CHICAGO – A large Danish registry-based study has confirmed an increased risk of acute pancreatitis for patients taking certain antithyroid drugs.

After 6 months of methimazole use, the odds ratio for acute pancreatitis was 2.02, with a nonsignificant risk elevation for propylthiouracil use after a similar duration, Laszlo Hegedüs, MD, reported at the annual meeting of the American Thyroid Association.

“Ongoing methimazole, but not propylthiouracil, use is associated with an increased risk of acute pancreatitis,” he said.

Dr. Hegedüs, professor of endocrinology and metabolism at the University of Southern Denmark, Odense, said that the European Medicines Agency has noted a few postmarketing reports of acute pancreatitis in patients who received the antithyroid drug methimazole, as well as its prodrug, carbimazole. The agency has accordingly contraindicated antithyroid drug use for patients who previously experienced acute pancreatitis after receiving this drug, advising that methimazole should be “discontinued immediately” should a patient develop acute pancreatitis.

However, investigation of the antithyroid drug–pancreatitis association had been limited to aggregating those case reports, so Dr. Hegedüs and colleagues decided to use Danish medical record and registry data to investigate the association in a nationwide, controlled study that looked at both duration of therapy and total antithyroid drug use.

During the period from 1995-2018, a total of 118,649 patients who used antithyroid drugs were found in the 5.5 million individuals in the Statistics Denmark registry. Dr. Hegedüs and his colleagues also pulled in patient registry and national prescription registry data, as well as civil vital statistics data.

Of those who used antithyroid drugs, 103,825 patients used methimazole, and 14,824 used propylthiouracil. The researchers found 43,580 instances of hospitalization for first-time acute pancreatitis in the pooled antithyroid drug data. Of those, however, just 226 (0.5%) occurred in patients using methimazole, and 19 (0.04%) in those using propylthiouracil at the time of pancreatitis onset.

To ascertain the risk of acute pancreatitis in patients using antithyroid drugs for various durations, Dr. Hegedüs and his colleagues used a case-crossover study design. In the case-crossover technique, patients served as their own controls, because each patient was both exposed and not exposed to antithyroid drugs at some point during the study period. Antithyroid drugs are well suited to this study design, explained Dr. Hegedüs, because they are given for a limited time. A case-crossover design can be used with a small sample size and effectively controls for potentially confounding variables.

The odds ratio for acute pancreatitis in methimazole users after 3 months of exposure was 1.51, with a 95% confidence interval of 1.12-2.02. After 3 months of propylthiouracil exposure, the odds ratio for acute pancreatitis was 1.16 (95% CI 0.46-2.3). At 6 months, the odds ratio of 2.02 for methimazole was similarly statistically significant (95% CI, 1.50-2.78), whereas the odds ratio of 1.40 for propylthiouracil use was not significant (95% CI, 0.58-3.34).

The researchers also wanted to find out whether the cumulative drug dose affected the risk of acute pancreatitis, so they drew from the antithyroid drug population to conduct a case-control study. Here, the investigators matched data from four control patients to each case of acute pancreatitis. The researchers also controlled for sex, age, comorbidities, and prior use of drugs associated with pancreatitis.

Overall, 20% of the 692 methimazole users and their controls were men, as were 16% of the 108 propylthiouracil users, in the case-control study.

Just more than half of patients overall had a total dose exposure of 200 to 1,200 defined daily dose (DDD) – a measure developed by the World Health Organization to denote the assumed average adult dose per day of a medication – with about a quarter of patients receiving a total antithyroid drug dose more than 1,200 DDD and about 20% receiving a dose exposure of less than 200 DDD. The risk of acute pancreatitis did not increase with increased total exposure to antithyroid drugs.

“There is no evidence of a cumulative dose effect of either methimazole or propylthiouracil on the risk of acute pancreatitis,” said Dr. Hegedüs. However, “the warning of the European Medicines Agency seems justified,” he added. “The frequency of acute pancreatitis in acute methimazole users is of a similar magnitude [to that] reported for agranulocytosis,” a known, dire complication of antithyroid drug use. Patients should be advised of the potential complication and informed of signs and symptoms of acute pancreatitis, he said.

Dr. Hegedüs noted that the study had the advantage of using validated epidemiologic methods to look at drug exposure and outcomes at a nationwide scale. However, the registries from which the data were drawn also have limitations. The investigators could not determine the severity of hyperthyroidism, he said, and the relatively rare occurrence of acute pancreatitis meant that there was not sufficient statistical power to look at the subgroup of individuals who had Graves disease and to compare them with those with nodular toxic goiter.

He advised conducting a confirmatory study in an independent cohort, as well as further investigating the yet unknown mechanism of action for the link between the antithyroid drug and acute pancreatitis.

Dr. Hegedüs reported that he had no relevant conflicts of interest and reported no outside sources of funding.
 

SOURCE: Hegedüs, L. et al. ATA 2019, Short Call Oral Abstract 6 .

CHICAGO – A large Danish registry-based study has confirmed an increased risk of acute pancreatitis for patients taking certain antithyroid drugs.

After 6 months of methimazole use, the odds ratio for acute pancreatitis was 2.02, with a nonsignificant risk elevation for propylthiouracil use after a similar duration, Laszlo Hegedüs, MD, reported at the annual meeting of the American Thyroid Association.

“Ongoing methimazole, but not propylthiouracil, use is associated with an increased risk of acute pancreatitis,” he said.

Dr. Hegedüs, professor of endocrinology and metabolism at the University of Southern Denmark, Odense, said that the European Medicines Agency has noted a few postmarketing reports of acute pancreatitis in patients who received the antithyroid drug methimazole, as well as its prodrug, carbimazole. The agency has accordingly contraindicated antithyroid drug use for patients who previously experienced acute pancreatitis after receiving this drug, advising that methimazole should be “discontinued immediately” should a patient develop acute pancreatitis.

However, investigation of the antithyroid drug–pancreatitis association had been limited to aggregating those case reports, so Dr. Hegedüs and colleagues decided to use Danish medical record and registry data to investigate the association in a nationwide, controlled study that looked at both duration of therapy and total antithyroid drug use.

During the period from 1995-2018, a total of 118,649 patients who used antithyroid drugs were found in the 5.5 million individuals in the Statistics Denmark registry. Dr. Hegedüs and his colleagues also pulled in patient registry and national prescription registry data, as well as civil vital statistics data.

Of those who used antithyroid drugs, 103,825 patients used methimazole, and 14,824 used propylthiouracil. The researchers found 43,580 instances of hospitalization for first-time acute pancreatitis in the pooled antithyroid drug data. Of those, however, just 226 (0.5%) occurred in patients using methimazole, and 19 (0.04%) in those using propylthiouracil at the time of pancreatitis onset.

To ascertain the risk of acute pancreatitis in patients using antithyroid drugs for various durations, Dr. Hegedüs and his colleagues used a case-crossover study design. In the case-crossover technique, patients served as their own controls, because each patient was both exposed and not exposed to antithyroid drugs at some point during the study period. Antithyroid drugs are well suited to this study design, explained Dr. Hegedüs, because they are given for a limited time. A case-crossover design can be used with a small sample size and effectively controls for potentially confounding variables.

