Patients with rheumatoid arthritis who are treated with methotrexate (MTX) are more than twice as likely to develop venous thromboembolism (VTE) when compared with patients who use hydroxychloroquine, according to data from a propensity score–matched cohort study.

“As the effect of these medications on the risk of VTE is largely unknown, we aimed to compare the rate of incident VTE after initiating MTX versus hydroxychloroquine among older patients with RA,” wrote Mengdong He, MHS, and coauthors from Brigham and Women’s Hospital and Harvard Medical School, both in Boston. Ms. At the time of the study, Ms. He was a research specialist but is now a medical student at the University of California, Los Angeles.

The results were published in Seminars in Arthritis and Rheumatism.

Using U.S. Medicare claims data from 2008 to 2017, the researchers identified patients with RA aged 65 years and older who initiated MTX or hydroxychloroquine without prior use of any immunomodulators for at least 365 days (that is, index date). Patients who used any conventional (other than methotrexate and hydroxychloroquine), biologic, or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) any time prior to the index date were excluded.

The primary outcome of interest was incident VTE, a composite endpoint of pulmonary embolism (PE) or deep vein thrombosis (DVT). Secondary outcomes were PE, DVT, and all-cause mortality.

Results

After applying the eligibility criteria, a total of 68,648 RA patients who initiated either MTX (n = 41,197) or hydroxychloroquine (n = 27,451) as their first DMARD were identified and included in the analysis.

After 1:1 propensity score matching, the cohort consisted of 26,534 matched pairs of MTX and hydroxychloroquine initiators. The mean age was 74 years (standard deviation, 7 years), and 79% of the patients were female.

During a total of 56,686 person-years of follow-up, VTE occurred in 208 MTX (incidence, 6.94 per 1,000 person-years) and 83 hydroxychloroquine initiators (incidence, 3.11 per 1,000 person-years).

Patients who initiated MTX without prior use of any DMARDs had a higher risk of PE (hazard ratio, 3.30; 95% confidence interval, 2.28-4.77) and DVT (HR, 1.53; 95% CI, 1.07-2.19) than hydroxychloroquine initiators. However, all-cause mortality did not differ between the two groups (HR, 0.91; 95% CI, 0.83-1.00).

“MTX initiators had a relative risk of VTE higher than 2 and an absolute risk increase of about 4 per 1,000 person-years, compared with hydroxychloroquine initiators,” the authors wrote. “Results from the secondary outcome analyses were consistent and subgroup analyses found no meaningful treatment effect heterogeneity.”

The researchers acknowledged that a key limitation of the study was the use of claims-based algorithms to define outcomes. As a result, outcome misclassification is possible.

“While the study methodology was sound, patients with RA who receive hydroxychloroquine are very different than those who receive MTX, and it’s difficult to fully account for these differences using an administrative data set,” commented Kaleb Michaud, PhD, professor of internal medicine at the University of Nebraska, Omaha.

“Most clinicians are more interested in understanding the differences in VTE risk between MTX and Jakinibs [Janus kinase inhibitors] or MTX and biologics,” Dr. Michaud said.

“More research, particularly with randomized trials including the placebo arm, is needed to determine the causal relationships between the study drugs and VTE and whether MTX elevates or hydroxychloroquine reduces the risk of VTE,” the authors concluded.

The study was funded by internal resources in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School. Several authors reported financial relationships with the pharmaceutical industry.

Patients with rheumatoid arthritis who are treated with methotrexate (MTX) are more than twice as likely to develop venous thromboembolism (VTE) when compared with patients who use hydroxychloroquine, according to data from a propensity score–matched cohort study.

“As the effect of these medications on the risk of VTE is largely unknown, we aimed to compare the rate of incident VTE after initiating MTX versus hydroxychloroquine among older patients with RA,” wrote Mengdong He, MHS, and coauthors from Brigham and Women’s Hospital and Harvard Medical School, both in Boston. Ms. At the time of the study, Ms. He was a research specialist but is now a medical student at the University of California, Los Angeles.

The results were published in Seminars in Arthritis and Rheumatism.

Using U.S. Medicare claims data from 2008 to 2017, the researchers identified patients with RA aged 65 years and older who initiated MTX or hydroxychloroquine without prior use of any immunomodulators for at least 365 days (that is, index date). Patients who used any conventional (other than methotrexate and hydroxychloroquine), biologic, or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) any time prior to the index date were excluded.

The primary outcome of interest was incident VTE, a composite endpoint of pulmonary embolism (PE) or deep vein thrombosis (DVT). Secondary outcomes were PE, DVT, and all-cause mortality.

Results

After applying the eligibility criteria, a total of 68,648 RA patients who initiated either MTX (n = 41,197) or hydroxychloroquine (n = 27,451) as their first DMARD were identified and included in the analysis.

After 1:1 propensity score matching, the cohort consisted of 26,534 matched pairs of MTX and hydroxychloroquine initiators. The mean age was 74 years (standard deviation, 7 years), and 79% of the patients were female.

During a total of 56,686 person-years of follow-up, VTE occurred in 208 MTX (incidence, 6.94 per 1,000 person-years) and 83 hydroxychloroquine initiators (incidence, 3.11 per 1,000 person-years).

Patients who initiated MTX without prior use of any DMARDs had a higher risk of PE (hazard ratio, 3.30; 95% confidence interval, 2.28-4.77) and DVT (HR, 1.53; 95% CI, 1.07-2.19) than hydroxychloroquine initiators. However, all-cause mortality did not differ between the two groups (HR, 0.91; 95% CI, 0.83-1.00).

“MTX initiators had a relative risk of VTE higher than 2 and an absolute risk increase of about 4 per 1,000 person-years, compared with hydroxychloroquine initiators,” the authors wrote. “Results from the secondary outcome analyses were consistent and subgroup analyses found no meaningful treatment effect heterogeneity.”

The researchers acknowledged that a key limitation of the study was the use of claims-based algorithms to define outcomes. As a result, outcome misclassification is possible.

“While the study methodology was sound, patients with RA who receive hydroxychloroquine are very different than those who receive MTX, and it’s difficult to fully account for these differences using an administrative data set,” commented Kaleb Michaud, PhD, professor of internal medicine at the University of Nebraska, Omaha.

“Most clinicians are more interested in understanding the differences in VTE risk between MTX and Jakinibs [Janus kinase inhibitors] or MTX and biologics,” Dr. Michaud said.

“More research, particularly with randomized trials including the placebo arm, is needed to determine the causal relationships between the study drugs and VTE and whether MTX elevates or hydroxychloroquine reduces the risk of VTE,” the authors concluded.

The study was funded by internal resources in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School. Several authors reported financial relationships with the pharmaceutical industry.

Patients with rheumatoid arthritis who are treated with methotrexate (MTX) are more than twice as likely to develop venous thromboembolism (VTE) when compared with patients who use hydroxychloroquine, according to data from a propensity score–matched cohort study.

“As the effect of these medications on the risk of VTE is largely unknown, we aimed to compare the rate of incident VTE after initiating MTX versus hydroxychloroquine among older patients with RA,” wrote Mengdong He, MHS, and coauthors from Brigham and Women’s Hospital and Harvard Medical School, both in Boston. Ms. At the time of the study, Ms. He was a research specialist but is now a medical student at the University of California, Los Angeles.

The results were published in Seminars in Arthritis and Rheumatism.

Using U.S. Medicare claims data from 2008 to 2017, the researchers identified patients with RA aged 65 years and older who initiated MTX or hydroxychloroquine without prior use of any immunomodulators for at least 365 days (that is, index date). Patients who used any conventional (other than methotrexate and hydroxychloroquine), biologic, or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) any time prior to the index date were excluded.

The primary outcome of interest was incident VTE, a composite endpoint of pulmonary embolism (PE) or deep vein thrombosis (DVT). Secondary outcomes were PE, DVT, and all-cause mortality.

Results

After applying the eligibility criteria, a total of 68,648 RA patients who initiated either MTX (n = 41,197) or hydroxychloroquine (n = 27,451) as their first DMARD were identified and included in the analysis.

After 1:1 propensity score matching, the cohort consisted of 26,534 matched pairs of MTX and hydroxychloroquine initiators. The mean age was 74 years (standard deviation, 7 years), and 79% of the patients were female.

During a total of 56,686 person-years of follow-up, VTE occurred in 208 MTX (incidence, 6.94 per 1,000 person-years) and 83 hydroxychloroquine initiators (incidence, 3.11 per 1,000 person-years).

Patients who initiated MTX without prior use of any DMARDs had a higher risk of PE (hazard ratio, 3.30; 95% confidence interval, 2.28-4.77) and DVT (HR, 1.53; 95% CI, 1.07-2.19) than hydroxychloroquine initiators. However, all-cause mortality did not differ between the two groups (HR, 0.91; 95% CI, 0.83-1.00).

“MTX initiators had a relative risk of VTE higher than 2 and an absolute risk increase of about 4 per 1,000 person-years, compared with hydroxychloroquine initiators,” the authors wrote. “Results from the secondary outcome analyses were consistent and subgroup analyses found no meaningful treatment effect heterogeneity.”

The researchers acknowledged that a key limitation of the study was the use of claims-based algorithms to define outcomes. As a result, outcome misclassification is possible.

“While the study methodology was sound, patients with RA who receive hydroxychloroquine are very different than those who receive MTX, and it’s difficult to fully account for these differences using an administrative data set,” commented Kaleb Michaud, PhD, professor of internal medicine at the University of Nebraska, Omaha.

“Most clinicians are more interested in understanding the differences in VTE risk between MTX and Jakinibs [Janus kinase inhibitors] or MTX and biologics,” Dr. Michaud said.

“More research, particularly with randomized trials including the placebo arm, is needed to determine the causal relationships between the study drugs and VTE and whether MTX elevates or hydroxychloroquine reduces the risk of VTE,” the authors concluded.

