Weibull survival regression in order to estimate the median time to EDSS 3.0. The model produced three categories with widely divergent predicted times from CIS to EDSS 3.0: low risk, medium risk, and high risk.

In the current report, the researchers compared the model to a “360 degree” measure of measures in 1,308 patients, including clinical milestones (McDonald 2017 MS, confirmed secondary progressive MS, progression independent of relapse activity [PIRA], EDSS disability, number of T2 MRI lesions and brain atrophy, and Patient Reported Outcomes for MS [walking speed, manual dexterity, processing speed, and contrast sensitivity]).

At 30 years after CIS, the risk of reaching EDSS 3.0 was higher in the medium risk (hazard ratio, 3.0 versus low risk) and in the high risk group (HR, 8.3 versus low risk). At 10 years, the low risk group had a 40% risk of fulfilling McDonald 2017 criteria, versus 89% in the intermediate group, and 98% in the high risk group. A similar relationship was seen for SPMS (1%, 8%, 16%) and PIRA (17%, 26%, 35%).

At 10 years, the estimated accumulated T2 lesions was 7 in the low-risk group (95% CI, 5-9), 15 in the medium-risk group (95% CI, 12-17), and 21 in the high-risk group (95% CI, 15-27).

Compared with the low- and medium-risk groups, the high-risk group had lower brain parenchymal fraction and gray-matter fraction at 5 years. They also experienced higher stigma, had worse perception of upper and lower limb function as measured by Neuro QoL, and had worse cognitive performance.

Dr. Tintoré has received compensation for consulting services and speaking honoraria from Aimirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals, and Viela Bio. Dr. Coyle has no relevant disclosures.

The Barcelona baseline risk score predicted progression of multiple sclerosis (MS) in patients by assigning them to low-, medium-, and high-risk groups. The high-risk group had the shortest time to progression to an Expanded Disability Status Score (EDSS) of 3.0, and were also more likely to progress by MRI and quality of life measures.

The ranking is based on sex, age at the first clinically isolated syndrome, CIS topography, the number of T2 lesions, and the presence of infratentorial and spinal cord lesions, contrast-enhancing lesions, and oligoclonal bands.

“What we wanted to do is merge all of the different prognostic variables for one single patient into one single score,” said Mar Tintoré, MD, PhD, in an interview. Dr. Tintoré is a professor of neurology at Vall d’Hebron University Hospital in Barcelona and a senior consultant at the Multiple Sclerosis Centre of Catalonia (Cemcat). Dr. Tintoré presented the results of the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

The three groups had different outcomes in MRI, clinical factors, and MRI scans, and quality of life outcomes over the course of their disease. “So this is a confirmation that this classification at baseline is really meaningful,” Dr. Tintoré said in an interview.

She attributed the success of the model to its reliance on multiple factors, but it is also designed to be simple to use. “We have been trying to use it with simple factors, [information] that you always have, like age, sex, gender, number of lesions, and topography of the region. Everybody has this information at their desk.”
 

Proof of concept

The study validates the approach that neurologists already utilize, according to Patricia Coyle, MD, who moderated the session. “I think the prospective study is a really unique and powerful concept,” said Dr. Coyle, who is a professor of neurology, vice chair of neurology, and director of the Stony Brook (N.Y.) Comprehensive Care Center.

The new study “kind of confirmed their concept of the initial rating, judging long-term disability progression measures in subsets. They also looked at brain atrophy, they looked at gray-matter atrophy, and that also traveled with these three different groups of severity. So it kind of gives value to looking at prognostic indicators at a first attack,” said Dr. Coyle.

The results also validate the Barcelona group’s heavy emphasis on MRI, which Dr. Coyle pointed out is common practice. “If the brain MRI looks very bad, if there are a lot of spinal cord lesions, then that’s somebody we’re much more worried about.”

Once the model is confirmed in other cohorts, the researchers plan to release the model as a generally available algorithm that clinicians could use to help manage patients. Dr. Tintoré pointed out the debate over when to begin a patient on high-efficacy disease-modifying therapies. That choice depends on a lot of factors, including patient choice, safety, and comorbidities. “But knowing that your patient is at risk of having a bad prognosis is something that is helpful” in that decision-making process, she said.
 

Predicting time to EDSS 3.0

The researchers used the Barcelona CIS cohort to build a Weibull survival regression in order to estimate the median time to EDSS 3.0. The model produced three categories with widely divergent predicted times from CIS to EDSS 3.0: low risk, medium risk, and high risk.

In the current report, the researchers compared the model to a “360 degree” measure of measures in 1,308 patients, including clinical milestones (McDonald 2017 MS, confirmed secondary progressive MS, progression independent of relapse activity [PIRA], EDSS disability, number of T2 MRI lesions and brain atrophy, and Patient Reported Outcomes for MS [walking speed, manual dexterity, processing speed, and contrast sensitivity]).