The odds ratio for acute pancreatitis in methimazole users after 3 months of exposure was 1.51, with a 95% confidence interval of 1.12-2.02. After 3 months of propylthiouracil exposure, the odds ratio for acute pancreatitis was 1.16 (95% CI 0.46-2.3). At 6 months, the odds ratio of 2.02 for methimazole was similarly statistically significant (95% CI, 1.50-2.78), whereas the odds ratio of 1.40 for propylthiouracil use was not significant (95% CI, 0.58-3.34).

The researchers also wanted to find out whether the cumulative drug dose affected the risk of acute pancreatitis, so they drew from the antithyroid drug population to conduct a case-control study. Here, the investigators matched data from four control patients to each case of acute pancreatitis. The researchers also controlled for sex, age, comorbidities, and prior use of drugs associated with pancreatitis.

Overall, 20% of the 692 methimazole users and their controls were men, as were 16% of the 108 propylthiouracil users, in the case-control study.

Just more than half of patients overall had a total dose exposure of 200 to 1,200 defined daily dose (DDD) – a measure developed by the World Health Organization to denote the assumed average adult dose per day of a medication – with about a quarter of patients receiving a total antithyroid drug dose more than 1,200 DDD and about 20% receiving a dose exposure of less than 200 DDD. The risk of acute pancreatitis did not increase with increased total exposure to antithyroid drugs.

“There is no evidence of a cumulative dose effect of either methimazole or propylthiouracil on the risk of acute pancreatitis,” said Dr. Hegedüs. However, “the warning of the European Medicines Agency seems justified,” he added. “The frequency of acute pancreatitis in acute methimazole users is of a similar magnitude [to that] reported for agranulocytosis,” a known, dire complication of antithyroid drug use. Patients should be advised of the potential complication and informed of signs and symptoms of acute pancreatitis, he said.

Dr. Hegedüs noted that the study had the advantage of using validated epidemiologic methods to look at drug exposure and outcomes at a nationwide scale. However, the registries from which the data were drawn also have limitations. The investigators could not determine the severity of hyperthyroidism, he said, and the relatively rare occurrence of acute pancreatitis meant that there was not sufficient statistical power to look at the subgroup of individuals who had Graves disease and to compare them with those with nodular toxic goiter.

He advised conducting a confirmatory study in an independent cohort, as well as further investigating the yet unknown mechanism of action for the link between the antithyroid drug and acute pancreatitis.

Dr. Hegedüs reported that he had no relevant conflicts of interest and reported no outside sources of funding.
 

SOURCE: Hegedüs, L. et al. ATA 2019, Short Call Oral Abstract 6 .

CHICAGO – A large Danish registry-based study has confirmed an increased risk of acute pancreatitis for patients taking certain antithyroid drugs.

After 6 months of methimazole use, the odds ratio for acute pancreatitis was 2.02, with a nonsignificant risk elevation for propylthiouracil use after a similar duration, Laszlo Hegedüs, MD, reported at the annual meeting of the American Thyroid Association.

“Ongoing methimazole, but not propylthiouracil, use is associated with an increased risk of acute pancreatitis,” he said.

Dr. Hegedüs, professor of endocrinology and metabolism at the University of Southern Denmark, Odense, said that the European Medicines Agency has noted a few postmarketing reports of acute pancreatitis in patients who received the antithyroid drug methimazole, as well as its prodrug, carbimazole. The agency has accordingly contraindicated antithyroid drug use for patients who previously experienced acute pancreatitis after receiving this drug, advising that methimazole should be “discontinued immediately” should a patient develop acute pancreatitis.

However, investigation of the antithyroid drug–pancreatitis association had been limited to aggregating those case reports, so Dr. Hegedüs and colleagues decided to use Danish medical record and registry data to investigate the association in a nationwide, controlled study that looked at both duration of therapy and total antithyroid drug use.

During the period from 1995-2018, a total of 118,649 patients who used antithyroid drugs were found in the 5.5 million individuals in the Statistics Denmark registry. Dr. Hegedüs and his colleagues also pulled in patient registry and national prescription registry data, as well as civil vital statistics data.

Of those who used antithyroid drugs, 103,825 patients used methimazole, and 14,824 used propylthiouracil. The researchers found 43,580 instances of hospitalization for first-time acute pancreatitis in the pooled antithyroid drug data. Of those, however, just 226 (0.5%) occurred in patients using methimazole, and 19 (0.04%) in those using propylthiouracil at the time of pancreatitis onset.

To ascertain the risk of acute pancreatitis in patients using antithyroid drugs for various durations, Dr. Hegedüs and his colleagues used a case-crossover study design. In the case-crossover technique, patients served as their own controls, because each patient was both exposed and not exposed to antithyroid drugs at some point during the study period. Antithyroid drugs are well suited to this study design, explained Dr. Hegedüs, because they are given for a limited time. A case-crossover design can be used with a small sample size and effectively controls for potentially confounding variables.

The odds ratio for acute pancreatitis in methimazole users after 3 months of exposure was 1.51, with a 95% confidence interval of 1.12-2.02. After 3 months of propylthiouracil exposure, the odds ratio for acute pancreatitis was 1.16 (95% CI 0.46-2.3). At 6 months, the odds ratio of 2.02 for methimazole was similarly statistically significant (95% CI, 1.50-2.78), whereas the odds ratio of 1.40 for propylthiouracil use was not significant (95% CI, 0.58-3.34).

The researchers also wanted to find out whether the cumulative drug dose affected the risk of acute pancreatitis, so they drew from the antithyroid drug population to conduct a case-control study. Here, the investigators matched data from four control patients to each case of acute pancreatitis. The researchers also controlled for sex, age, comorbidities, and prior use of drugs associated with pancreatitis.

Overall, 20% of the 692 methimazole users and their controls were men, as were 16% of the 108 propylthiouracil users, in the case-control study.

Just more than half of patients overall had a total dose exposure of 200 to 1,200 defined daily dose (DDD) – a measure developed by the World Health Organization to denote the assumed average adult dose per day of a medication – with about a quarter of patients receiving a total antithyroid drug dose more than 1,200 DDD and about 20% receiving a dose exposure of less than 200 DDD. The risk of acute pancreatitis did not increase with increased total exposure to antithyroid drugs.

“There is no evidence of a cumulative dose effect of either methimazole or propylthiouracil on the risk of acute pancreatitis,” said Dr. Hegedüs. However, “the warning of the European Medicines Agency seems justified,” he added. “The frequency of acute pancreatitis in acute methimazole users is of a similar magnitude [to that] reported for agranulocytosis,” a known, dire complication of antithyroid drug use. Patients should be advised of the potential complication and informed of signs and symptoms of acute pancreatitis, he said.

Dr. Hegedüs noted that the study had the advantage of using validated epidemiologic methods to look at drug exposure and outcomes at a nationwide scale. However, the registries from which the data were drawn also have limitations. The investigators could not determine the severity of hyperthyroidism, he said, and the relatively rare occurrence of acute pancreatitis meant that there was not sufficient statistical power to look at the subgroup of individuals who had Graves disease and to compare them with those with nodular toxic goiter.

He advised conducting a confirmatory study in an independent cohort, as well as further investigating the yet unknown mechanism of action for the link between the antithyroid drug and acute pancreatitis.

Dr. Hegedüs reported that he had no relevant conflicts of interest and reported no outside sources of funding.
 

SOURCE: Hegedüs, L. et al. ATA 2019, Short Call Oral Abstract 6 .