The study was funded by internal resources in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School. Several authors reported financial relationships with the pharmaceutical industry.

Influenza infection is linked to a subsequent diagnosis of Parkinson’s disease (PD) more than 10 years later, resurfacing a long-held debate about whether infection increases the risk for movement disorders over the long term.

In a large case-control study, investigators found the odds of PD were elevated by approximately 90% for PD that occurred more than 15 years after influenza infection and by more than 70% for PD occurring more than 10 years after the flu.

“This study is not definitive by any means, but it certainly suggests there are potential long-term consequences from influenza,” study investigator Noelle M. Cocoros, DSc, research scientist at Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, said in an interview.

The study was published online Oct. 25 in JAMA Neurology.

Ongoing debate

The debate about whether influenza is associated with PD has been going on as far back as the 1918 influenza pandemic, when experts documented parkinsonism in affected individuals.

Using data from the Danish patient registry, researchers identified 10,271 subjects diagnosed with PD during a 17-year period (2000-2016). Of these, 38.7% were female, and the mean age was 71.4 years.

They matched these subjects for age and sex to 51,355 controls without PD. Compared with controls, slightly fewer individuals with PD had chronic obstructive pulmonary disease (COPD) or emphysema, but there was a similar distribution of cardiovascular disease and various other conditions.

Researchers collected data on influenza diagnoses from inpatient and outpatient hospital clinics from 1977 to 2016. They plotted these by month and year on a graph, calculated the median number of diagnoses per month, and identified peaks as those with more than threefold the median.

They categorized cases in groups related to the time between the infection and PD: More than 10 years, 10-15 years, and more than 15 years.

The time lapse accounts for a rather long “run-up” to PD, said Dr. Cocoros. There’s a sometimes decades-long preclinical phase before patients develop typical motor signs and a prodromal phase where they may present with nonmotor symptoms such as sleep disorders and constipation.

“We expected there would be at least 10 years between any infection and PD if there was an association present,” said Dr. Cocoros.

Investigators found an association between influenza exposure and PD diagnosis “that held up over time,” she said.

For more than 10 years before PD, the likelihood of a diagnosis for the infected compared with the unexposed was increased 73% (odds ratio [OR] 1.73; 95% confidence interval, 1.11-2.71; P = .02) after adjustment for cardiovascular disease, diabetes, chronic obstructive pulmonary disease, emphysema, lung cancer, Crohn’s disease, and ulcerative colitis.

The odds increased with more time from infection. For more than 15 years, the adjusted OR was 1.91 (95% CI, 1.14 - 3.19; P =.01).

However, for the 10- to 15-year time frame, the point estimate was reduced and the CI nonsignificant (OR, 1.33; 95% CI, 0.54-3.27; P = .53). This “is a little hard to interpret,” but could be a result of the small numbers, exposure misclassification, or because “the longer time interval is what’s meaningful,” said Dr. Cocoros.
 

Potential COVID-19–related PD surge?

In a sensitivity analysis, researchers looked at peak infection activity. “We wanted to increase the likelihood of these diagnoses representing actual infection,” Dr. Cocoros noted.

Here, the OR was still elevated at more than 10 years, but the CI was quite wide and included 1 (OR, 1.52; 95% CI, 0.80-2.89; P = .21). “So the association holds up, but the estimates are quite unstable,” said Dr. Cocoros.

Researchers examined associations with numerous other infection types, but did not see the same trend over time. Some infections – for example, gastrointestinal infections and septicemia – were associated with PD within 5 years, but most associations appeared to be null after more than 10 years.

“There seemed to be associations earlier between the infection and PD, which we interpret to suggest there’s actually not a meaningful association,” said Dr. Cocoros.

An exception might be urinary tract infections (UTIs), where after 10 years, the adjusted OR was 1.19 (95% CI, 1.01-1.40). Research suggests patients with PD often have UTIs and neurogenic bladder.

“It’s possible that UTIs could be an early symptom of PD rather than a causative factor,” said Dr. Cocoros.

It’s unclear how influenza might lead to PD but it could be that the virus gets into the central nervous system, resulting in neuroinflammation. Cytokines generated in response to the influenza infection might damage the brain.

“The infection could be a ‘primer’ or an initial ‘hit’ to the system, maybe setting people up for PD,” said Dr. Cocoros.

As for the current COVID-19 pandemic, some experts are concerned about a potential surge in PD cases in decades to come, and are calling for prospective monitoring of patients with this infection, said Dr. Cocoros.

However, she noted that infections don’t account for all PD cases and that genetic and environmental factors also influence risk.

Many individuals who contract influenza don’t seek medical care or get tested, so it’s possible the study counted those who had the infection as unexposed. Another potential study limitation was that small numbers for some infections, for example, Helicobacter pylori and hepatitis C, limited the ability to interpret results.
 

‘Exciting and important’ findings

Commenting on the research for this news organization, Aparna Wagle Shukla, MD, professor, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, said the results amid the current pandemic are “exciting and important” and “have reinvigorated interest” in the role of infection in PD.

However, the study had some limitations, an important one being lack of accounting for confounding factors, including environmental factors, she said. Exposure to pesticides, living in a rural area, drinking well water, and having had a head injury may increase PD risk, whereas high intake of caffeine, nicotine, alcohol, and nonsteroidal anti-inflammatory drugs might lower the risk.

The researchers did not take into account exposure to multiple microbes or “infection burden,” said Dr. Wagle Shukla, who was not involved in the current study. In addition, as the data are from a single country with exposure to specific influenza strains, application of the findings elsewhere may be limited.

Dr. Wagle Shukla noted that a case-control design “isn’t ideal” from an epidemiological perspective. “Future studies should involve large cohorts followed longitudinally.”

The study was supported by grants from the Lundbeck Foundation and the Augustinus Foundation. Dr. Cocoros has disclosed no relevant financial relationships. Several coauthors have disclosed relationships with industry. The full list can be found with the original article.

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

Influenza infection is linked to a subsequent diagnosis of Parkinson’s disease (PD) more than 10 years later, resurfacing a long-held debate about whether infection increases the risk for movement disorders over the long term.

In a large case-control study, investigators found the odds of PD were elevated by approximately 90% for PD that occurred more than 15 years after influenza infection and by more than 70% for PD occurring more than 10 years after the flu.

“This study is not definitive by any means, but it certainly suggests there are potential long-term consequences from influenza,” study investigator Noelle M. Cocoros, DSc, research scientist at Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, said in an interview.

The study was published online Oct. 25 in JAMA Neurology.

Ongoing debate

The debate about whether influenza is associated with PD has been going on as far back as the 1918 influenza pandemic, when experts documented parkinsonism in affected individuals.

Using data from the Danish patient registry, researchers identified 10,271 subjects diagnosed with PD during a 17-year period (2000-2016). Of these, 38.7% were female, and the mean age was 71.4 years.

They matched these subjects for age and sex to 51,355 controls without PD. Compared with controls, slightly fewer individuals with PD had chronic obstructive pulmonary disease (COPD) or emphysema, but there was a similar distribution of cardiovascular disease and various other conditions.

Researchers collected data on influenza diagnoses from inpatient and outpatient hospital clinics from 1977 to 2016. They plotted these by month and year on a graph, calculated the median number of diagnoses per month, and identified peaks as those with more than threefold the median.

They categorized cases in groups related to the time between the infection and PD: More than 10 years, 10-15 years, and more than 15 years.

The time lapse accounts for a rather long “run-up” to PD, said Dr. Cocoros. There’s a sometimes decades-long preclinical phase before patients develop typical motor signs and a prodromal phase where they may present with nonmotor symptoms such as sleep disorders and constipation.

“We expected there would be at least 10 years between any infection and PD if there was an association present,” said Dr. Cocoros.

Investigators found an association between influenza exposure and PD diagnosis “that held up over time,” she said.

For more than 10 years before PD, the likelihood of a diagnosis for the infected compared with the unexposed was increased 73% (odds ratio [OR] 1.73; 95% confidence interval, 1.11-2.71; P = .02) after adjustment for cardiovascular disease, diabetes, chronic obstructive pulmonary disease, emphysema, lung cancer, Crohn’s disease, and ulcerative colitis.

The odds increased with more time from infection. For more than 15 years, the adjusted OR was 1.91 (95% CI, 1.14 - 3.19; P =.01).

However, for the 10- to 15-year time frame, the point estimate was reduced and the CI nonsignificant (OR, 1.33; 95% CI, 0.54-3.27; P = .53). This “is a little hard to interpret,” but could be a result of the small numbers, exposure misclassification, or because “the longer time interval is what’s meaningful,” said Dr. Cocoros.
 

Potential COVID-19–related PD surge?

In a sensitivity analysis, researchers looked at peak infection activity. “We wanted to increase the likelihood of these diagnoses representing actual infection,” Dr. Cocoros noted.

Here, the OR was still elevated at more than 10 years, but the CI was quite wide and included 1 (OR, 1.52; 95% CI, 0.80-2.89; P = .21). “So the association holds up, but the estimates are quite unstable,” said Dr. Cocoros.

Researchers examined associations with numerous other infection types, but did not see the same trend over time. Some infections – for example, gastrointestinal infections and septicemia – were associated with PD within 5 years, but most associations appeared to be null after more than 10 years.

“There seemed to be associations earlier between the infection and PD, which we interpret to suggest there’s actually not a meaningful association,” said Dr. Cocoros.

An exception might be urinary tract infections (UTIs), where after 10 years, the adjusted OR was 1.19 (95% CI, 1.01-1.40). Research suggests patients with PD often have UTIs and neurogenic bladder.

“It’s possible that UTIs could be an early symptom of PD rather than a causative factor,” said Dr. Cocoros.

It’s unclear how influenza might lead to PD but it could be that the virus gets into the central nervous system, resulting in neuroinflammation. Cytokines generated in response to the influenza infection might damage the brain.