At 30 years after CIS, the risk of reaching EDSS 3.0 was higher in the medium risk (hazard ratio, 3.0 versus low risk) and in the high risk group (HR, 8.3 versus low risk). At 10 years, the low risk group had a 40% risk of fulfilling McDonald 2017 criteria, versus 89% in the intermediate group, and 98% in the high risk group. A similar relationship was seen for SPMS (1%, 8%, 16%) and PIRA (17%, 26%, 35%).

At 10 years, the estimated accumulated T2 lesions was 7 in the low-risk group (95% CI, 5-9), 15 in the medium-risk group (95% CI, 12-17), and 21 in the high-risk group (95% CI, 15-27).

Compared with the low- and medium-risk groups, the high-risk group had lower brain parenchymal fraction and gray-matter fraction at 5 years. They also experienced higher stigma, had worse perception of upper and lower limb function as measured by Neuro QoL, and had worse cognitive performance.

Dr. Tintoré has received compensation for consulting services and speaking honoraria from Aimirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals, and Viela Bio. Dr. Coyle has no relevant disclosures.

The Barcelona baseline risk score predicted progression of multiple sclerosis (MS) in patients by assigning them to low-, medium-, and high-risk groups. The high-risk group had the shortest time to progression to an Expanded Disability Status Score (EDSS) of 3.0, and were also more likely to progress by MRI and quality of life measures.

The ranking is based on sex, age at the first clinically isolated syndrome, CIS topography, the number of T2 lesions, and the presence of infratentorial and spinal cord lesions, contrast-enhancing lesions, and oligoclonal bands.

“What we wanted to do is merge all of the different prognostic variables for one single patient into one single score,” said Mar Tintoré, MD, PhD, in an interview. Dr. Tintoré is a professor of neurology at Vall d’Hebron University Hospital in Barcelona and a senior consultant at the Multiple Sclerosis Centre of Catalonia (Cemcat). Dr. Tintoré presented the results of the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

The three groups had different outcomes in MRI, clinical factors, and MRI scans, and quality of life outcomes over the course of their disease. “So this is a confirmation that this classification at baseline is really meaningful,” Dr. Tintoré said in an interview.

She attributed the success of the model to its reliance on multiple factors, but it is also designed to be simple to use. “We have been trying to use it with simple factors, [information] that you always have, like age, sex, gender, number of lesions, and topography of the region. Everybody has this information at their desk.”
 

Proof of concept

The study validates the approach that neurologists already utilize, according to Patricia Coyle, MD, who moderated the session. “I think the prospective study is a really unique and powerful concept,” said Dr. Coyle, who is a professor of neurology, vice chair of neurology, and director of the Stony Brook (N.Y.) Comprehensive Care Center.

The new study “kind of confirmed their concept of the initial rating, judging long-term disability progression measures in subsets. They also looked at brain atrophy, they looked at gray-matter atrophy, and that also traveled with these three different groups of severity. So it kind of gives value to looking at prognostic indicators at a first attack,” said Dr. Coyle.

The results also validate the Barcelona group’s heavy emphasis on MRI, which Dr. Coyle pointed out is common practice. “If the brain MRI looks very bad, if there are a lot of spinal cord lesions, then that’s somebody we’re much more worried about.”

Once the model is confirmed in other cohorts, the researchers plan to release the model as a generally available algorithm that clinicians could use to help manage patients. Dr. Tintoré pointed out the debate over when to begin a patient on high-efficacy disease-modifying therapies. That choice depends on a lot of factors, including patient choice, safety, and comorbidities. “But knowing that your patient is at risk of having a bad prognosis is something that is helpful” in that decision-making process, she said.
 

Predicting time to EDSS 3.0

The researchers used the Barcelona CIS cohort to build a Weibull survival regression in order to estimate the median time to EDSS 3.0. The model produced three categories with widely divergent predicted times from CIS to EDSS 3.0: low risk, medium risk, and high risk.

In the current report, the researchers compared the model to a “360 degree” measure of measures in 1,308 patients, including clinical milestones (McDonald 2017 MS, confirmed secondary progressive MS, progression independent of relapse activity [PIRA], EDSS disability, number of T2 MRI lesions and brain atrophy, and Patient Reported Outcomes for MS [walking speed, manual dexterity, processing speed, and contrast sensitivity]).

At 30 years after CIS, the risk of reaching EDSS 3.0 was higher in the medium risk (hazard ratio, 3.0 versus low risk) and in the high risk group (HR, 8.3 versus low risk). At 10 years, the low risk group had a 40% risk of fulfilling McDonald 2017 criteria, versus 89% in the intermediate group, and 98% in the high risk group. A similar relationship was seen for SPMS (1%, 8%, 16%) and PIRA (17%, 26%, 35%).

At 10 years, the estimated accumulated T2 lesions was 7 in the low-risk group (95% CI, 5-9), 15 in the medium-risk group (95% CI, 12-17), and 21 in the high-risk group (95% CI, 15-27).