Focused ultrasound thalamotomy provides continued benefits for tremor, disability, and quality of life at 3 years in patients with medically refractory essential tremor, according to data published Nov. 20 in Neurology. Improvement from baseline remains significant at that time point, although the magnitude of effect may decrease. In addition, the treatment is not associated with progressive or delayed complications.

“For people who have disabling essential tremor that is not responding to medication, this treatment should be considered as a safe and effective option,” Casey H. Halpern, MD, assistant professor of neurosurgery at Stanford (Calif.) University, said in a press release.
 

Long-term follow-up of a prospective trial

Focused ultrasound thalamotomy is an emerging treatment for essential tremor. The procedure, which does not require an incision, is conducted with the guidance of magnetic resonance thermometry and patient feedback. A randomized controlled trial conducted by Elias and colleagues indicated that focused ultrasound ventral intermediate nucleus thalamotomy significantly suppressed tremor, reduced disability, and improved quality of life at 3 months, compared with sham treatment. This improvement was sustained at 12 months, and a follow-up study showed that improvements in tremor and functional disability were sustained at 24 months.

Dr. Halpern and colleagues sought to evaluate the continued safety and efficacy of focused ultrasound thalamotomy at 3 years’ follow-up in patients who participated in the original trial. Movement disorder specialists evaluated participants’ tremor severity and functional impairment using the Clinical Rating Scale for Tremor (CRST) at baseline and at 12, 24, and 36 months after treatment. Patients responded to the Quality of Life in Essential Tremor (QUEST) questionnaire, which assesses quality of life at baseline and at each follow-up visit. Neurologists evaluated and recorded all adverse events that occurred during the trial.
 

Postural tremor was eliminated

The original population included 75 patients who underwent focused ultrasound thalamotomy during the randomized, blinded phase or in an unblinded fashion during the crossover phase. The mean age of all treated patients was 71 years, and disease duration at treatment was 16.8 years. Fifty-two participants were observed at 36 months, and the 3-year attrition rate thus was 31%.

Dr. Halpern and colleagues found that the hand combined tremor–motor score, which was the trial’s primary endpoint, was significantly improved from baseline at 3 years. The median improvement from baseline was 56%. The median disability score decreased by 63% from baseline. Postural tremor was eliminated at 36 months, and QUEST score improved by 50%.

For patients who were missing at 3-year follow-up, data obtained at 3 months was used for comparison. These patients had less improvement in hand tremor–motor score, less reduction in disability, and less reduction in postural tremor, compared with patients who presented for 3-year follow-up. When the investigators reanalyzed their results to account for missing data, they found that the improvement from baseline remained significant.

Dr. Halpern and colleagues compared scores at 36 months and at 6 months to evaluate the durability of the treatment effect. Data were available for 49 patients at both time points, and their combined tremor–motor score had increased by a median of one point at 36 months. Disability score increased by a median of 2 points at 36 months. Posture and QUEST scores did not change significantly. About 58% of patients had at least 50% improvement in hand combined tremor–motor score at 36 months, compared with 64% at 24 months and 61% at 12 months.

The investigators described all adverse events as mild or moderate. No new procedure-related adverse events occurred between 24 and 36 months of follow-up, and none worsened during this period. Two adverse events, however, resolved between 24 and 36 months: one case of dysarthria and one of imbalance.
 

Reduction in improvement may have many causes

“A reduction in improvement is not unexpected, as essential tremor is a progressive disease,” wrote Dr. Halpern and colleagues. “In addition, diminishing performance of motor–functional tasks over time, particularly in this elderly population, may be multifactorial.” Decrease in tremor control has been reported after all surgical treatments for essential tremor (e.g., deep brain stimulation [DBS] and radiofrequency thalamotomy). Retreatment with invasive therapies or ionizing irradiation would be more problematic than retreatment with focused ultrasound thalamotomy, they added.

The researchers acknowledged that the main limitations of their study were the 31% dropout rate at 3 years and the fact that the cohort at 3-year follow-up differed from those at 2-year follow-up and in the original trial. The results nevertheless “demonstrate persistent, significant tremor reduction, as well as functional and quality of life improvement, with a positive safety profile,” they wrote.

Study funding was provided by the Focused Ultrasound Foundation, the Binational Industrial Research and Development Foundation of Israel, and InSightec, the maker of the focused ultrasound equipment that the researchers used. Dr. Halpern and other investigators received research funding from InSightec. One of the researchers is on the company’s medical advisory board, and another served as a consultant to the company.
 

Effect on axial tremor is unclear

The 50% improvement in hand tremor, disability, and quality of life that Halpern et al. report is similar to the improvement observed following DBS therapy, said Aparna Wagle Shukla, MD, director of the neurophysiology laboratory at the University of Florida in Gainesville, in an interview. Although the results are promising, neurologists should bear several points in mind, she added.

“DBS-induced side effects often are amenable to programming adjustments. However, similar to radiofrequency thalamotomy, focused ultrasound thalamotomy causes lesion effects. While the study discusses the nature of thalamotomy-induced adverse effects, the clinical practitioners also will benefit from learning about the severity of side effects and how they were individually addressed,” said Dr. Wagle Shukla. “The study acknowledges that there was a 30% dropout rate at 3 years’ follow-up. As the original plan included a 5-year follow-up, it would be beneficial to know why a large fraction of participants discontinued participation earlier than expected.”

Furthermore, the study by Halpern et al. leaves several questions unanswered. It does not indicate, for example, whether focused ultrasound thalamotomy can affect the control of axial tremor, including head and voice tremor, said Dr. Wagle Shukla. “Also, the potential of focused ultrasound thalamotomy to treat complex tremors with possible targeting of multiple brain regions such as ventralis oralis anterior and posterior and zona incerta stimulation is currently not known.

“There is no doubt that focused ultrasound thalamotomy is useful for the control of hand tremors in patients diagnosed with essential tremor, with long-term improvements in quality of life,” Dr. Wagle Shukla continued. “However, it is presently limited in its scope as a unilateral, single-target brain procedure.”

egreb@mdedge.com

SOURCE: Halpern CH et al. Neurology. 2019 Nov 20 (Epub ahead of print).

Focused ultrasound thalamotomy provides continued benefits for tremor, disability, and quality of life at 3 years in patients with medically refractory essential tremor, according to data published Nov. 20 in Neurology. Improvement from baseline remains significant at that time point, although the magnitude of effect may decrease. In addition, the treatment is not associated with progressive or delayed complications.

“For people who have disabling essential tremor that is not responding to medication, this treatment should be considered as a safe and effective option,” Casey H. Halpern, MD, assistant professor of neurosurgery at Stanford (Calif.) University, said in a press release.
 

Long-term follow-up of a prospective trial

Focused ultrasound thalamotomy is an emerging treatment for essential tremor. The procedure, which does not require an incision, is conducted with the guidance of magnetic resonance thermometry and patient feedback. A randomized controlled trial conducted by Elias and colleagues indicated that focused ultrasound ventral intermediate nucleus thalamotomy significantly suppressed tremor, reduced disability, and improved quality of life at 3 months, compared with sham treatment. This improvement was sustained at 12 months, and a follow-up study showed that improvements in tremor and functional disability were sustained at 24 months.