“The infection could be a ‘primer’ or an initial ‘hit’ to the system, maybe setting people up for PD,” said Dr. Cocoros.

As for the current COVID-19 pandemic, some experts are concerned about a potential surge in PD cases in decades to come, and are calling for prospective monitoring of patients with this infection, said Dr. Cocoros.

However, she noted that infections don’t account for all PD cases and that genetic and environmental factors also influence risk.

Many individuals who contract influenza don’t seek medical care or get tested, so it’s possible the study counted those who had the infection as unexposed. Another potential study limitation was that small numbers for some infections, for example, Helicobacter pylori and hepatitis C, limited the ability to interpret results.
 

‘Exciting and important’ findings

Commenting on the research for this news organization, Aparna Wagle Shukla, MD, professor, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, said the results amid the current pandemic are “exciting and important” and “have reinvigorated interest” in the role of infection in PD.

However, the study had some limitations, an important one being lack of accounting for confounding factors, including environmental factors, she said. Exposure to pesticides, living in a rural area, drinking well water, and having had a head injury may increase PD risk, whereas high intake of caffeine, nicotine, alcohol, and nonsteroidal anti-inflammatory drugs might lower the risk.

The researchers did not take into account exposure to multiple microbes or “infection burden,” said Dr. Wagle Shukla, who was not involved in the current study. In addition, as the data are from a single country with exposure to specific influenza strains, application of the findings elsewhere may be limited.

Dr. Wagle Shukla noted that a case-control design “isn’t ideal” from an epidemiological perspective. “Future studies should involve large cohorts followed longitudinally.”

The study was supported by grants from the Lundbeck Foundation and the Augustinus Foundation. Dr. Cocoros has disclosed no relevant financial relationships. Several coauthors have disclosed relationships with industry. The full list can be found with the original article.

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

Influenza infection is linked to a subsequent diagnosis of Parkinson’s disease (PD) more than 10 years later, resurfacing a long-held debate about whether infection increases the risk for movement disorders over the long term.

In a large case-control study, investigators found the odds of PD were elevated by approximately 90% for PD that occurred more than 15 years after influenza infection and by more than 70% for PD occurring more than 10 years after the flu.

“This study is not definitive by any means, but it certainly suggests there are potential long-term consequences from influenza,” study investigator Noelle M. Cocoros, DSc, research scientist at Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, said in an interview.

The study was published online Oct. 25 in JAMA Neurology.

Ongoing debate

The debate about whether influenza is associated with PD has been going on as far back as the 1918 influenza pandemic, when experts documented parkinsonism in affected individuals.

Using data from the Danish patient registry, researchers identified 10,271 subjects diagnosed with PD during a 17-year period (2000-2016). Of these, 38.7% were female, and the mean age was 71.4 years.

They matched these subjects for age and sex to 51,355 controls without PD. Compared with controls, slightly fewer individuals with PD had chronic obstructive pulmonary disease (COPD) or emphysema, but there was a similar distribution of cardiovascular disease and various other conditions.

Researchers collected data on influenza diagnoses from inpatient and outpatient hospital clinics from 1977 to 2016. They plotted these by month and year on a graph, calculated the median number of diagnoses per month, and identified peaks as those with more than threefold the median.

They categorized cases in groups related to the time between the infection and PD: More than 10 years, 10-15 years, and more than 15 years.

The time lapse accounts for a rather long “run-up” to PD, said Dr. Cocoros. There’s a sometimes decades-long preclinical phase before patients develop typical motor signs and a prodromal phase where they may present with nonmotor symptoms such as sleep disorders and constipation.

“We expected there would be at least 10 years between any infection and PD if there was an association present,” said Dr. Cocoros.

Investigators found an association between influenza exposure and PD diagnosis “that held up over time,” she said.

For more than 10 years before PD, the likelihood of a diagnosis for the infected compared with the unexposed was increased 73% (odds ratio [OR] 1.73; 95% confidence interval, 1.11-2.71; P = .02) after adjustment for cardiovascular disease, diabetes, chronic obstructive pulmonary disease, emphysema, lung cancer, Crohn’s disease, and ulcerative colitis.

The odds increased with more time from infection. For more than 15 years, the adjusted OR was 1.91 (95% CI, 1.14 - 3.19; P =.01).

However, for the 10- to 15-year time frame, the point estimate was reduced and the CI nonsignificant (OR, 1.33; 95% CI, 0.54-3.27; P = .53). This “is a little hard to interpret,” but could be a result of the small numbers, exposure misclassification, or because “the longer time interval is what’s meaningful,” said Dr. Cocoros.
 

Potential COVID-19–related PD surge?

In a sensitivity analysis, researchers looked at peak infection activity. “We wanted to increase the likelihood of these diagnoses representing actual infection,” Dr. Cocoros noted.

Here, the OR was still elevated at more than 10 years, but the CI was quite wide and included 1 (OR, 1.52; 95% CI, 0.80-2.89; P = .21). “So the association holds up, but the estimates are quite unstable,” said Dr. Cocoros.

Researchers examined associations with numerous other infection types, but did not see the same trend over time. Some infections – for example, gastrointestinal infections and septicemia – were associated with PD within 5 years, but most associations appeared to be null after more than 10 years.

“There seemed to be associations earlier between the infection and PD, which we interpret to suggest there’s actually not a meaningful association,” said Dr. Cocoros.

An exception might be urinary tract infections (UTIs), where after 10 years, the adjusted OR was 1.19 (95% CI, 1.01-1.40). Research suggests patients with PD often have UTIs and neurogenic bladder.

“It’s possible that UTIs could be an early symptom of PD rather than a causative factor,” said Dr. Cocoros.

It’s unclear how influenza might lead to PD but it could be that the virus gets into the central nervous system, resulting in neuroinflammation. Cytokines generated in response to the influenza infection might damage the brain.

“The infection could be a ‘primer’ or an initial ‘hit’ to the system, maybe setting people up for PD,” said Dr. Cocoros.

As for the current COVID-19 pandemic, some experts are concerned about a potential surge in PD cases in decades to come, and are calling for prospective monitoring of patients with this infection, said Dr. Cocoros.

However, she noted that infections don’t account for all PD cases and that genetic and environmental factors also influence risk.

Many individuals who contract influenza don’t seek medical care or get tested, so it’s possible the study counted those who had the infection as unexposed. Another potential study limitation was that small numbers for some infections, for example, Helicobacter pylori and hepatitis C, limited the ability to interpret results.
 

‘Exciting and important’ findings

Commenting on the research for this news organization, Aparna Wagle Shukla, MD, professor, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, said the results amid the current pandemic are “exciting and important” and “have reinvigorated interest” in the role of infection in PD.

However, the study had some limitations, an important one being lack of accounting for confounding factors, including environmental factors, she said. Exposure to pesticides, living in a rural area, drinking well water, and having had a head injury may increase PD risk, whereas high intake of caffeine, nicotine, alcohol, and nonsteroidal anti-inflammatory drugs might lower the risk.

The researchers did not take into account exposure to multiple microbes or “infection burden,” said Dr. Wagle Shukla, who was not involved in the current study. In addition, as the data are from a single country with exposure to specific influenza strains, application of the findings elsewhere may be limited.

Dr. Wagle Shukla noted that a case-control design “isn’t ideal” from an epidemiological perspective. “Future studies should involve large cohorts followed longitudinally.”

The study was supported by grants from the Lundbeck Foundation and the Augustinus Foundation. Dr. Cocoros has disclosed no relevant financial relationships. Several coauthors have disclosed relationships with industry. The full list can be found with the original article.

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

Sleeping too much or too little can lead to cognitive decline over time, but new research suggests there could be a sleep time “sweet spot” that stabilizes cognitive function.

JGI/Tom Grill/Getty Images

In a longitudinal study, investigators found older adults who slept less than 4.5 hours or more than 6.5 hours a night reported significant cognitive decline over time, but cognitive scores for those with sleep duration in between that range remained stable.

“This really suggests that there’s this middle range, a ‘sweet spot,’ where your sleep is really optimal,” lead author Brendan Lucey, MD, MSCI, associate professor of neurology and director of the Washington University Sleep Medicine Center, St. Louis, said in an interview.

The study, published online Oct. 20, 2021, in the journal Brain, is part of a growing body of research that seeks to determine if sleep can be used as a marker of Alzheimer’s disease progression.
 

A complex relationship

Studies suggest a strong relationship between sleep patterns and Alzheimer’s disease, which affects nearly 6 million Americans. The challenge, Dr. Lucey said, is unwinding the complex links between sleep, AD, and cognitive function.

An earlier study by Dr. Lucey and colleagues found that poor sleep quality is associated with early signs of AD, and a report published in September found that elderly people who slept less than 6 hours a night had a greater burden of amyloid-beta, a hallmark sign of AD.

For this new study, researchers monitored sleep-wake activity over 4-6 nights in 100 participants who underwent annual cognitive assessments and clinical studies, including APOE genotyping, as part of a longitudinal study at the Knight Alzheimer Disease Research Center at Washington University.

Participants also provided cerebrospinal fluid (CSF) total tau and amyloid-beta 42 and wore a small EEG device on their forehead while they slept.

The majority of participants had a clinical dementia rating (CDR) score of 0, indicating no cognitive impairment. Twelve individuals had a CDR greater than 0, with most reporting mild cognitive impairment.

As expected, CSF analysis showed greater evidence of AD pathology in those with a baseline CDR greater than 0.

Changes in cognitive function were measured using a Preclinical Alzheimer Cognitive Composite (PACC) score, a composite of results from a neuropsychological testing battery that included the Free and Cued Selective Reminding Test, the Logical Memory Delayed Recall Test from the Wechsler Memory Scale–Revised, the Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale–Revised, and the Mini-Mental State Examination.