Compared with the low- and medium-risk groups, the high-risk group had lower brain parenchymal fraction and gray-matter fraction at 5 years. They also experienced higher stigma, had worse perception of upper and lower limb function as measured by Neuro QoL, and had worse cognitive performance.

Dr. Tintoré has received compensation for consulting services and speaking honoraria from Aimirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Teva Pharmaceuticals, and Viela Bio. Dr. Coyle has no relevant disclosures.

Physician employment contracts include some new dangers. This includes physicians taking a new job, but it also includes already-employed doctors who are being asked to resign a new contract that contains new conditions. A number of these new clauses have arisen because of COVID-19. When the pandemic dramatically reduced patient flow, many employers didn’t have enough money to pay doctors and didn’t always have physicians in the right location or practice setting.

Vowing this would never happen again, some employers have rewritten their physician contracts to make it easier to reassign and terminate physicians.

Here are 12 potential land mines in a physician employment contract, some of which were added as a result of the pandemic.
 

You could be immediately terminated without notice

One outcome of the pandemic is the growing use of “force majeure” clauses, which give the employer the right to reduce your compensation or even terminate you due to a natural disaster, which could include COVID.

“COVID made employers aware of the potential impact of disasters on their operations,” said Dan Shay, a health law attorney at Alice Gosfield & Associates in Philadelphia. “Therefore, even as the threat of COVID abates in many places, employers are continuing to put this provision in the contract.”

What can you do? “One way to get some protection is to rule out a termination without cause in the first year,” said Michael A. Cassidy, a physician contract attorney at Tucker Arensberg in Pittsburgh.

The force majeure clause is less likely to affect salary, but could impact bonus and incentive tied to performance. It’s wise to try to specifically limit how much the force majeure could reduce pay tied to performance, and to be prepared to negotiate that aspect of your contract.
 

No protections if you’re let go through no fault of your own

You could lose your job if your employer could not generate enough business and has to let some doctors go. This happened quite often in the early days of the COVID pandemic.

In these situations, the doctor has not done anything wrong to prompt the termination, but the restrictive covenant may still apply, meaning that the doctor would have to leave the area to find work.

What can you do? You’re in a good position to get this changed, said Christopher L. Nuland, a solo physician contract attorney in Jacksonville, Fla. “Many employers recognize that it would be draconian to require a restrictive covenant in this case, and they will agree to modify this provision.”

Similarly, the employer may not cover your tail insurance even if you were let go from your work through no fault of your own. Most malpractice policies for employer physicians require buying an extra policy, called a tail, if you leave. In some cases, the employer won’t provide a tail and will make the departing doctor buy it.

In these cases, “try for a compromise, such as stipulating that the party that caused the termination should pay for the tail,” Mr. Nuland said. “The employer may not agree to anything more than that because they want to set up a disincentive against you leaving.”
 

Employer could unilaterally alter your compensation

Many recent contracts give the employer the option to unilaterally modify compensation, such as changing the base salary or raising the target required for meeting the productivity bonus, said Ericka L. Adler, a physician contract attorney at Roetzel & Andress in Chicago.

Ms. Adler thought this change could have been prompted by employers’ financial problems during the pandemic. In the early months of COVID, many physicians were not making much money for the employer but still had to be paid. So employers added a clause saying they could reduce compensation at any time, she said.

What can you do? Harsh provisions like this often come up in contracts with private equity firms, Mr. Cassidy said. “The contract might say the employer can adjust compensation or even terminate physicians based on productivity or their profitability. And it may say that if they reassign you to a new location and you refuse, they can terminate you.”

“If you can’t get these clauses removed, try to reduce the impact of a termination by providing longer notice periods or by inserting a severance agreement,” Mr. Cassidy said.
 

Accelerating notice for without-cause terminations

Physicians who are convicted of a felony or other moral issue can usually be terminated immediately. But if you are terminated for other reasons – that is, “without cause” – you are given notice at a certain number of days before you have to leave (typically 60-90 days), so that you have time to find a new job.

Some recent contracts, however, allow for very little notice in without-cause terminations, which allows the employer to fire you in as little as 0 days after providing notice, Ms. Adler said.

“This means that, even if 90 days’ notice is provided in the contract, the employer can decide that your last day will be an earlier date,” she said.

Why is this happening? Ms. Adler said employers want to begin reallocating resources and patients as soon as possible. The problem came to employers’ attention during the COVID pandemic, when they were contractually forced to pay doctors for doing little or nothing during the notice period.

What can you do? Possibly not much, other than attempt to negotiate. “Large employers typically don’t want to drop this provision, but at the least, the doctor needs to understand the risk it creates for them,” she said.
 

You could be assigned to far-off locations

As patient care needs changed dramatically during the pandemic, employers needed to reassign doctors to new locations.

Some new contracts allow employers to simply inform the doctor that they are changing the work location. However, “you don’t want to be assigned to a new work location that is 50 miles away,” Mr. Nuland said.