Dr. Halpern and colleagues sought to evaluate the continued safety and efficacy of focused ultrasound thalamotomy at 3 years’ follow-up in patients who participated in the original trial. Movement disorder specialists evaluated participants’ tremor severity and functional impairment using the Clinical Rating Scale for Tremor (CRST) at baseline and at 12, 24, and 36 months after treatment. Patients responded to the Quality of Life in Essential Tremor (QUEST) questionnaire, which assesses quality of life at baseline and at each follow-up visit. Neurologists evaluated and recorded all adverse events that occurred during the trial.
 

Postural tremor was eliminated

The original population included 75 patients who underwent focused ultrasound thalamotomy during the randomized, blinded phase or in an unblinded fashion during the crossover phase. The mean age of all treated patients was 71 years, and disease duration at treatment was 16.8 years. Fifty-two participants were observed at 36 months, and the 3-year attrition rate thus was 31%.

Dr. Halpern and colleagues found that the hand combined tremor–motor score, which was the trial’s primary endpoint, was significantly improved from baseline at 3 years. The median improvement from baseline was 56%. The median disability score decreased by 63% from baseline. Postural tremor was eliminated at 36 months, and QUEST score improved by 50%.

For patients who were missing at 3-year follow-up, data obtained at 3 months was used for comparison. These patients had less improvement in hand tremor–motor score, less reduction in disability, and less reduction in postural tremor, compared with patients who presented for 3-year follow-up. When the investigators reanalyzed their results to account for missing data, they found that the improvement from baseline remained significant.

Dr. Halpern and colleagues compared scores at 36 months and at 6 months to evaluate the durability of the treatment effect. Data were available for 49 patients at both time points, and their combined tremor–motor score had increased by a median of one point at 36 months. Disability score increased by a median of 2 points at 36 months. Posture and QUEST scores did not change significantly. About 58% of patients had at least 50% improvement in hand combined tremor–motor score at 36 months, compared with 64% at 24 months and 61% at 12 months.

The investigators described all adverse events as mild or moderate. No new procedure-related adverse events occurred between 24 and 36 months of follow-up, and none worsened during this period. Two adverse events, however, resolved between 24 and 36 months: one case of dysarthria and one of imbalance.
 

Reduction in improvement may have many causes

“A reduction in improvement is not unexpected, as essential tremor is a progressive disease,” wrote Dr. Halpern and colleagues. “In addition, diminishing performance of motor–functional tasks over time, particularly in this elderly population, may be multifactorial.” Decrease in tremor control has been reported after all surgical treatments for essential tremor (e.g., deep brain stimulation [DBS] and radiofrequency thalamotomy). Retreatment with invasive therapies or ionizing irradiation would be more problematic than retreatment with focused ultrasound thalamotomy, they added.

The researchers acknowledged that the main limitations of their study were the 31% dropout rate at 3 years and the fact that the cohort at 3-year follow-up differed from those at 2-year follow-up and in the original trial. The results nevertheless “demonstrate persistent, significant tremor reduction, as well as functional and quality of life improvement, with a positive safety profile,” they wrote.

Study funding was provided by the Focused Ultrasound Foundation, the Binational Industrial Research and Development Foundation of Israel, and InSightec, the maker of the focused ultrasound equipment that the researchers used. Dr. Halpern and other investigators received research funding from InSightec. One of the researchers is on the company’s medical advisory board, and another served as a consultant to the company.
 

Effect on axial tremor is unclear

The 50% improvement in hand tremor, disability, and quality of life that Halpern et al. report is similar to the improvement observed following DBS therapy, said Aparna Wagle Shukla, MD, director of the neurophysiology laboratory at the University of Florida in Gainesville, in an interview. Although the results are promising, neurologists should bear several points in mind, she added.

“DBS-induced side effects often are amenable to programming adjustments. However, similar to radiofrequency thalamotomy, focused ultrasound thalamotomy causes lesion effects. While the study discusses the nature of thalamotomy-induced adverse effects, the clinical practitioners also will benefit from learning about the severity of side effects and how they were individually addressed,” said Dr. Wagle Shukla. “The study acknowledges that there was a 30% dropout rate at 3 years’ follow-up. As the original plan included a 5-year follow-up, it would be beneficial to know why a large fraction of participants discontinued participation earlier than expected.”

Furthermore, the study by Halpern et al. leaves several questions unanswered. It does not indicate, for example, whether focused ultrasound thalamotomy can affect the control of axial tremor, including head and voice tremor, said Dr. Wagle Shukla. “Also, the potential of focused ultrasound thalamotomy to treat complex tremors with possible targeting of multiple brain regions such as ventralis oralis anterior and posterior and zona incerta stimulation is currently not known.

“There is no doubt that focused ultrasound thalamotomy is useful for the control of hand tremors in patients diagnosed with essential tremor, with long-term improvements in quality of life,” Dr. Wagle Shukla continued. “However, it is presently limited in its scope as a unilateral, single-target brain procedure.”

egreb@mdedge.com

SOURCE: Halpern CH et al. Neurology. 2019 Nov 20 (Epub ahead of print).

Focused ultrasound thalamotomy provides continued benefits for tremor, disability, and quality of life at 3 years in patients with medically refractory essential tremor, according to data published Nov. 20 in Neurology. Improvement from baseline remains significant at that time point, although the magnitude of effect may decrease. In addition, the treatment is not associated with progressive or delayed complications.

“For people who have disabling essential tremor that is not responding to medication, this treatment should be considered as a safe and effective option,” Casey H. Halpern, MD, assistant professor of neurosurgery at Stanford (Calif.) University, said in a press release.
 

Long-term follow-up of a prospective trial

Focused ultrasound thalamotomy is an emerging treatment for essential tremor. The procedure, which does not require an incision, is conducted with the guidance of magnetic resonance thermometry and patient feedback. A randomized controlled trial conducted by Elias and colleagues indicated that focused ultrasound ventral intermediate nucleus thalamotomy significantly suppressed tremor, reduced disability, and improved quality of life at 3 months, compared with sham treatment. This improvement was sustained at 12 months, and a follow-up study showed that improvements in tremor and functional disability were sustained at 24 months.

Dr. Halpern and colleagues sought to evaluate the continued safety and efficacy of focused ultrasound thalamotomy at 3 years’ follow-up in patients who participated in the original trial. Movement disorder specialists evaluated participants’ tremor severity and functional impairment using the Clinical Rating Scale for Tremor (CRST) at baseline and at 12, 24, and 36 months after treatment. Patients responded to the Quality of Life in Essential Tremor (QUEST) questionnaire, which assesses quality of life at baseline and at each follow-up visit. Neurologists evaluated and recorded all adverse events that occurred during the trial.
 

Postural tremor was eliminated

The original population included 75 patients who underwent focused ultrasound thalamotomy during the randomized, blinded phase or in an unblinded fashion during the crossover phase. The mean age of all treated patients was 71 years, and disease duration at treatment was 16.8 years. Fifty-two participants were observed at 36 months, and the 3-year attrition rate thus was 31%.

Dr. Halpern and colleagues found that the hand combined tremor–motor score, which was the trial’s primary endpoint, was significantly improved from baseline at 3 years. The median improvement from baseline was 56%. The median disability score decreased by 63% from baseline. Postural tremor was eliminated at 36 months, and QUEST score improved by 50%.

For patients who were missing at 3-year follow-up, data obtained at 3 months was used for comparison. These patients had less improvement in hand tremor–motor score, less reduction in disability, and less reduction in postural tremor, compared with patients who presented for 3-year follow-up. When the investigators reanalyzed their results to account for missing data, they found that the improvement from baseline remained significant.