Researchers found an upside-down U-shaped relationship between PACC scores and sleep duration, with dramatic cognitive decline in those who slept less than 4.5 hours or more than 6.5 hours a night (P < .001 for both).

The U-shaped relationship was also found with measures of sleep phases, including time spent in rapid eye movement and in non-REM sleep (P < .001 for both).

The findings persisted even after controlling for confounders that can affect sleep and cognition, such as age, CSF total tau/amyloid-beta ₄₂ ratio, apo E four-allele carrier status, years of education, and sex.

Understanding how sleep changes at different stages of AD could help researchers determine if sleep can be used as a marker of disease progression, Dr. Lucey said. That could lead to interventions to slow that process.

“We’re not at the point yet where we can say that we need to monitor someone’s sleep time and then do an intervention to see if it would improve their risk for cognitive decline,” said Dr. Lucey, who plans to repeat this sleep study with the same cohort to track changes in sleep patterns and cognitive function over time. “But that’s a question I’m very excited to try to answer.”
 

A component of cognitive health

Commenting on the findings for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, noted that the study adds to a body of evidence linking sleep and cognition, especially how sleep quality can optimize brain function.

“We’ve seen previous research that’s shown poor sleep contributes to dementia risk, as well as research showing sleep duration may play a role in cognition,” she said.

“We also need studies that look at sleep as an intervention for cognitive health,” Dr. Snyder said. “Sleep is an important aspect of our overall health. Clinicians should have conversations with their patients about sleep as part of standard discussions about their health habits and wellness.”

The study was funded by the National Institutes of Health, the American Sleep Medicine Foundation, the Roger and Paula Riney Fund, and the Daniel J. Brennan, MD Fund. Dr. Lucey consults for Merck and Eli Lilly. Dr. Snyder has disclosed no relevant financial relationships.

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

Sleeping too much or too little can lead to cognitive decline over time, but new research suggests there could be a sleep time “sweet spot” that stabilizes cognitive function.

JGI/Tom Grill/Getty Images

In a longitudinal study, investigators found older adults who slept less than 4.5 hours or more than 6.5 hours a night reported significant cognitive decline over time, but cognitive scores for those with sleep duration in between that range remained stable.

“This really suggests that there’s this middle range, a ‘sweet spot,’ where your sleep is really optimal,” lead author Brendan Lucey, MD, MSCI, associate professor of neurology and director of the Washington University Sleep Medicine Center, St. Louis, said in an interview.

The study, published online Oct. 20, 2021, in the journal Brain, is part of a growing body of research that seeks to determine if sleep can be used as a marker of Alzheimer’s disease progression.
 

A complex relationship

Studies suggest a strong relationship between sleep patterns and Alzheimer’s disease, which affects nearly 6 million Americans. The challenge, Dr. Lucey said, is unwinding the complex links between sleep, AD, and cognitive function.

An earlier study by Dr. Lucey and colleagues found that poor sleep quality is associated with early signs of AD, and a report published in September found that elderly people who slept less than 6 hours a night had a greater burden of amyloid-beta, a hallmark sign of AD.

For this new study, researchers monitored sleep-wake activity over 4-6 nights in 100 participants who underwent annual cognitive assessments and clinical studies, including APOE genotyping, as part of a longitudinal study at the Knight Alzheimer Disease Research Center at Washington University.

Participants also provided cerebrospinal fluid (CSF) total tau and amyloid-beta 42 and wore a small EEG device on their forehead while they slept.

The majority of participants had a clinical dementia rating (CDR) score of 0, indicating no cognitive impairment. Twelve individuals had a CDR greater than 0, with most reporting mild cognitive impairment.

As expected, CSF analysis showed greater evidence of AD pathology in those with a baseline CDR greater than 0.

Changes in cognitive function were measured using a Preclinical Alzheimer Cognitive Composite (PACC) score, a composite of results from a neuropsychological testing battery that included the Free and Cued Selective Reminding Test, the Logical Memory Delayed Recall Test from the Wechsler Memory Scale–Revised, the Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale–Revised, and the Mini-Mental State Examination.

Researchers found an upside-down U-shaped relationship between PACC scores and sleep duration, with dramatic cognitive decline in those who slept less than 4.5 hours or more than 6.5 hours a night (P < .001 for both).

The U-shaped relationship was also found with measures of sleep phases, including time spent in rapid eye movement and in non-REM sleep (P < .001 for both).

The findings persisted even after controlling for confounders that can affect sleep and cognition, such as age, CSF total tau/amyloid-beta ₄₂ ratio, apo E four-allele carrier status, years of education, and sex.

Understanding how sleep changes at different stages of AD could help researchers determine if sleep can be used as a marker of disease progression, Dr. Lucey said. That could lead to interventions to slow that process.

“We’re not at the point yet where we can say that we need to monitor someone’s sleep time and then do an intervention to see if it would improve their risk for cognitive decline,” said Dr. Lucey, who plans to repeat this sleep study with the same cohort to track changes in sleep patterns and cognitive function over time. “But that’s a question I’m very excited to try to answer.”
 

A component of cognitive health

Commenting on the findings for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, noted that the study adds to a body of evidence linking sleep and cognition, especially how sleep quality can optimize brain function.

“We’ve seen previous research that’s shown poor sleep contributes to dementia risk, as well as research showing sleep duration may play a role in cognition,” she said.

“We also need studies that look at sleep as an intervention for cognitive health,” Dr. Snyder said. “Sleep is an important aspect of our overall health. Clinicians should have conversations with their patients about sleep as part of standard discussions about their health habits and wellness.”

The study was funded by the National Institutes of Health, the American Sleep Medicine Foundation, the Roger and Paula Riney Fund, and the Daniel J. Brennan, MD Fund. Dr. Lucey consults for Merck and Eli Lilly. Dr. Snyder has disclosed no relevant financial relationships.

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

Sleeping too much or too little can lead to cognitive decline over time, but new research suggests there could be a sleep time “sweet spot” that stabilizes cognitive function.

JGI/Tom Grill/Getty Images

In a longitudinal study, investigators found older adults who slept less than 4.5 hours or more than 6.5 hours a night reported significant cognitive decline over time, but cognitive scores for those with sleep duration in between that range remained stable.

“This really suggests that there’s this middle range, a ‘sweet spot,’ where your sleep is really optimal,” lead author Brendan Lucey, MD, MSCI, associate professor of neurology and director of the Washington University Sleep Medicine Center, St. Louis, said in an interview.

The study, published online Oct. 20, 2021, in the journal Brain, is part of a growing body of research that seeks to determine if sleep can be used as a marker of Alzheimer’s disease progression.
 

A complex relationship

Studies suggest a strong relationship between sleep patterns and Alzheimer’s disease, which affects nearly 6 million Americans. The challenge, Dr. Lucey said, is unwinding the complex links between sleep, AD, and cognitive function.

An earlier study by Dr. Lucey and colleagues found that poor sleep quality is associated with early signs of AD, and a report published in September found that elderly people who slept less than 6 hours a night had a greater burden of amyloid-beta, a hallmark sign of AD.

For this new study, researchers monitored sleep-wake activity over 4-6 nights in 100 participants who underwent annual cognitive assessments and clinical studies, including APOE genotyping, as part of a longitudinal study at the Knight Alzheimer Disease Research Center at Washington University.

Participants also provided cerebrospinal fluid (CSF) total tau and amyloid-beta 42 and wore a small EEG device on their forehead while they slept.

The majority of participants had a clinical dementia rating (CDR) score of 0, indicating no cognitive impairment. Twelve individuals had a CDR greater than 0, with most reporting mild cognitive impairment.

As expected, CSF analysis showed greater evidence of AD pathology in those with a baseline CDR greater than 0.

Changes in cognitive function were measured using a Preclinical Alzheimer Cognitive Composite (PACC) score, a composite of results from a neuropsychological testing battery that included the Free and Cued Selective Reminding Test, the Logical Memory Delayed Recall Test from the Wechsler Memory Scale–Revised, the Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale–Revised, and the Mini-Mental State Examination.

Researchers found an upside-down U-shaped relationship between PACC scores and sleep duration, with dramatic cognitive decline in those who slept less than 4.5 hours or more than 6.5 hours a night (P < .001 for both).

The U-shaped relationship was also found with measures of sleep phases, including time spent in rapid eye movement and in non-REM sleep (P < .001 for both).

The findings persisted even after controlling for confounders that can affect sleep and cognition, such as age, CSF total tau/amyloid-beta ₄₂ ratio, apo E four-allele carrier status, years of education, and sex.

Understanding how sleep changes at different stages of AD could help researchers determine if sleep can be used as a marker of disease progression, Dr. Lucey said. That could lead to interventions to slow that process.

“We’re not at the point yet where we can say that we need to monitor someone’s sleep time and then do an intervention to see if it would improve their risk for cognitive decline,” said Dr. Lucey, who plans to repeat this sleep study with the same cohort to track changes in sleep patterns and cognitive function over time. “But that’s a question I’m very excited to try to answer.”
 

A component of cognitive health

Commenting on the findings for this news organization, Heather Snyder, PhD, vice president of medical and scientific relations for the Alzheimer’s Association, noted that the study adds to a body of evidence linking sleep and cognition, especially how sleep quality can optimize brain function.

“We’ve seen previous research that’s shown poor sleep contributes to dementia risk, as well as research showing sleep duration may play a role in cognition,” she said.

“We also need studies that look at sleep as an intervention for cognitive health,” Dr. Snyder said. “Sleep is an important aspect of our overall health. Clinicians should have conversations with their patients about sleep as part of standard discussions about their health habits and wellness.”

The study was funded by the National Institutes of Health, the American Sleep Medicine Foundation, the Roger and Paula Riney Fund, and the Daniel J. Brennan, MD Fund. Dr. Lucey consults for Merck and Eli Lilly. Dr. Snyder has disclosed no relevant financial relationships.