What can you do? Mr. Nuland recommended adding new language saying that, if the new assignment is more than 20 miles away, both parties would have to approve it.

You could end up working too many off-hours

“Most employers won’t issue a specific work schedule,” Mr. Nuland said. “They want the flexibility to assign evening or weekend work, and it would be difficult for a young doctor to change this.”

What can you do? Mr. Nuland recommended trying to set some limits. “You can try to limit off-hours work to two times a month or something like that,” she said. And if you need to have a special schedule, such as not working on Fridays, Adler advises that this should be put into the contract.

If you can’t get anything changed in the contract, Mr. Nuland said the next-best thing is to ask employers to tell you specifically what they plan to do with you. “Most employers will give you an informal idea of what’s expected – maybe not an exact schedule, but it’s quite likely they will honor it.”
 

You wouldn’t be able to work nearby if you left the job

Most contracts have a noncompete clause, also known as a “restrictive covenant,” which prevents employed physicians from working in the area if they left the job.

“Almost every doctor I represent has told me that they’re not concerned about the noncompete clause because, they believe, it is not enforceable anyway,” Ms. Adler said. “This is incorrect.”

Mr. Nuland said the faster pace of job-changing during the pandemic makes it all the more likely that doctors have to deal with a restrictive covenant. At the same time, some employers have been expanding the restriction – either by enlarging the radius where the restriction applies or by making the restriction apply to each of their sites, so that each one has a restricted radius around it.

For example, one contract Mr. Nuland is currently reviewing has a 20-mile radius that in effect becomes a 120-mile radius because the employer is counting four offices.

What can you do? Mr. Nuland advised trying to reduce the impact of the noncompete – for instance, making it apply only to the offices where you worked, or trading more time for less distance. “If you have a 2-year, 20-mile restriction, ask for a 3-year, 10-mile restriction, where the radius could be easier to deal with,” he said.
 

You might end up with too much call

Contracts rarely detail your call schedule because employers want flexibility to expand call as patient care needs change, but you can try adding some specificity, said Sanja Ord, a physician contract attorney at Greensfelder, Hemker & Gale in St. Louis.

Contracts often use wide-open language to describe call, such as simply making it “subject to the house call policies,” Mr. Cassidy said. Language that is more beneficial to the physician would say that call must be “equal” among “similarly situated” physicians.

But Ms. Ord said even provisions for equal call can turn out to be onerous if there are too few doctors in the call roster, so it’s a good idea to find out just how many doctors will be participating in call.

Still, Adler said even that strategy can’t remove all risk. What happens, she asked, if several physicians participating in call decide to leave? Then you might end up with call every other night.

What can you do? Mr. Cassidy recommends specifying a maximum amount of call – for example, no more frequent than one in four nights.
 

Physician must pay for reimbursement claw-backs by payers

When auditors for Medicare or other payers find overpayments after the fact, called a ‘claw-back,’ the provider must pay them back. But which provider has to do that – you or your employer?

In many cases, your employer’s billing office may have introduced the error, but there may be a clause in the contract stating that the physician is solely responsible for all claw-backs. That could be costly.

What can you do? Mr. Shay said the clause should state that you have to pay only when it is the result of your own error or omission, and also not when it was made at the direction of the employer.
 

Some work may be outside of your subspecialty

In some cases, the employer may assign subspecialized doctors to work outside their subspecialty, Mr. Nuland said.

For example, he said he represented an endocrinologist who expected to see only diabetes patients but was assigned to some general internal medicine work as well, and an otolaryngologist client of his who completed a fellowship on facial plastic surgery was expected to do liposuction in a cosmetic surgery group.

What can you do? To prevent this from happening, Mr. Nuland recommends a clause stating that your work will be restricted to your subspecialty.

What the employer promised isn’t in the contract

“Beware of promises that are not in the contract,” Mr. Shay said. “You might feel you can really trust your new boss and what he tells you, but what if that person resigns, or the organization gets a new owner who doesn’t honor unwritten agreements?”

Many contracts have an integration clause, which specifies that the contract constitutes the complete agreement between the two parties, and it nullifies any other oral or written promises made to the physician.

For example, the employer might have promised a relocation bonus and a sign-on bonus, but for some reason it didn’t get into the contract, Ms. Ord said. In those cases, the employer is under no obligation to honor the promise.

What can you do? Mr. Cassidy said it is possible to hold the employer to a commitment made outside the contract. The alternative document, such as an offer letter, has to specifically state that the commitment is protected from the integration clause in the contract, he said, adding: “It is still better to have the commitment put into the contract.”
 

Contract is simply accepted as is

“Generally, the bigger the employer, the less likely they will alter an agreement just to make you happy,” Mr. Shay said.

But even in these contracts, he said there is still opportunity to fix errors and ambiguities that could harm you later – or even alter a provision if you can’t remove it outright.

The back-and-forth is important, Ms. Adler said. “Negotiation means trying to have some control over your job and your life.”