Dr. Halpern and colleagues compared scores at 36 months and at 6 months to evaluate the durability of the treatment effect. Data were available for 49 patients at both time points, and their combined tremor–motor score had increased by a median of one point at 36 months. Disability score increased by a median of 2 points at 36 months. Posture and QUEST scores did not change significantly. About 58% of patients had at least 50% improvement in hand combined tremor–motor score at 36 months, compared with 64% at 24 months and 61% at 12 months.

The investigators described all adverse events as mild or moderate. No new procedure-related adverse events occurred between 24 and 36 months of follow-up, and none worsened during this period. Two adverse events, however, resolved between 24 and 36 months: one case of dysarthria and one of imbalance.
 

Reduction in improvement may have many causes

“A reduction in improvement is not unexpected, as essential tremor is a progressive disease,” wrote Dr. Halpern and colleagues. “In addition, diminishing performance of motor–functional tasks over time, particularly in this elderly population, may be multifactorial.” Decrease in tremor control has been reported after all surgical treatments for essential tremor (e.g., deep brain stimulation [DBS] and radiofrequency thalamotomy). Retreatment with invasive therapies or ionizing irradiation would be more problematic than retreatment with focused ultrasound thalamotomy, they added.

The researchers acknowledged that the main limitations of their study were the 31% dropout rate at 3 years and the fact that the cohort at 3-year follow-up differed from those at 2-year follow-up and in the original trial. The results nevertheless “demonstrate persistent, significant tremor reduction, as well as functional and quality of life improvement, with a positive safety profile,” they wrote.

Study funding was provided by the Focused Ultrasound Foundation, the Binational Industrial Research and Development Foundation of Israel, and InSightec, the maker of the focused ultrasound equipment that the researchers used. Dr. Halpern and other investigators received research funding from InSightec. One of the researchers is on the company’s medical advisory board, and another served as a consultant to the company.
 

Effect on axial tremor is unclear

The 50% improvement in hand tremor, disability, and quality of life that Halpern et al. report is similar to the improvement observed following DBS therapy, said Aparna Wagle Shukla, MD, director of the neurophysiology laboratory at the University of Florida in Gainesville, in an interview. Although the results are promising, neurologists should bear several points in mind, she added.

“DBS-induced side effects often are amenable to programming adjustments. However, similar to radiofrequency thalamotomy, focused ultrasound thalamotomy causes lesion effects. While the study discusses the nature of thalamotomy-induced adverse effects, the clinical practitioners also will benefit from learning about the severity of side effects and how they were individually addressed,” said Dr. Wagle Shukla. “The study acknowledges that there was a 30% dropout rate at 3 years’ follow-up. As the original plan included a 5-year follow-up, it would be beneficial to know why a large fraction of participants discontinued participation earlier than expected.”

Furthermore, the study by Halpern et al. leaves several questions unanswered. It does not indicate, for example, whether focused ultrasound thalamotomy can affect the control of axial tremor, including head and voice tremor, said Dr. Wagle Shukla. “Also, the potential of focused ultrasound thalamotomy to treat complex tremors with possible targeting of multiple brain regions such as ventralis oralis anterior and posterior and zona incerta stimulation is currently not known.

“There is no doubt that focused ultrasound thalamotomy is useful for the control of hand tremors in patients diagnosed with essential tremor, with long-term improvements in quality of life,” Dr. Wagle Shukla continued. “However, it is presently limited in its scope as a unilateral, single-target brain procedure.”

egreb@mdedge.com

SOURCE: Halpern CH et al. Neurology. 2019 Nov 20 (Epub ahead of print).

BOSTON – For treatment of nonalcoholic fatty liver disease, cotadutide, licogliflozin, tropifexor, saroglitazar, and PF-05221304 are just a few of the drugs with promising data, Kathleen E. Corey, MD, MPH, said at the annual meeting of the American Association for the Study of Liver Diseases.

Andrew D. Bowser/MDedge News

By contrast, selonsertib and emricasan did not achieve their endpoints in studies described here at the meeting, “but we have a lot to learn from them,” said Dr. Corey, director of the Mass General Fatty Liver Clinic and assistant professor at Harvard Medical School, Boston.

“This is an exciting time,” Dr. Corey said in a special debriefing oral session held on the final day of the conference. “There are many novel mechanisms of action out there, as well as some known mechanisms of action, with a considerable amount of promise.”
 

Cotadutide (MEDI0382)

Narha and coauthors (Abstract 35) described the effects of cotadutide, a GLP-1/glucagon receptor dual agonist on biomarkers of nonalcoholic steatohepatitis (NASH) at 26 weeks in overweight or obese patients with type 2 diabetes mellitus. In the randomized, phase 2b study, cotadutide produced superior reductions versus liraglutide, the GLP-1 receptor agonist, in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and body weight, which investigators said supported prospective trials of the drug for a potential indication in NASH.

“The adverse events were fairly typical for what we see with the GLP-1s – GI side effects that usually over 8 weeks improve,” Dr. Corey told attendees at the debrief session.
 

Licogliflozin (LIK066)

Interim analysis of a 12-week, randomized, placebo-controlled, phase 2a study showed that this SGLT1/2 inhibitor produced “robust” decreases in ALT and improvements in markers of hepatic and metabolic health in patients with NASH, according to Zhang and coauthors (Abstract L07).

Some 67% of those who received licogliflozin had at least a 30% decrease in their liver fat, while decreases in weight and hemoglobin A_1c were also reported, according to Dr. Corey. “It was associated with diarrhea in about 97%, but this was considered mild, and certainly, we’re seeing good metabolic effects overall,” she said.
 

Tropifexor

Treatment for 12 weeks with this potent FXR agonist resulted in robust, dose-dependent reductions in hepatic fat and serum ALT in patients with fibrotic NASH, according to investigators in a phase 2 randomized, placebo-controlled trial known as FLIGHT-FXR (Abstract L04).

A total of 65% of patients achieved a 30% or greater reduction in liver fat, and decreases in weight and insulin resistance were reported. “Similar to other FXRs, they did have this concerning although potentially manageable increase in low-density lipoprotein (LDL)-cholesterol, and the adverse event of pruritis,” said Dr. Corey.
 

Saroglitazar

Gawrieh and coauthors presented results from EVIDENCES IV, a phase 2, double-blind, randomized, placebo-controlled study of saroglitazar, a novel dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist, in patients with NAFLD or NASH (Abstract LO10).

The investigators found that 41% of patients achieved a 30% or greater relative reduction in liver fat, as well as reductions in hemoglobin A_1c and lipids, but the treatment was “weight neutral,” Dr. Corey said, adding that no serious adverse events were reported.
 

PF-05221304

This liver-targeted acetyl-CoA carboxylase inhibitor (ACCI) demonstrated robust reduction in liver fat and ALT in a 16-week phase 2a, dose-ranging study in adults with NAFLD, according to Amin and coinvestigators (Abstract 31).

There was a “dramatic” decrease in liver fat in this study, said Dr. Corey, with 90% of treated patients experiencing a 30% or greater decrease. Side effects included a “significant” increase in triglycerides, she added, as well as transient increases in ALT and AST.
 