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

Hair follicle miniaturization was a prominent feature of persistent chemotherapy-induced alopecia (pCIA) in breast cancer survivors who presented to four specialty hair clinics, and treatment with minoxidil (sometimes with antiandrogen therapy) was associated with improved hair density, according to a recently published retrospective case series.

“An improvement in hair density was observed in most of the patients treated with topical minoxidil or LDOM [low-dose oral minoxidil], with a more favorable outcome seen with LDOM with or without antiandrogens,” reported Bevin Bhoyrul, MBBS, of Sinclair Dermatology in Melbourne and coauthors from the United Kingdom and Germany.

The findings, published in JAMA Dermatology, suggest that pCIA “may be at least partly reversible,” they wrote.

The investigators analyzed the clinicopathologic characteristics of pCIA in 100 patients presenting to the hair clinics, as well as the results of trichoscopy performed in 90 of the patients and biopsies in 18. The researchers also assessed the effectiveness of treatment in 49 of these patients who met their criteria of completing at least 6 months of therapy with minoxidil.

Almost all patients in their series – 92% – were treated with taxanes and had more severe alopecia than those who weren’t exposed to taxanes (a median Sinclair scale grade of 4 vs. 2). Defined as absent or incomplete hair regrowth 6 months or more after completion of chemotherapy, pCIA has been increasingly reported in the literature, the authors note.

Of the 100 patients, all but one of whom were women, 39 had globally-reduced hair density that also involved the occipital area (diffuse alopecia), and 55 patients had thinning of the centroparietal scalp hair in a female pattern hair loss (FPHL) distribution. Patients presented between November 2011 and February 2020 and had a mean age of 54. The Sinclair scale, which grades from 1 to 5, was used to assess the severity of hair loss in these patients.

Five female patients had bitemporal recession or balding of the crown in a male pattern hair loss (MPHL) distribution, and the one male patient had extensive baldness resembling Hamilton-Norwood type VII.

The vast majority of patients who had trichoscopy performed – 88% – had trichoscopic features that were “indistinguishable from those of androgenetic alopecia,” most commonly hair shaft diameter variability, increased vellus hairs, and predominant single-hair follicular units, the authors reported.

Of the 18 patients who had biopsies, 14 had androgenetic alopecia-like features with decreased terminal hairs, increased vellus hairs, and fibrous streamers. The reduced terminal-to-vellus ratio characterizes hair follicle miniaturization, a hallmark of androgenetic alopecia, they said. (Two patients had cicatricial alopecia, and two had features of both.)

“The predominant phenotypes of pCIA show prominent vellus hairs both clinically and histologically, suggesting that terminal hair follicles undergo miniaturization,” Dr. Bhoyrul and coauthors wrote. Among the 49 patients who completed 6 months or more of treatment, the median Sinclair grade improved from 4 to 3 in 21 patients who received topical minoxidil for a median duration of 17 months; from 4 to 2.5 in 18 patients who received LDOM for a median duration of 29 months; and from 5 to 3 in 10 patients who received LDOM combined with an antiandrogen, such as spironolactone, for a median of 33 months.

Almost three-quarters of the patients in the series received adjuvant hormone therapy, which is independently associated with hair loss, the authors noted. However, there was no statistically significant difference in the pattern or severity of alopecia between patients who were treated with endocrine therapy and those who weren’t.

Asked to comment on the study and on the care of patients with pCIA, Maria K. Hordinsky, MD, professor and chair of dermatology at the University of Minnesota, Minneapolis, and an expert in hair diseases, said the case series points to the value of biopsies in patients with pCIA.

“Some patients really do have a loss of hair follicles,” she said. “But if you do a biopsy and see this miniaturization of the hair follicles, then we have tools to stimulate the hair follicles to become more normal. ... These patients can be successfully treated.”

For patients who do not want to do a biopsy, a therapeutic trial is acceptable. “But knowing helps set expectations for people,” she said. “If the follicles are really small, it will take months [of therapy].”

In addition to topical minoxidil, which she said “is always a good tool,” and LDOM, which is “becoming very popular,” Dr. Hordinsky has used low-level laser light successfully. She cautioned against the use of spironolactone and other hair-growth promoting therapies with potentially significant hormonal impacts unless there is discussion between the dermatologist, oncologist, and patient.

The authors of the case series called in their conclusion for wider use of hair-protective strategies such as scalp hypothermia. But Dr. Hordinsky said that, in the United States, there are divergent opinions among oncologists and among cancer centers on the use of scalp cooling and whether or not it might lessen response to chemotherapy.

More research is needed, she noted, on chemotherapy-induced hair loss in patients of different races and ethnicities. Of the 100 patients in the case series, 91 were European; others were Afro Caribbean, Middle Eastern, and South Asian.

Dr. Bhoyrul is supported by the Geoffrey Dowling Fellowship from the British Association of Dermatologists. One coauthor disclosed serving as a principal investigator and/or scientific board member for various pharmaceutical companies, outside of the submitted study. There were no other disclosures reported. Dr. Hordinsky, the immediate past president of the American Hair Research Society and a section editor for hair diseases in UpToDate, had no relevant disclosures.

Hair follicle miniaturization was a prominent feature of persistent chemotherapy-induced alopecia (pCIA) in breast cancer survivors who presented to four specialty hair clinics, and treatment with minoxidil (sometimes with antiandrogen therapy) was associated with improved hair density, according to a recently published retrospective case series.

“An improvement in hair density was observed in most of the patients treated with topical minoxidil or LDOM [low-dose oral minoxidil], with a more favorable outcome seen with LDOM with or without antiandrogens,” reported Bevin Bhoyrul, MBBS, of Sinclair Dermatology in Melbourne and coauthors from the United Kingdom and Germany.

The findings, published in JAMA Dermatology, suggest that pCIA “may be at least partly reversible,” they wrote.

The investigators analyzed the clinicopathologic characteristics of pCIA in 100 patients presenting to the hair clinics, as well as the results of trichoscopy performed in 90 of the patients and biopsies in 18. The researchers also assessed the effectiveness of treatment in 49 of these patients who met their criteria of completing at least 6 months of therapy with minoxidil.

Almost all patients in their series – 92% – were treated with taxanes and had more severe alopecia than those who weren’t exposed to taxanes (a median Sinclair scale grade of 4 vs. 2). Defined as absent or incomplete hair regrowth 6 months or more after completion of chemotherapy, pCIA has been increasingly reported in the literature, the authors note.

Of the 100 patients, all but one of whom were women, 39 had globally-reduced hair density that also involved the occipital area (diffuse alopecia), and 55 patients had thinning of the centroparietal scalp hair in a female pattern hair loss (FPHL) distribution. Patients presented between November 2011 and February 2020 and had a mean age of 54. The Sinclair scale, which grades from 1 to 5, was used to assess the severity of hair loss in these patients.

Five female patients had bitemporal recession or balding of the crown in a male pattern hair loss (MPHL) distribution, and the one male patient had extensive baldness resembling Hamilton-Norwood type VII.

The vast majority of patients who had trichoscopy performed – 88% – had trichoscopic features that were “indistinguishable from those of androgenetic alopecia,” most commonly hair shaft diameter variability, increased vellus hairs, and predominant single-hair follicular units, the authors reported.

Of the 18 patients who had biopsies, 14 had androgenetic alopecia-like features with decreased terminal hairs, increased vellus hairs, and fibrous streamers. The reduced terminal-to-vellus ratio characterizes hair follicle miniaturization, a hallmark of androgenetic alopecia, they said. (Two patients had cicatricial alopecia, and two had features of both.)

“The predominant phenotypes of pCIA show prominent vellus hairs both clinically and histologically, suggesting that terminal hair follicles undergo miniaturization,” Dr. Bhoyrul and coauthors wrote. Among the 49 patients who completed 6 months or more of treatment, the median Sinclair grade improved from 4 to 3 in 21 patients who received topical minoxidil for a median duration of 17 months; from 4 to 2.5 in 18 patients who received LDOM for a median duration of 29 months; and from 5 to 3 in 10 patients who received LDOM combined with an antiandrogen, such as spironolactone, for a median of 33 months.

Almost three-quarters of the patients in the series received adjuvant hormone therapy, which is independently associated with hair loss, the authors noted. However, there was no statistically significant difference in the pattern or severity of alopecia between patients who were treated with endocrine therapy and those who weren’t.

Asked to comment on the study and on the care of patients with pCIA, Maria K. Hordinsky, MD, professor and chair of dermatology at the University of Minnesota, Minneapolis, and an expert in hair diseases, said the case series points to the value of biopsies in patients with pCIA.

“Some patients really do have a loss of hair follicles,” she said. “But if you do a biopsy and see this miniaturization of the hair follicles, then we have tools to stimulate the hair follicles to become more normal. ... These patients can be successfully treated.”

For patients who do not want to do a biopsy, a therapeutic trial is acceptable. “But knowing helps set expectations for people,” she said. “If the follicles are really small, it will take months [of therapy].”

In addition to topical minoxidil, which she said “is always a good tool,” and LDOM, which is “becoming very popular,” Dr. Hordinsky has used low-level laser light successfully. She cautioned against the use of spironolactone and other hair-growth promoting therapies with potentially significant hormonal impacts unless there is discussion between the dermatologist, oncologist, and patient.

The authors of the case series called in their conclusion for wider use of hair-protective strategies such as scalp hypothermia. But Dr. Hordinsky said that, in the United States, there are divergent opinions among oncologists and among cancer centers on the use of scalp cooling and whether or not it might lessen response to chemotherapy.

More research is needed, she noted, on chemotherapy-induced hair loss in patients of different races and ethnicities. Of the 100 patients in the case series, 91 were European; others were Afro Caribbean, Middle Eastern, and South Asian.