Mr. Cassidy said a big part of contract review is facing up to the possibility that you may have to resign or be let go.

“Many physicians don’t like to think about leaving when they’re just starting a job, but they need to,” he said. “You need to begin with the end in mind. Think about what would happen if this job didn’t work out.”

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

Physician employment contracts include some new dangers. This includes physicians taking a new job, but it also includes already-employed doctors who are being asked to resign a new contract that contains new conditions. A number of these new clauses have arisen because of COVID-19. When the pandemic dramatically reduced patient flow, many employers didn’t have enough money to pay doctors and didn’t always have physicians in the right location or practice setting.

Vowing this would never happen again, some employers have rewritten their physician contracts to make it easier to reassign and terminate physicians.

Here are 12 potential land mines in a physician employment contract, some of which were added as a result of the pandemic.
 

You could be immediately terminated without notice

One outcome of the pandemic is the growing use of “force majeure” clauses, which give the employer the right to reduce your compensation or even terminate you due to a natural disaster, which could include COVID.

“COVID made employers aware of the potential impact of disasters on their operations,” said Dan Shay, a health law attorney at Alice Gosfield & Associates in Philadelphia. “Therefore, even as the threat of COVID abates in many places, employers are continuing to put this provision in the contract.”

What can you do? “One way to get some protection is to rule out a termination without cause in the first year,” said Michael A. Cassidy, a physician contract attorney at Tucker Arensberg in Pittsburgh.

The force majeure clause is less likely to affect salary, but could impact bonus and incentive tied to performance. It’s wise to try to specifically limit how much the force majeure could reduce pay tied to performance, and to be prepared to negotiate that aspect of your contract.
 

No protections if you’re let go through no fault of your own

You could lose your job if your employer could not generate enough business and has to let some doctors go. This happened quite often in the early days of the COVID pandemic.

In these situations, the doctor has not done anything wrong to prompt the termination, but the restrictive covenant may still apply, meaning that the doctor would have to leave the area to find work.

What can you do? You’re in a good position to get this changed, said Christopher L. Nuland, a solo physician contract attorney in Jacksonville, Fla. “Many employers recognize that it would be draconian to require a restrictive covenant in this case, and they will agree to modify this provision.”

Similarly, the employer may not cover your tail insurance even if you were let go from your work through no fault of your own. Most malpractice policies for employer physicians require buying an extra policy, called a tail, if you leave. In some cases, the employer won’t provide a tail and will make the departing doctor buy it.

In these cases, “try for a compromise, such as stipulating that the party that caused the termination should pay for the tail,” Mr. Nuland said. “The employer may not agree to anything more than that because they want to set up a disincentive against you leaving.”
 

Employer could unilaterally alter your compensation

Many recent contracts give the employer the option to unilaterally modify compensation, such as changing the base salary or raising the target required for meeting the productivity bonus, said Ericka L. Adler, a physician contract attorney at Roetzel & Andress in Chicago.

Ms. Adler thought this change could have been prompted by employers’ financial problems during the pandemic. In the early months of COVID, many physicians were not making much money for the employer but still had to be paid. So employers added a clause saying they could reduce compensation at any time, she said.

What can you do? Harsh provisions like this often come up in contracts with private equity firms, Mr. Cassidy said. “The contract might say the employer can adjust compensation or even terminate physicians based on productivity or their profitability. And it may say that if they reassign you to a new location and you refuse, they can terminate you.”

“If you can’t get these clauses removed, try to reduce the impact of a termination by providing longer notice periods or by inserting a severance agreement,” Mr. Cassidy said.
 

Accelerating notice for without-cause terminations

Physicians who are convicted of a felony or other moral issue can usually be terminated immediately. But if you are terminated for other reasons – that is, “without cause” – you are given notice at a certain number of days before you have to leave (typically 60-90 days), so that you have time to find a new job.

Some recent contracts, however, allow for very little notice in without-cause terminations, which allows the employer to fire you in as little as 0 days after providing notice, Ms. Adler said.

“This means that, even if 90 days’ notice is provided in the contract, the employer can decide that your last day will be an earlier date,” she said.

Why is this happening? Ms. Adler said employers want to begin reallocating resources and patients as soon as possible. The problem came to employers’ attention during the COVID pandemic, when they were contractually forced to pay doctors for doing little or nothing during the notice period.

What can you do? Possibly not much, other than attempt to negotiate. “Large employers typically don’t want to drop this provision, but at the least, the doctor needs to understand the risk it creates for them,” she said.
 

You could be assigned to far-off locations

As patient care needs changed dramatically during the pandemic, employers needed to reassign doctors to new locations.

Some new contracts allow employers to simply inform the doctor that they are changing the work location. However, “you don’t want to be assigned to a new work location that is 50 miles away,” Mr. Nuland said.

What can you do? Mr. Nuland recommended adding new language saying that, if the new assignment is more than 20 miles away, both parties would have to approve it.