Selonsertib and emricasan

One agent not meeting study endpoints was selonsertib, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor. While safe and well tolerated, the drug was nevertheless not effective as monotherapy in phase 3 double-blind, placebo-controlled trials including patients with advanced fibrosis due to NASH, investigators said (Abstract 64). Currently, the agent is being evaluated in combination with firsocostat – an ACCI – in a phase 2 study called ATLAS, according to the authors.

Emricasan, an oral pan-caspase inhibitor that suppresses apoptosis, did not improve fibrosis or resolve NASH in a multicenter, double-blind, placebo-controlled randomized trial, and may have even worsened histology, according to Dr. Corey. Investigators said further evaluation of the mechanisms underlying findings could provide insights into the role of necro-apoptosis in NASH pathophysiology (Abstract 61).

Dr. Corey provided disclosures related to BMS, Novo Nordisk, Boehringer Ingelheim, and Gilead.

BOSTON – For treatment of nonalcoholic fatty liver disease, cotadutide, licogliflozin, tropifexor, saroglitazar, and PF-05221304 are just a few of the drugs with promising data, Kathleen E. Corey, MD, MPH, said at the annual meeting of the American Association for the Study of Liver Diseases.

Andrew D. Bowser/MDedge News

By contrast, selonsertib and emricasan did not achieve their endpoints in studies described here at the meeting, “but we have a lot to learn from them,” said Dr. Corey, director of the Mass General Fatty Liver Clinic and assistant professor at Harvard Medical School, Boston.

“This is an exciting time,” Dr. Corey said in a special debriefing oral session held on the final day of the conference. “There are many novel mechanisms of action out there, as well as some known mechanisms of action, with a considerable amount of promise.”
 

Cotadutide (MEDI0382)

Narha and coauthors (Abstract 35) described the effects of cotadutide, a GLP-1/glucagon receptor dual agonist on biomarkers of nonalcoholic steatohepatitis (NASH) at 26 weeks in overweight or obese patients with type 2 diabetes mellitus. In the randomized, phase 2b study, cotadutide produced superior reductions versus liraglutide, the GLP-1 receptor agonist, in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and body weight, which investigators said supported prospective trials of the drug for a potential indication in NASH.

“The adverse events were fairly typical for what we see with the GLP-1s – GI side effects that usually over 8 weeks improve,” Dr. Corey told attendees at the debrief session.
 

Licogliflozin (LIK066)

Interim analysis of a 12-week, randomized, placebo-controlled, phase 2a study showed that this SGLT1/2 inhibitor produced “robust” decreases in ALT and improvements in markers of hepatic and metabolic health in patients with NASH, according to Zhang and coauthors (Abstract L07).

Some 67% of those who received licogliflozin had at least a 30% decrease in their liver fat, while decreases in weight and hemoglobin A_1c were also reported, according to Dr. Corey. “It was associated with diarrhea in about 97%, but this was considered mild, and certainly, we’re seeing good metabolic effects overall,” she said.
 

Tropifexor

Treatment for 12 weeks with this potent FXR agonist resulted in robust, dose-dependent reductions in hepatic fat and serum ALT in patients with fibrotic NASH, according to investigators in a phase 2 randomized, placebo-controlled trial known as FLIGHT-FXR (Abstract L04).

A total of 65% of patients achieved a 30% or greater reduction in liver fat, and decreases in weight and insulin resistance were reported. “Similar to other FXRs, they did have this concerning although potentially manageable increase in low-density lipoprotein (LDL)-cholesterol, and the adverse event of pruritis,” said Dr. Corey.
 

Saroglitazar

Gawrieh and coauthors presented results from EVIDENCES IV, a phase 2, double-blind, randomized, placebo-controlled study of saroglitazar, a novel dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist, in patients with NAFLD or NASH (Abstract LO10).

The investigators found that 41% of patients achieved a 30% or greater relative reduction in liver fat, as well as reductions in hemoglobin A_1c and lipids, but the treatment was “weight neutral,” Dr. Corey said, adding that no serious adverse events were reported.
 

PF-05221304

This liver-targeted acetyl-CoA carboxylase inhibitor (ACCI) demonstrated robust reduction in liver fat and ALT in a 16-week phase 2a, dose-ranging study in adults with NAFLD, according to Amin and coinvestigators (Abstract 31).

There was a “dramatic” decrease in liver fat in this study, said Dr. Corey, with 90% of treated patients experiencing a 30% or greater decrease. Side effects included a “significant” increase in triglycerides, she added, as well as transient increases in ALT and AST.
 

Selonsertib and emricasan

One agent not meeting study endpoints was selonsertib, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor. While safe and well tolerated, the drug was nevertheless not effective as monotherapy in phase 3 double-blind, placebo-controlled trials including patients with advanced fibrosis due to NASH, investigators said (Abstract 64). Currently, the agent is being evaluated in combination with firsocostat – an ACCI – in a phase 2 study called ATLAS, according to the authors.

Emricasan, an oral pan-caspase inhibitor that suppresses apoptosis, did not improve fibrosis or resolve NASH in a multicenter, double-blind, placebo-controlled randomized trial, and may have even worsened histology, according to Dr. Corey. Investigators said further evaluation of the mechanisms underlying findings could provide insights into the role of necro-apoptosis in NASH pathophysiology (Abstract 61).

Dr. Corey provided disclosures related to BMS, Novo Nordisk, Boehringer Ingelheim, and Gilead.

BOSTON – For treatment of nonalcoholic fatty liver disease, cotadutide, licogliflozin, tropifexor, saroglitazar, and PF-05221304 are just a few of the drugs with promising data, Kathleen E. Corey, MD, MPH, said at the annual meeting of the American Association for the Study of Liver Diseases.

Andrew D. Bowser/MDedge News

By contrast, selonsertib and emricasan did not achieve their endpoints in studies described here at the meeting, “but we have a lot to learn from them,” said Dr. Corey, director of the Mass General Fatty Liver Clinic and assistant professor at Harvard Medical School, Boston.

“This is an exciting time,” Dr. Corey said in a special debriefing oral session held on the final day of the conference. “There are many novel mechanisms of action out there, as well as some known mechanisms of action, with a considerable amount of promise.”
 

Cotadutide (MEDI0382)

Narha and coauthors (Abstract 35) described the effects of cotadutide, a GLP-1/glucagon receptor dual agonist on biomarkers of nonalcoholic steatohepatitis (NASH) at 26 weeks in overweight or obese patients with type 2 diabetes mellitus. In the randomized, phase 2b study, cotadutide produced superior reductions versus liraglutide, the GLP-1 receptor agonist, in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and body weight, which investigators said supported prospective trials of the drug for a potential indication in NASH.

“The adverse events were fairly typical for what we see with the GLP-1s – GI side effects that usually over 8 weeks improve,” Dr. Corey told attendees at the debrief session.
 

Licogliflozin (LIK066)

Interim analysis of a 12-week, randomized, placebo-controlled, phase 2a study showed that this SGLT1/2 inhibitor produced “robust” decreases in ALT and improvements in markers of hepatic and metabolic health in patients with NASH, according to Zhang and coauthors (Abstract L07).

Some 67% of those who received licogliflozin had at least a 30% decrease in their liver fat, while decreases in weight and hemoglobin A_1c were also reported, according to Dr. Corey. “It was associated with diarrhea in about 97%, but this was considered mild, and certainly, we’re seeing good metabolic effects overall,” she said.
 