Dr. Bhoyrul is supported by the Geoffrey Dowling Fellowship from the British Association of Dermatologists. One coauthor disclosed serving as a principal investigator and/or scientific board member for various pharmaceutical companies, outside of the submitted study. There were no other disclosures reported. Dr. Hordinsky, the immediate past president of the American Hair Research Society and a section editor for hair diseases in UpToDate, had no relevant disclosures.

Hair follicle miniaturization was a prominent feature of persistent chemotherapy-induced alopecia (pCIA) in breast cancer survivors who presented to four specialty hair clinics, and treatment with minoxidil (sometimes with antiandrogen therapy) was associated with improved hair density, according to a recently published retrospective case series.

“An improvement in hair density was observed in most of the patients treated with topical minoxidil or LDOM [low-dose oral minoxidil], with a more favorable outcome seen with LDOM with or without antiandrogens,” reported Bevin Bhoyrul, MBBS, of Sinclair Dermatology in Melbourne and coauthors from the United Kingdom and Germany.

The findings, published in JAMA Dermatology, suggest that pCIA “may be at least partly reversible,” they wrote.

The investigators analyzed the clinicopathologic characteristics of pCIA in 100 patients presenting to the hair clinics, as well as the results of trichoscopy performed in 90 of the patients and biopsies in 18. The researchers also assessed the effectiveness of treatment in 49 of these patients who met their criteria of completing at least 6 months of therapy with minoxidil.

Almost all patients in their series – 92% – were treated with taxanes and had more severe alopecia than those who weren’t exposed to taxanes (a median Sinclair scale grade of 4 vs. 2). Defined as absent or incomplete hair regrowth 6 months or more after completion of chemotherapy, pCIA has been increasingly reported in the literature, the authors note.

Of the 100 patients, all but one of whom were women, 39 had globally-reduced hair density that also involved the occipital area (diffuse alopecia), and 55 patients had thinning of the centroparietal scalp hair in a female pattern hair loss (FPHL) distribution. Patients presented between November 2011 and February 2020 and had a mean age of 54. The Sinclair scale, which grades from 1 to 5, was used to assess the severity of hair loss in these patients.

Five female patients had bitemporal recession or balding of the crown in a male pattern hair loss (MPHL) distribution, and the one male patient had extensive baldness resembling Hamilton-Norwood type VII.

The vast majority of patients who had trichoscopy performed – 88% – had trichoscopic features that were “indistinguishable from those of androgenetic alopecia,” most commonly hair shaft diameter variability, increased vellus hairs, and predominant single-hair follicular units, the authors reported.

Of the 18 patients who had biopsies, 14 had androgenetic alopecia-like features with decreased terminal hairs, increased vellus hairs, and fibrous streamers. The reduced terminal-to-vellus ratio characterizes hair follicle miniaturization, a hallmark of androgenetic alopecia, they said. (Two patients had cicatricial alopecia, and two had features of both.)

“The predominant phenotypes of pCIA show prominent vellus hairs both clinically and histologically, suggesting that terminal hair follicles undergo miniaturization,” Dr. Bhoyrul and coauthors wrote. Among the 49 patients who completed 6 months or more of treatment, the median Sinclair grade improved from 4 to 3 in 21 patients who received topical minoxidil for a median duration of 17 months; from 4 to 2.5 in 18 patients who received LDOM for a median duration of 29 months; and from 5 to 3 in 10 patients who received LDOM combined with an antiandrogen, such as spironolactone, for a median of 33 months.

Almost three-quarters of the patients in the series received adjuvant hormone therapy, which is independently associated with hair loss, the authors noted. However, there was no statistically significant difference in the pattern or severity of alopecia between patients who were treated with endocrine therapy and those who weren’t.

Asked to comment on the study and on the care of patients with pCIA, Maria K. Hordinsky, MD, professor and chair of dermatology at the University of Minnesota, Minneapolis, and an expert in hair diseases, said the case series points to the value of biopsies in patients with pCIA.

“Some patients really do have a loss of hair follicles,” she said. “But if you do a biopsy and see this miniaturization of the hair follicles, then we have tools to stimulate the hair follicles to become more normal. ... These patients can be successfully treated.”

For patients who do not want to do a biopsy, a therapeutic trial is acceptable. “But knowing helps set expectations for people,” she said. “If the follicles are really small, it will take months [of therapy].”

In addition to topical minoxidil, which she said “is always a good tool,” and LDOM, which is “becoming very popular,” Dr. Hordinsky has used low-level laser light successfully. She cautioned against the use of spironolactone and other hair-growth promoting therapies with potentially significant hormonal impacts unless there is discussion between the dermatologist, oncologist, and patient.

The authors of the case series called in their conclusion for wider use of hair-protective strategies such as scalp hypothermia. But Dr. Hordinsky said that, in the United States, there are divergent opinions among oncologists and among cancer centers on the use of scalp cooling and whether or not it might lessen response to chemotherapy.

More research is needed, she noted, on chemotherapy-induced hair loss in patients of different races and ethnicities. Of the 100 patients in the case series, 91 were European; others were Afro Caribbean, Middle Eastern, and South Asian.

Dr. Bhoyrul is supported by the Geoffrey Dowling Fellowship from the British Association of Dermatologists. One coauthor disclosed serving as a principal investigator and/or scientific board member for various pharmaceutical companies, outside of the submitted study. There were no other disclosures reported. Dr. Hordinsky, the immediate past president of the American Hair Research Society and a section editor for hair diseases in UpToDate, had no relevant disclosures.

A Twitter post of an unmasked nurse being escorted from a Kaiser Permanente hospital for what she called “sincerely held religious beliefs” has gone viral. It had been viewed more than 6 million times at press time.

The 5-minute video of the nurse leaving the hospital, both of which are unidentified in the clip, was a peaceful protest by the frontline worker against COVID-19 vaccine mandates, which many employers globally are enforcing.

In her video, which was originally posted October 30 on Rumble, the nurse explained, “I am being escorted out of Kaiser Permanente hospital for my religious beliefs because I don’t want to get the jab. And I asked all day for someone to explain to me why my sincerely held religious beliefs are not good enough for Kaiser. And no one was able to do that for me,” she continued.

“So now they’re escorting me out because I wanted an answer. And I’m not leaving without an answer. I have some nurses here who are standing with me in solidarity, and I appreciate that.”

The nurse, seen walking through the halls of the hospital surrounded by masked personnel, including a security guard, further stated that she had been put on unpaid administrative leave. Kaiser Permanente had not responded at press time to media requests for comment.

“I just want all of you to count the costs,” she said. “I want you to watch this and think, what really matters to me? Because I am willing to lose my safety and security, my house, everything, for my freedom. And I want you to think about that.”

While waiting for an elevator, she also posed questions to a few random people about their views on the subject. “Let me ask you, do you believe in religious freedom?” Offscreen, those responding indicated affirmatively. “Well, Kaiser doesn’t. Because they are not accepting my religious exemption based on my sincerely held religious beliefs. So that’s a problem.”

Also on the video she stated that she has worked since the beginning of the pandemic, “when we didn’t know what was going on,” and that she had shown up the day of her expulsion “happy to work.” She also touted Kaiser for paying well. She even quoted the company’s signs in a parking garage that encourages employees to climb the stairs for exercise as she went with the security guard who was escorting her up seven flights to the top of the parking garage.

“It’s a sad day. I don’t know what kind of a pandemic it is if they’re firing nurses who are willing to work. I don’t know,” she concluded. “It doesn’t make sense to me. So you have got to ask yourself that question: what kind of world are we living in when we have a pandemic where my kids have to wear masks at school and they have to get a vaccine for something that they are not at risk of dying from at all.”

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

A Twitter post of an unmasked nurse being escorted from a Kaiser Permanente hospital for what she called “sincerely held religious beliefs” has gone viral. It had been viewed more than 6 million times at press time.

The 5-minute video of the nurse leaving the hospital, both of which are unidentified in the clip, was a peaceful protest by the frontline worker against COVID-19 vaccine mandates, which many employers globally are enforcing.

In her video, which was originally posted October 30 on Rumble, the nurse explained, “I am being escorted out of Kaiser Permanente hospital for my religious beliefs because I don’t want to get the jab. And I asked all day for someone to explain to me why my sincerely held religious beliefs are not good enough for Kaiser. And no one was able to do that for me,” she continued.

“So now they’re escorting me out because I wanted an answer. And I’m not leaving without an answer. I have some nurses here who are standing with me in solidarity, and I appreciate that.”

The nurse, seen walking through the halls of the hospital surrounded by masked personnel, including a security guard, further stated that she had been put on unpaid administrative leave. Kaiser Permanente had not responded at press time to media requests for comment.

“I just want all of you to count the costs,” she said. “I want you to watch this and think, what really matters to me? Because I am willing to lose my safety and security, my house, everything, for my freedom. And I want you to think about that.”

While waiting for an elevator, she also posed questions to a few random people about their views on the subject. “Let me ask you, do you believe in religious freedom?” Offscreen, those responding indicated affirmatively. “Well, Kaiser doesn’t. Because they are not accepting my religious exemption based on my sincerely held religious beliefs. So that’s a problem.”

Also on the video she stated that she has worked since the beginning of the pandemic, “when we didn’t know what was going on,” and that she had shown up the day of her expulsion “happy to work.” She also touted Kaiser for paying well. She even quoted the company’s signs in a parking garage that encourages employees to climb the stairs for exercise as she went with the security guard who was escorting her up seven flights to the top of the parking garage.

“It’s a sad day. I don’t know what kind of a pandemic it is if they’re firing nurses who are willing to work. I don’t know,” she concluded. “It doesn’t make sense to me. So you have got to ask yourself that question: what kind of world are we living in when we have a pandemic where my kids have to wear masks at school and they have to get a vaccine for something that they are not at risk of dying from at all.”