You could end up working too many off-hours

“Most employers won’t issue a specific work schedule,” Mr. Nuland said. “They want the flexibility to assign evening or weekend work, and it would be difficult for a young doctor to change this.”

What can you do? Mr. Nuland recommended trying to set some limits. “You can try to limit off-hours work to two times a month or something like that,” she said. And if you need to have a special schedule, such as not working on Fridays, Adler advises that this should be put into the contract.

If you can’t get anything changed in the contract, Mr. Nuland said the next-best thing is to ask employers to tell you specifically what they plan to do with you. “Most employers will give you an informal idea of what’s expected – maybe not an exact schedule, but it’s quite likely they will honor it.”
 

You wouldn’t be able to work nearby if you left the job

Most contracts have a noncompete clause, also known as a “restrictive covenant,” which prevents employed physicians from working in the area if they left the job.

“Almost every doctor I represent has told me that they’re not concerned about the noncompete clause because, they believe, it is not enforceable anyway,” Ms. Adler said. “This is incorrect.”

Mr. Nuland said the faster pace of job-changing during the pandemic makes it all the more likely that doctors have to deal with a restrictive covenant. At the same time, some employers have been expanding the restriction – either by enlarging the radius where the restriction applies or by making the restriction apply to each of their sites, so that each one has a restricted radius around it.

For example, one contract Mr. Nuland is currently reviewing has a 20-mile radius that in effect becomes a 120-mile radius because the employer is counting four offices.

What can you do? Mr. Nuland advised trying to reduce the impact of the noncompete – for instance, making it apply only to the offices where you worked, or trading more time for less distance. “If you have a 2-year, 20-mile restriction, ask for a 3-year, 10-mile restriction, where the radius could be easier to deal with,” he said.
 

You might end up with too much call

Contracts rarely detail your call schedule because employers want flexibility to expand call as patient care needs change, but you can try adding some specificity, said Sanja Ord, a physician contract attorney at Greensfelder, Hemker & Gale in St. Louis.

Contracts often use wide-open language to describe call, such as simply making it “subject to the house call policies,” Mr. Cassidy said. Language that is more beneficial to the physician would say that call must be “equal” among “similarly situated” physicians.

But Ms. Ord said even provisions for equal call can turn out to be onerous if there are too few doctors in the call roster, so it’s a good idea to find out just how many doctors will be participating in call.

Still, Adler said even that strategy can’t remove all risk. What happens, she asked, if several physicians participating in call decide to leave? Then you might end up with call every other night.

What can you do? Mr. Cassidy recommends specifying a maximum amount of call – for example, no more frequent than one in four nights.
 

Physician must pay for reimbursement claw-backs by payers

When auditors for Medicare or other payers find overpayments after the fact, called a ‘claw-back,’ the provider must pay them back. But which provider has to do that – you or your employer?

In many cases, your employer’s billing office may have introduced the error, but there may be a clause in the contract stating that the physician is solely responsible for all claw-backs. That could be costly.

What can you do? Mr. Shay said the clause should state that you have to pay only when it is the result of your own error or omission, and also not when it was made at the direction of the employer.
 

Some work may be outside of your subspecialty

In some cases, the employer may assign subspecialized doctors to work outside their subspecialty, Mr. Nuland said.

For example, he said he represented an endocrinologist who expected to see only diabetes patients but was assigned to some general internal medicine work as well, and an otolaryngologist client of his who completed a fellowship on facial plastic surgery was expected to do liposuction in a cosmetic surgery group.

What can you do? To prevent this from happening, Mr. Nuland recommends a clause stating that your work will be restricted to your subspecialty.

What the employer promised isn’t in the contract

“Beware of promises that are not in the contract,” Mr. Shay said. “You might feel you can really trust your new boss and what he tells you, but what if that person resigns, or the organization gets a new owner who doesn’t honor unwritten agreements?”

Many contracts have an integration clause, which specifies that the contract constitutes the complete agreement between the two parties, and it nullifies any other oral or written promises made to the physician.

For example, the employer might have promised a relocation bonus and a sign-on bonus, but for some reason it didn’t get into the contract, Ms. Ord said. In those cases, the employer is under no obligation to honor the promise.

What can you do? Mr. Cassidy said it is possible to hold the employer to a commitment made outside the contract. The alternative document, such as an offer letter, has to specifically state that the commitment is protected from the integration clause in the contract, he said, adding: “It is still better to have the commitment put into the contract.”
 

Contract is simply accepted as is

“Generally, the bigger the employer, the less likely they will alter an agreement just to make you happy,” Mr. Shay said.

But even in these contracts, he said there is still opportunity to fix errors and ambiguities that could harm you later – or even alter a provision if you can’t remove it outright.

The back-and-forth is important, Ms. Adler said. “Negotiation means trying to have some control over your job and your life.”

Mr. Cassidy said a big part of contract review is facing up to the possibility that you may have to resign or be let go.