Tropifexor

Treatment for 12 weeks with this potent FXR agonist resulted in robust, dose-dependent reductions in hepatic fat and serum ALT in patients with fibrotic NASH, according to investigators in a phase 2 randomized, placebo-controlled trial known as FLIGHT-FXR (Abstract L04).

A total of 65% of patients achieved a 30% or greater reduction in liver fat, and decreases in weight and insulin resistance were reported. “Similar to other FXRs, they did have this concerning although potentially manageable increase in low-density lipoprotein (LDL)-cholesterol, and the adverse event of pruritis,” said Dr. Corey.
 

Saroglitazar

Gawrieh and coauthors presented results from EVIDENCES IV, a phase 2, double-blind, randomized, placebo-controlled study of saroglitazar, a novel dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist, in patients with NAFLD or NASH (Abstract LO10).

The investigators found that 41% of patients achieved a 30% or greater relative reduction in liver fat, as well as reductions in hemoglobin A_1c and lipids, but the treatment was “weight neutral,” Dr. Corey said, adding that no serious adverse events were reported.
 

PF-05221304

This liver-targeted acetyl-CoA carboxylase inhibitor (ACCI) demonstrated robust reduction in liver fat and ALT in a 16-week phase 2a, dose-ranging study in adults with NAFLD, according to Amin and coinvestigators (Abstract 31).

There was a “dramatic” decrease in liver fat in this study, said Dr. Corey, with 90% of treated patients experiencing a 30% or greater decrease. Side effects included a “significant” increase in triglycerides, she added, as well as transient increases in ALT and AST.
 

Selonsertib and emricasan

One agent not meeting study endpoints was selonsertib, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor. While safe and well tolerated, the drug was nevertheless not effective as monotherapy in phase 3 double-blind, placebo-controlled trials including patients with advanced fibrosis due to NASH, investigators said (Abstract 64). Currently, the agent is being evaluated in combination with firsocostat – an ACCI – in a phase 2 study called ATLAS, according to the authors.

Emricasan, an oral pan-caspase inhibitor that suppresses apoptosis, did not improve fibrosis or resolve NASH in a multicenter, double-blind, placebo-controlled randomized trial, and may have even worsened histology, according to Dr. Corey. Investigators said further evaluation of the mechanisms underlying findings could provide insights into the role of necro-apoptosis in NASH pathophysiology (Abstract 61).

Dr. Corey provided disclosures related to BMS, Novo Nordisk, Boehringer Ingelheim, and Gilead.

ATLANTA – Rituximab (Rituxan) is superior to azathioprine (Imuran) for preventing ANCA-associated vasculitis relapses in patients with histories of previous relapses, according to a randomized trial of 170 patients presented at the annual meeting of the American College of Rheumatology.

Rituximab has been previously shown to be the superior remission maintenance option in the French MAINRITSAN trial (N Engl J Med. 2014 Nov 6;371[19]:1771-80), but mostly in newly diagnosed patients after cyclophosphamide induction. The results expand the finding to those with relapsing disease who previously had remission induced with rituximab, said lead investigator Rona Smith, MD, a clinical lecturer at Cambridge (England) University.

Subjects in the RITAZAREM trial (rituximab versus azathioprine as therapy for maintenance of remission for antineutrophil cytoplasmic antibody [ANCA]–associated vasculitis) were enrolled during a relapse of either granulomatosis with polyangiitis or microscopic polyangiitis and underwent remission induction with rituximab 375 mg/m² per week for 4 weeks coupled with prednisone, either 1 or 0.5 mg/kg per day at provider discretion.

After successful induction – defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis of 1 point or less on no more than 10 mg/day prednisone – 85 patients were randomized to rituximab 1 g every 4 months for 20 months and 85 to azathioprine 2 mg/kg per day for 20 months, followed by a taper. Prednisone was tapered per protocol to discontinuation at 20 months.

Eleven rituximab patients (13%) relapsed during the 20-month maintenance phase; two relapses were major. There were 32 relapses (38%) in the azathioprine group, 12 of them (38%) major (hazard ratio for rituximab versus azathioprine, 0.3; 95% CI, 0.15-0.60; P less than .001). ANCA type, glucocorticoid induction regimen, and severity of the enrollment relapse did not affect the outcomes.

Also, “there was an increase in the proportion of patients who became ANCA negative” in the rituximab arm, while “there was really no change” with azathioprine. In short, “rituximab is superior to azathioprine for prevention of disease relapse,” Dr. Smith said.

Her audience had a few questions about the rituximab regimen. The French MAINRITSAN trial dosed rituximab every 6 months instead of every 4, for a cumulative dose of 2.5 g, not 5 g, which an audience member said is the standard approach.

Dr. Smith explained that she and her colleagues have seen relapses with rituximab maintenance at 5 and 6 months, so they wanted to move to a shorter schedule. As for the higher dose, they wanted to “achieve complete B-cell depletion for the duration of the treatment period” to see if it translates into longer lasting remissions. “We will hopefully be able to address that question” with further analysis, she said.

There were no new safety signals; 19 rituximab patients (22%) and 31 azathioprine subjects (36%) had at least one serious adverse event; an infection requiring hospitalization occurred in 7 rituximab patients (8%) and 11 azathioprine patients (13%). Twenty-five (29%) rituximab and 21 (25%) azathioprine subjects developed hypogammaglobulinemia (IgG less than 5 g/L), and about half of each group developed an infection that required antibiotics, but not hospitalization.

There was one death in the azathioprine arm from malignancy, and three in the rituximab group, one from infection and two as of yet unclassified.

The groups were well balanced. Subjects were a median of 59 years old, with a median disease duration of 5.3 years. Refractory patients – those who had not achieved remission during a previous relapse – were excluded, as were patients who had received a B cell–depleting treatment in the previous 6 months and those with eosinophilic granulomatosis with polyangiitis or a malignancy in the past 5 years. Among patients in the study, 72% had tested positive for anti–proteinase 3 ANCA, and 28% for myeloperoxidase ANCA.

The work was funded by Versus Arthritis (formerly Arthritis Research UK), the National Institutes of Health, and the makers of rituximab, Roche/Genentech. Dr. Smith reported ties to Roche, Sanofi, and MedImmune.

aotto@mdedge.com

SOURCE: Smith R et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 806.

ATLANTA – Rituximab (Rituxan) is superior to azathioprine (Imuran) for preventing ANCA-associated vasculitis relapses in patients with histories of previous relapses, according to a randomized trial of 170 patients presented at the annual meeting of the American College of Rheumatology.

Rituximab has been previously shown to be the superior remission maintenance option in the French MAINRITSAN trial (N Engl J Med. 2014 Nov 6;371[19]:1771-80), but mostly in newly diagnosed patients after cyclophosphamide induction. The results expand the finding to those with relapsing disease who previously had remission induced with rituximab, said lead investigator Rona Smith, MD, a clinical lecturer at Cambridge (England) University.

Subjects in the RITAZAREM trial (rituximab versus azathioprine as therapy for maintenance of remission for antineutrophil cytoplasmic antibody [ANCA]–associated vasculitis) were enrolled during a relapse of either granulomatosis with polyangiitis or microscopic polyangiitis and underwent remission induction with rituximab 375 mg/m² per week for 4 weeks coupled with prednisone, either 1 or 0.5 mg/kg per day at provider discretion.