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

A Twitter post of an unmasked nurse being escorted from a Kaiser Permanente hospital for what she called “sincerely held religious beliefs” has gone viral. It had been viewed more than 6 million times at press time.

The 5-minute video of the nurse leaving the hospital, both of which are unidentified in the clip, was a peaceful protest by the frontline worker against COVID-19 vaccine mandates, which many employers globally are enforcing.

In her video, which was originally posted October 30 on Rumble, the nurse explained, “I am being escorted out of Kaiser Permanente hospital for my religious beliefs because I don’t want to get the jab. And I asked all day for someone to explain to me why my sincerely held religious beliefs are not good enough for Kaiser. And no one was able to do that for me,” she continued.

“So now they’re escorting me out because I wanted an answer. And I’m not leaving without an answer. I have some nurses here who are standing with me in solidarity, and I appreciate that.”

The nurse, seen walking through the halls of the hospital surrounded by masked personnel, including a security guard, further stated that she had been put on unpaid administrative leave. Kaiser Permanente had not responded at press time to media requests for comment.

“I just want all of you to count the costs,” she said. “I want you to watch this and think, what really matters to me? Because I am willing to lose my safety and security, my house, everything, for my freedom. And I want you to think about that.”

While waiting for an elevator, she also posed questions to a few random people about their views on the subject. “Let me ask you, do you believe in religious freedom?” Offscreen, those responding indicated affirmatively. “Well, Kaiser doesn’t. Because they are not accepting my religious exemption based on my sincerely held religious beliefs. So that’s a problem.”

Also on the video she stated that she has worked since the beginning of the pandemic, “when we didn’t know what was going on,” and that she had shown up the day of her expulsion “happy to work.” She also touted Kaiser for paying well. She even quoted the company’s signs in a parking garage that encourages employees to climb the stairs for exercise as she went with the security guard who was escorting her up seven flights to the top of the parking garage.

“It’s a sad day. I don’t know what kind of a pandemic it is if they’re firing nurses who are willing to work. I don’t know,” she concluded. “It doesn’t make sense to me. So you have got to ask yourself that question: what kind of world are we living in when we have a pandemic where my kids have to wear masks at school and they have to get a vaccine for something that they are not at risk of dying from at all.”

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

The first report from a Spanish registry of patients with acquired hemophilia A shows a strikingly high rate of infection-related deaths among older patients in the 2 months after they start immunosuppressive therapy.

The findings also indicate that an unusually large proportion of patients were on antithrombotic therapy, which may have led to misdiagnosis or delayed diagnosis of acquired hemophilia A (AHA) in some cases, Marıa-Eva Mingot-Castellano, MD, PhD, of Hospital Universitario Virgen del Rocıo, Seville, Spain, and Hospital Regional Universitario de Malaga (Spain) and colleagues reported on behalf of the Acquired Haemophilia-A Spanish Registry (AHASR).

The report was published online in Blood Advances.

These data provide useful clinical information about a rare disease, and they underscore the need for vigilance when prescribing immunosuppressive therapy for frail, elderly patients with AHA, hematologist Nigel Key, MD, said in an interview.

“The findings point to the fact that we still have a high death rate with this disorder, whether directly or indirectly related,” said Dr. Key, the Harold R. Roberts Distinguished Professor and vice chief for research in the division of hematology at the University of North Carolina at Chapel Hill. “[AHA] is still a high-morbidity, high-mortality condition, and these are very high-risk patients.”



The Spanish AHA registry data

The authors retrospectively collected data on 154 patients who were diagnosed with AHA at 36 Spanish hospitals from May 2014 through September 2020 and followed for a median of 12 months.

The patients were mostly men (56.3%) and had a median age of 74 years at diagnosis.

A third were on antithrombotic therapy at diagnosis, and hemostatic treatment was used in 70% of cases.

“Only one patient did not achieve control of hemorrhage. Complete remission (CR) was achieved by 84.2% of cases after immunosuppressive therapy,” the authors wrote, noting that “steroids alone were less efficient than the other strategies (68.2% vs. 87.2%), whereas no differences existed among these (steroids/cyclophosphamide, 88.5%; vs. steroids/calcineurin inhibitors, 81.2%; vs. rituximab-based regimens, 87.5%).

Women and those with high inhibitor levels were less likely to achieve CR, they said.

Of the 154 registry participants, 36 died, and 15 (9.9%) of those died as a result of infection, the leading cause of death. Five (3.3%) died as a result of hemorrhage. All of the hemorrhage-related deaths and half of the infection-related deaths occurred within 2 months of diagnosis, they noted, adding that “prior antithrombotic therapy was inversely associated with survival, irrespective of age.”

The median age of nonsurvivors was significantly higher than that of survivors (79 vs. 73 years), and the median age of those who died from infection was significantly higher than that of patients who died from other causes (85 vs. 78 years).



Additional insights

“One remarkable finding, not described before in AHA, was the high proportion of patients on antithrombotic therapy in the days before AHA diagnosis, namely one-third of the whole series,” the authors wrote. “This proportion is comparable to that of the Spanish population of similar age groups.”

Further, the use of antithrombotic therapy prior to AHA diagnosis was associated with mortality during follow-up in patients aged 75 years and older, they noted.

The older age and comorbidity burden among affected patients underscores their vulnerability and the importance of prompt diagnosis, they added, explaining how misdiagnosis might occur: “Attributing the bleeding episode to a hemostatic imbalance caused by the antithrombotic therapy may entail a risk of misdiagnosis. Frail patients could be admitted to hospital shortly after having been administered anticoagulants. In these cases, misdiagnosis would prevent early [immunosuppressive therapy], and patients could be exposed to potentially life-threatening bleedings.”

Delayed diagnoses have also been described in other registries. For example, in the China Acquired Hemophilia Registry (CARE), nearly half of participants had a delayed diagnosis, and younger patients were more likely than older patients to be referred for consultation, the authors explained.

“Interestingly, antiplatelet therapy has been described to delay AHA diagnosis or lead to misdiagnosis of AHA patients. Furthermore, the underlying diseases that prompted antithrombotic therapy highlight the vulnerability of these patients and could contribute to a negative outcome,” they noted.

Given the high rate of fatal infection in the first months of immunosuppressive therapy in the series, and the association between antithrombotic therapy and mortality, particular care should be taken to avoid misdiagnosis, the authors stressed.

They noted, however, that the study has some important limitations inherent in retrospective analyses and studies with limited sample size and missing data.

Still, the findings add value, they said.

“AHA is not well-known among clinicians unfamiliar with hemostatic disorders. Lack of awareness may preclude early diagnosis, thus exposing patients to an unacceptably high bleeding risk,” they explained, adding that existing management guidelines for the use of immunosuppressive therapy “rely on registry findings and authors’ experience rather than on comparative studies.”

“Therefore, any valuable knowledge regarding clinical experience in managing this disorder should be helpful,” they wrote. “The rarity of the condition prompts the design of registries to compile as much information as possible concerning baseline status, diagnosis, treatment, and follow-up ... to continuously update guidelines on disease management procedures.”

Indeed, the AHASR is “a good-sized registry” and these data are valuable, Dr. Key said.

“I like the fact that they focused on a couple of things here to do with outcomes, particularly analyzing the causes of death,” he said, noting that the reported death is not remarkably different from what has been reported previously, but it does “raise the question of morbidity also related to the therapy – particularly infection.”

The data are especially useful with respect to use of immunosuppressive regimens, he said.

“These are, for the most part, old or frail patients. ... They can’t just be put on cyclophosphamide and sent away without monitoring blood counts and being given advice about what to look out for regarding infection and when to seek treatment,” he said, adding that immunosuppressive regimens are “given for very good and necessary reasons, but are not benign.”

“There ought to be consideration, if necessary, of advice from an infectious disease specialist,” he added, noting that “rheumatologists deal with this all the time, but hematologists often underestimate the infectious morbidity of [immunosuppressive therapy].”

The study authors reported having no conflicts of interest to disclose. Dr. Key has served at the chair of a grant committee for Novo Nordisk.

[email protected]

The first report from a Spanish registry of patients with acquired hemophilia A shows a strikingly high rate of infection-related deaths among older patients in the 2 months after they start immunosuppressive therapy.

The findings also indicate that an unusually large proportion of patients were on antithrombotic therapy, which may have led to misdiagnosis or delayed diagnosis of acquired hemophilia A (AHA) in some cases, Marıa-Eva Mingot-Castellano, MD, PhD, of Hospital Universitario Virgen del Rocıo, Seville, Spain, and Hospital Regional Universitario de Malaga (Spain) and colleagues reported on behalf of the Acquired Haemophilia-A Spanish Registry (AHASR).

The report was published online in Blood Advances.

These data provide useful clinical information about a rare disease, and they underscore the need for vigilance when prescribing immunosuppressive therapy for frail, elderly patients with AHA, hematologist Nigel Key, MD, said in an interview.

“The findings point to the fact that we still have a high death rate with this disorder, whether directly or indirectly related,” said Dr. Key, the Harold R. Roberts Distinguished Professor and vice chief for research in the division of hematology at the University of North Carolina at Chapel Hill. “[AHA] is still a high-morbidity, high-mortality condition, and these are very high-risk patients.”



The Spanish AHA registry data

The authors retrospectively collected data on 154 patients who were diagnosed with AHA at 36 Spanish hospitals from May 2014 through September 2020 and followed for a median of 12 months.

The patients were mostly men (56.3%) and had a median age of 74 years at diagnosis.

A third were on antithrombotic therapy at diagnosis, and hemostatic treatment was used in 70% of cases.

“Only one patient did not achieve control of hemorrhage. Complete remission (CR) was achieved by 84.2% of cases after immunosuppressive therapy,” the authors wrote, noting that “steroids alone were less efficient than the other strategies (68.2% vs. 87.2%), whereas no differences existed among these (steroids/cyclophosphamide, 88.5%; vs. steroids/calcineurin inhibitors, 81.2%; vs. rituximab-based regimens, 87.5%).