“Many physicians don’t like to think about leaving when they’re just starting a job, but they need to,” he said. “You need to begin with the end in mind. Think about what would happen if this job didn’t work out.”

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

Physician employment contracts include some new dangers. This includes physicians taking a new job, but it also includes already-employed doctors who are being asked to resign a new contract that contains new conditions. A number of these new clauses have arisen because of COVID-19. When the pandemic dramatically reduced patient flow, many employers didn’t have enough money to pay doctors and didn’t always have physicians in the right location or practice setting.

Vowing this would never happen again, some employers have rewritten their physician contracts to make it easier to reassign and terminate physicians.

Here are 12 potential land mines in a physician employment contract, some of which were added as a result of the pandemic.
 

You could be immediately terminated without notice

One outcome of the pandemic is the growing use of “force majeure” clauses, which give the employer the right to reduce your compensation or even terminate you due to a natural disaster, which could include COVID.

“COVID made employers aware of the potential impact of disasters on their operations,” said Dan Shay, a health law attorney at Alice Gosfield & Associates in Philadelphia. “Therefore, even as the threat of COVID abates in many places, employers are continuing to put this provision in the contract.”

What can you do? “One way to get some protection is to rule out a termination without cause in the first year,” said Michael A. Cassidy, a physician contract attorney at Tucker Arensberg in Pittsburgh.

The force majeure clause is less likely to affect salary, but could impact bonus and incentive tied to performance. It’s wise to try to specifically limit how much the force majeure could reduce pay tied to performance, and to be prepared to negotiate that aspect of your contract.
 

No protections if you’re let go through no fault of your own

You could lose your job if your employer could not generate enough business and has to let some doctors go. This happened quite often in the early days of the COVID pandemic.

In these situations, the doctor has not done anything wrong to prompt the termination, but the restrictive covenant may still apply, meaning that the doctor would have to leave the area to find work.

What can you do? You’re in a good position to get this changed, said Christopher L. Nuland, a solo physician contract attorney in Jacksonville, Fla. “Many employers recognize that it would be draconian to require a restrictive covenant in this case, and they will agree to modify this provision.”

Similarly, the employer may not cover your tail insurance even if you were let go from your work through no fault of your own. Most malpractice policies for employer physicians require buying an extra policy, called a tail, if you leave. In some cases, the employer won’t provide a tail and will make the departing doctor buy it.

In these cases, “try for a compromise, such as stipulating that the party that caused the termination should pay for the tail,” Mr. Nuland said. “The employer may not agree to anything more than that because they want to set up a disincentive against you leaving.”
 

Employer could unilaterally alter your compensation

Many recent contracts give the employer the option to unilaterally modify compensation, such as changing the base salary or raising the target required for meeting the productivity bonus, said Ericka L. Adler, a physician contract attorney at Roetzel & Andress in Chicago.

Ms. Adler thought this change could have been prompted by employers’ financial problems during the pandemic. In the early months of COVID, many physicians were not making much money for the employer but still had to be paid. So employers added a clause saying they could reduce compensation at any time, she said.

What can you do? Harsh provisions like this often come up in contracts with private equity firms, Mr. Cassidy said. “The contract might say the employer can adjust compensation or even terminate physicians based on productivity or their profitability. And it may say that if they reassign you to a new location and you refuse, they can terminate you.”

“If you can’t get these clauses removed, try to reduce the impact of a termination by providing longer notice periods or by inserting a severance agreement,” Mr. Cassidy said.
 

Accelerating notice for without-cause terminations

Physicians who are convicted of a felony or other moral issue can usually be terminated immediately. But if you are terminated for other reasons – that is, “without cause” – you are given notice at a certain number of days before you have to leave (typically 60-90 days), so that you have time to find a new job.

Some recent contracts, however, allow for very little notice in without-cause terminations, which allows the employer to fire you in as little as 0 days after providing notice, Ms. Adler said.

“This means that, even if 90 days’ notice is provided in the contract, the employer can decide that your last day will be an earlier date,” she said.

Why is this happening? Ms. Adler said employers want to begin reallocating resources and patients as soon as possible. The problem came to employers’ attention during the COVID pandemic, when they were contractually forced to pay doctors for doing little or nothing during the notice period.

What can you do? Possibly not much, other than attempt to negotiate. “Large employers typically don’t want to drop this provision, but at the least, the doctor needs to understand the risk it creates for them,” she said.
 

You could be assigned to far-off locations

As patient care needs changed dramatically during the pandemic, employers needed to reassign doctors to new locations.

Some new contracts allow employers to simply inform the doctor that they are changing the work location. However, “you don’t want to be assigned to a new work location that is 50 miles away,” Mr. Nuland said.

What can you do? Mr. Nuland recommended adding new language saying that, if the new assignment is more than 20 miles away, both parties would have to approve it.

You could end up working too many off-hours

“Most employers won’t issue a specific work schedule,” Mr. Nuland said. “They want the flexibility to assign evening or weekend work, and it would be difficult for a young doctor to change this.”

What can you do? Mr. Nuland recommended trying to set some limits. “You can try to limit off-hours work to two times a month or something like that,” she said. And if you need to have a special schedule, such as not working on Fridays, Adler advises that this should be put into the contract.

If you can’t get anything changed in the contract, Mr. Nuland said the next-best thing is to ask employers to tell you specifically what they plan to do with you. “Most employers will give you an informal idea of what’s expected – maybe not an exact schedule, but it’s quite likely they will honor it.”
 

You wouldn’t be able to work nearby if you left the job

Most contracts have a noncompete clause, also known as a “restrictive covenant,” which prevents employed physicians from working in the area if they left the job.

“Almost every doctor I represent has told me that they’re not concerned about the noncompete clause because, they believe, it is not enforceable anyway,” Ms. Adler said. “This is incorrect.”

Mr. Nuland said the faster pace of job-changing during the pandemic makes it all the more likely that doctors have to deal with a restrictive covenant. At the same time, some employers have been expanding the restriction – either by enlarging the radius where the restriction applies or by making the restriction apply to each of their sites, so that each one has a restricted radius around it.

For example, one contract Mr. Nuland is currently reviewing has a 20-mile radius that in effect becomes a 120-mile radius because the employer is counting four offices.

What can you do? Mr. Nuland advised trying to reduce the impact of the noncompete – for instance, making it apply only to the offices where you worked, or trading more time for less distance. “If you have a 2-year, 20-mile restriction, ask for a 3-year, 10-mile restriction, where the radius could be easier to deal with,” he said.
 

You might end up with too much call

Contracts rarely detail your call schedule because employers want flexibility to expand call as patient care needs change, but you can try adding some specificity, said Sanja Ord, a physician contract attorney at Greensfelder, Hemker & Gale in St. Louis.

Contracts often use wide-open language to describe call, such as simply making it “subject to the house call policies,” Mr. Cassidy said. Language that is more beneficial to the physician would say that call must be “equal” among “similarly situated” physicians.

But Ms. Ord said even provisions for equal call can turn out to be onerous if there are too few doctors in the call roster, so it’s a good idea to find out just how many doctors will be participating in call.

Still, Adler said even that strategy can’t remove all risk. What happens, she asked, if several physicians participating in call decide to leave? Then you might end up with call every other night.

What can you do? Mr. Cassidy recommends specifying a maximum amount of call – for example, no more frequent than one in four nights.
 

Physician must pay for reimbursement claw-backs by payers

When auditors for Medicare or other payers find overpayments after the fact, called a ‘claw-back,’ the provider must pay them back. But which provider has to do that – you or your employer?

In many cases, your employer’s billing office may have introduced the error, but there may be a clause in the contract stating that the physician is solely responsible for all claw-backs. That could be costly.

What can you do? Mr. Shay said the clause should state that you have to pay only when it is the result of your own error or omission, and also not when it was made at the direction of the employer.
 

Some work may be outside of your subspecialty

In some cases, the employer may assign subspecialized doctors to work outside their subspecialty, Mr. Nuland said.

For example, he said he represented an endocrinologist who expected to see only diabetes patients but was assigned to some general internal medicine work as well, and an otolaryngologist client of his who completed a fellowship on facial plastic surgery was expected to do liposuction in a cosmetic surgery group.

What can you do? To prevent this from happening, Mr. Nuland recommends a clause stating that your work will be restricted to your subspecialty.

What the employer promised isn’t in the contract

“Beware of promises that are not in the contract,” Mr. Shay said. “You might feel you can really trust your new boss and what he tells you, but what if that person resigns, or the organization gets a new owner who doesn’t honor unwritten agreements?”

Many contracts have an integration clause, which specifies that the contract constitutes the complete agreement between the two parties, and it nullifies any other oral or written promises made to the physician.

For example, the employer might have promised a relocation bonus and a sign-on bonus, but for some reason it didn’t get into the contract, Ms. Ord said. In those cases, the employer is under no obligation to honor the promise.

What can you do? Mr. Cassidy said it is possible to hold the employer to a commitment made outside the contract. The alternative document, such as an offer letter, has to specifically state that the commitment is protected from the integration clause in the contract, he said, adding: “It is still better to have the commitment put into the contract.”
 

Contract is simply accepted as is

“Generally, the bigger the employer, the less likely they will alter an agreement just to make you happy,” Mr. Shay said.

But even in these contracts, he said there is still opportunity to fix errors and ambiguities that could harm you later – or even alter a provision if you can’t remove it outright.

The back-and-forth is important, Ms. Adler said. “Negotiation means trying to have some control over your job and your life.”

Mr. Cassidy said a big part of contract review is facing up to the possibility that you may have to resign or be let go.

“Many physicians don’t like to think about leaving when they’re just starting a job, but they need to,” he said. “You need to begin with the end in mind. Think about what would happen if this job didn’t work out.”

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