Women and those with high inhibitor levels were less likely to achieve CR, they said.

Of the 154 registry participants, 36 died, and 15 (9.9%) of those died as a result of infection, the leading cause of death. Five (3.3%) died as a result of hemorrhage. All of the hemorrhage-related deaths and half of the infection-related deaths occurred within 2 months of diagnosis, they noted, adding that “prior antithrombotic therapy was inversely associated with survival, irrespective of age.”

The median age of nonsurvivors was significantly higher than that of survivors (79 vs. 73 years), and the median age of those who died from infection was significantly higher than that of patients who died from other causes (85 vs. 78 years).



Additional insights

“One remarkable finding, not described before in AHA, was the high proportion of patients on antithrombotic therapy in the days before AHA diagnosis, namely one-third of the whole series,” the authors wrote. “This proportion is comparable to that of the Spanish population of similar age groups.”

Further, the use of antithrombotic therapy prior to AHA diagnosis was associated with mortality during follow-up in patients aged 75 years and older, they noted.

The older age and comorbidity burden among affected patients underscores their vulnerability and the importance of prompt diagnosis, they added, explaining how misdiagnosis might occur: “Attributing the bleeding episode to a hemostatic imbalance caused by the antithrombotic therapy may entail a risk of misdiagnosis. Frail patients could be admitted to hospital shortly after having been administered anticoagulants. In these cases, misdiagnosis would prevent early [immunosuppressive therapy], and patients could be exposed to potentially life-threatening bleedings.”

Delayed diagnoses have also been described in other registries. For example, in the China Acquired Hemophilia Registry (CARE), nearly half of participants had a delayed diagnosis, and younger patients were more likely than older patients to be referred for consultation, the authors explained.

“Interestingly, antiplatelet therapy has been described to delay AHA diagnosis or lead to misdiagnosis of AHA patients. Furthermore, the underlying diseases that prompted antithrombotic therapy highlight the vulnerability of these patients and could contribute to a negative outcome,” they noted.

Given the high rate of fatal infection in the first months of immunosuppressive therapy in the series, and the association between antithrombotic therapy and mortality, particular care should be taken to avoid misdiagnosis, the authors stressed.

They noted, however, that the study has some important limitations inherent in retrospective analyses and studies with limited sample size and missing data.

Still, the findings add value, they said.

“AHA is not well-known among clinicians unfamiliar with hemostatic disorders. Lack of awareness may preclude early diagnosis, thus exposing patients to an unacceptably high bleeding risk,” they explained, adding that existing management guidelines for the use of immunosuppressive therapy “rely on registry findings and authors’ experience rather than on comparative studies.”

“Therefore, any valuable knowledge regarding clinical experience in managing this disorder should be helpful,” they wrote. “The rarity of the condition prompts the design of registries to compile as much information as possible concerning baseline status, diagnosis, treatment, and follow-up ... to continuously update guidelines on disease management procedures.”

Indeed, the AHASR is “a good-sized registry” and these data are valuable, Dr. Key said.

“I like the fact that they focused on a couple of things here to do with outcomes, particularly analyzing the causes of death,” he said, noting that the reported death is not remarkably different from what has been reported previously, but it does “raise the question of morbidity also related to the therapy – particularly infection.”

The data are especially useful with respect to use of immunosuppressive regimens, he said.

“These are, for the most part, old or frail patients. ... They can’t just be put on cyclophosphamide and sent away without monitoring blood counts and being given advice about what to look out for regarding infection and when to seek treatment,” he said, adding that immunosuppressive regimens are “given for very good and necessary reasons, but are not benign.”

“There ought to be consideration, if necessary, of advice from an infectious disease specialist,” he added, noting that “rheumatologists deal with this all the time, but hematologists often underestimate the infectious morbidity of [immunosuppressive therapy].”

The study authors reported having no conflicts of interest to disclose. Dr. Key has served at the chair of a grant committee for Novo Nordisk.

[email protected]

The first report from a Spanish registry of patients with acquired hemophilia A shows a strikingly high rate of infection-related deaths among older patients in the 2 months after they start immunosuppressive therapy.

The findings also indicate that an unusually large proportion of patients were on antithrombotic therapy, which may have led to misdiagnosis or delayed diagnosis of acquired hemophilia A (AHA) in some cases, Marıa-Eva Mingot-Castellano, MD, PhD, of Hospital Universitario Virgen del Rocıo, Seville, Spain, and Hospital Regional Universitario de Malaga (Spain) and colleagues reported on behalf of the Acquired Haemophilia-A Spanish Registry (AHASR).

The report was published online in Blood Advances.

These data provide useful clinical information about a rare disease, and they underscore the need for vigilance when prescribing immunosuppressive therapy for frail, elderly patients with AHA, hematologist Nigel Key, MD, said in an interview.

“The findings point to the fact that we still have a high death rate with this disorder, whether directly or indirectly related,” said Dr. Key, the Harold R. Roberts Distinguished Professor and vice chief for research in the division of hematology at the University of North Carolina at Chapel Hill. “[AHA] is still a high-morbidity, high-mortality condition, and these are very high-risk patients.”



The Spanish AHA registry data

The authors retrospectively collected data on 154 patients who were diagnosed with AHA at 36 Spanish hospitals from May 2014 through September 2020 and followed for a median of 12 months.

The patients were mostly men (56.3%) and had a median age of 74 years at diagnosis.

A third were on antithrombotic therapy at diagnosis, and hemostatic treatment was used in 70% of cases.

“Only one patient did not achieve control of hemorrhage. Complete remission (CR) was achieved by 84.2% of cases after immunosuppressive therapy,” the authors wrote, noting that “steroids alone were less efficient than the other strategies (68.2% vs. 87.2%), whereas no differences existed among these (steroids/cyclophosphamide, 88.5%; vs. steroids/calcineurin inhibitors, 81.2%; vs. rituximab-based regimens, 87.5%).

Women and those with high inhibitor levels were less likely to achieve CR, they said.

Of the 154 registry participants, 36 died, and 15 (9.9%) of those died as a result of infection, the leading cause of death. Five (3.3%) died as a result of hemorrhage. All of the hemorrhage-related deaths and half of the infection-related deaths occurred within 2 months of diagnosis, they noted, adding that “prior antithrombotic therapy was inversely associated with survival, irrespective of age.”

The median age of nonsurvivors was significantly higher than that of survivors (79 vs. 73 years), and the median age of those who died from infection was significantly higher than that of patients who died from other causes (85 vs. 78 years).



Additional insights

“One remarkable finding, not described before in AHA, was the high proportion of patients on antithrombotic therapy in the days before AHA diagnosis, namely one-third of the whole series,” the authors wrote. “This proportion is comparable to that of the Spanish population of similar age groups.”

Further, the use of antithrombotic therapy prior to AHA diagnosis was associated with mortality during follow-up in patients aged 75 years and older, they noted.

The older age and comorbidity burden among affected patients underscores their vulnerability and the importance of prompt diagnosis, they added, explaining how misdiagnosis might occur: “Attributing the bleeding episode to a hemostatic imbalance caused by the antithrombotic therapy may entail a risk of misdiagnosis. Frail patients could be admitted to hospital shortly after having been administered anticoagulants. In these cases, misdiagnosis would prevent early [immunosuppressive therapy], and patients could be exposed to potentially life-threatening bleedings.”

Delayed diagnoses have also been described in other registries. For example, in the China Acquired Hemophilia Registry (CARE), nearly half of participants had a delayed diagnosis, and younger patients were more likely than older patients to be referred for consultation, the authors explained.

“Interestingly, antiplatelet therapy has been described to delay AHA diagnosis or lead to misdiagnosis of AHA patients. Furthermore, the underlying diseases that prompted antithrombotic therapy highlight the vulnerability of these patients and could contribute to a negative outcome,” they noted.

Given the high rate of fatal infection in the first months of immunosuppressive therapy in the series, and the association between antithrombotic therapy and mortality, particular care should be taken to avoid misdiagnosis, the authors stressed.

They noted, however, that the study has some important limitations inherent in retrospective analyses and studies with limited sample size and missing data.

Still, the findings add value, they said.

“AHA is not well-known among clinicians unfamiliar with hemostatic disorders. Lack of awareness may preclude early diagnosis, thus exposing patients to an unacceptably high bleeding risk,” they explained, adding that existing management guidelines for the use of immunosuppressive therapy “rely on registry findings and authors’ experience rather than on comparative studies.”

“Therefore, any valuable knowledge regarding clinical experience in managing this disorder should be helpful,” they wrote. “The rarity of the condition prompts the design of registries to compile as much information as possible concerning baseline status, diagnosis, treatment, and follow-up ... to continuously update guidelines on disease management procedures.”

Indeed, the AHASR is “a good-sized registry” and these data are valuable, Dr. Key said.

“I like the fact that they focused on a couple of things here to do with outcomes, particularly analyzing the causes of death,” he said, noting that the reported death is not remarkably different from what has been reported previously, but it does “raise the question of morbidity also related to the therapy – particularly infection.”

The data are especially useful with respect to use of immunosuppressive regimens, he said.

“These are, for the most part, old or frail patients. ... They can’t just be put on cyclophosphamide and sent away without monitoring blood counts and being given advice about what to look out for regarding infection and when to seek treatment,” he said, adding that immunosuppressive regimens are “given for very good and necessary reasons, but are not benign.”

“There ought to be consideration, if necessary, of advice from an infectious disease specialist,” he added, noting that “rheumatologists deal with this all the time, but hematologists often underestimate the infectious morbidity of [immunosuppressive therapy].”

The study authors reported having no conflicts of interest to disclose. Dr. Key has served at the chair of a grant committee for Novo Nordisk.

[email protected]