After successful induction – defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis of 1 point or less on no more than 10 mg/day prednisone – 85 patients were randomized to rituximab 1 g every 4 months for 20 months and 85 to azathioprine 2 mg/kg per day for 20 months, followed by a taper. Prednisone was tapered per protocol to discontinuation at 20 months.

Eleven rituximab patients (13%) relapsed during the 20-month maintenance phase; two relapses were major. There were 32 relapses (38%) in the azathioprine group, 12 of them (38%) major (hazard ratio for rituximab versus azathioprine, 0.3; 95% CI, 0.15-0.60; P less than .001). ANCA type, glucocorticoid induction regimen, and severity of the enrollment relapse did not affect the outcomes.

Also, “there was an increase in the proportion of patients who became ANCA negative” in the rituximab arm, while “there was really no change” with azathioprine. In short, “rituximab is superior to azathioprine for prevention of disease relapse,” Dr. Smith said.

Her audience had a few questions about the rituximab regimen. The French MAINRITSAN trial dosed rituximab every 6 months instead of every 4, for a cumulative dose of 2.5 g, not 5 g, which an audience member said is the standard approach.

Dr. Smith explained that she and her colleagues have seen relapses with rituximab maintenance at 5 and 6 months, so they wanted to move to a shorter schedule. As for the higher dose, they wanted to “achieve complete B-cell depletion for the duration of the treatment period” to see if it translates into longer lasting remissions. “We will hopefully be able to address that question” with further analysis, she said.

There were no new safety signals; 19 rituximab patients (22%) and 31 azathioprine subjects (36%) had at least one serious adverse event; an infection requiring hospitalization occurred in 7 rituximab patients (8%) and 11 azathioprine patients (13%). Twenty-five (29%) rituximab and 21 (25%) azathioprine subjects developed hypogammaglobulinemia (IgG less than 5 g/L), and about half of each group developed an infection that required antibiotics, but not hospitalization.

There was one death in the azathioprine arm from malignancy, and three in the rituximab group, one from infection and two as of yet unclassified.

The groups were well balanced. Subjects were a median of 59 years old, with a median disease duration of 5.3 years. Refractory patients – those who had not achieved remission during a previous relapse – were excluded, as were patients who had received a B cell–depleting treatment in the previous 6 months and those with eosinophilic granulomatosis with polyangiitis or a malignancy in the past 5 years. Among patients in the study, 72% had tested positive for anti–proteinase 3 ANCA, and 28% for myeloperoxidase ANCA.

The work was funded by Versus Arthritis (formerly Arthritis Research UK), the National Institutes of Health, and the makers of rituximab, Roche/Genentech. Dr. Smith reported ties to Roche, Sanofi, and MedImmune.

aotto@mdedge.com

SOURCE: Smith R et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 806.

ATLANTA – Rituximab (Rituxan) is superior to azathioprine (Imuran) for preventing ANCA-associated vasculitis relapses in patients with histories of previous relapses, according to a randomized trial of 170 patients presented at the annual meeting of the American College of Rheumatology.

Rituximab has been previously shown to be the superior remission maintenance option in the French MAINRITSAN trial (N Engl J Med. 2014 Nov 6;371[19]:1771-80), but mostly in newly diagnosed patients after cyclophosphamide induction. The results expand the finding to those with relapsing disease who previously had remission induced with rituximab, said lead investigator Rona Smith, MD, a clinical lecturer at Cambridge (England) University.

Subjects in the RITAZAREM trial (rituximab versus azathioprine as therapy for maintenance of remission for antineutrophil cytoplasmic antibody [ANCA]–associated vasculitis) were enrolled during a relapse of either granulomatosis with polyangiitis or microscopic polyangiitis and underwent remission induction with rituximab 375 mg/m² per week for 4 weeks coupled with prednisone, either 1 or 0.5 mg/kg per day at provider discretion.

After successful induction – defined as a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis of 1 point or less on no more than 10 mg/day prednisone – 85 patients were randomized to rituximab 1 g every 4 months for 20 months and 85 to azathioprine 2 mg/kg per day for 20 months, followed by a taper. Prednisone was tapered per protocol to discontinuation at 20 months.

Eleven rituximab patients (13%) relapsed during the 20-month maintenance phase; two relapses were major. There were 32 relapses (38%) in the azathioprine group, 12 of them (38%) major (hazard ratio for rituximab versus azathioprine, 0.3; 95% CI, 0.15-0.60; P less than .001). ANCA type, glucocorticoid induction regimen, and severity of the enrollment relapse did not affect the outcomes.

Also, “there was an increase in the proportion of patients who became ANCA negative” in the rituximab arm, while “there was really no change” with azathioprine. In short, “rituximab is superior to azathioprine for prevention of disease relapse,” Dr. Smith said.

Her audience had a few questions about the rituximab regimen. The French MAINRITSAN trial dosed rituximab every 6 months instead of every 4, for a cumulative dose of 2.5 g, not 5 g, which an audience member said is the standard approach.

Dr. Smith explained that she and her colleagues have seen relapses with rituximab maintenance at 5 and 6 months, so they wanted to move to a shorter schedule. As for the higher dose, they wanted to “achieve complete B-cell depletion for the duration of the treatment period” to see if it translates into longer lasting remissions. “We will hopefully be able to address that question” with further analysis, she said.

There were no new safety signals; 19 rituximab patients (22%) and 31 azathioprine subjects (36%) had at least one serious adverse event; an infection requiring hospitalization occurred in 7 rituximab patients (8%) and 11 azathioprine patients (13%). Twenty-five (29%) rituximab and 21 (25%) azathioprine subjects developed hypogammaglobulinemia (IgG less than 5 g/L), and about half of each group developed an infection that required antibiotics, but not hospitalization.

There was one death in the azathioprine arm from malignancy, and three in the rituximab group, one from infection and two as of yet unclassified.

The groups were well balanced. Subjects were a median of 59 years old, with a median disease duration of 5.3 years. Refractory patients – those who had not achieved remission during a previous relapse – were excluded, as were patients who had received a B cell–depleting treatment in the previous 6 months and those with eosinophilic granulomatosis with polyangiitis or a malignancy in the past 5 years. Among patients in the study, 72% had tested positive for anti–proteinase 3 ANCA, and 28% for myeloperoxidase ANCA.

The work was funded by Versus Arthritis (formerly Arthritis Research UK), the National Institutes of Health, and the makers of rituximab, Roche/Genentech. Dr. Smith reported ties to Roche, Sanofi, and MedImmune.

aotto@mdedge.com

SOURCE: Smith R et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 806.

The FP referred the patient to a dermatology clinic that specialized in hair loss. Based on the clinical findings, physicians at the clinic suspected that this was a case of frontal fibrosing alopecia (FFA), a primary lymphocytic cicatricial (scarring) alopecia. A dermatopathologist confirmed the diagnosis via histologic review.

FFA is characterized by symmetric band-like hair loss with evidence of scarring in the frontal and temporal regions of the scalp. (The extent of hair loss can be assessed by retracting the patient’s hair and having the patient raise his or her eyebrows and wrinkle the forehead in a surprised look.) FFA is accompanied by eyebrow loss in 73% to 95% of patients. Mild to severe perifollicular (and possibly more generalized) erythema and scale are usually present. In addition, erythematous or skin-colored papules may appear on the face, and marked exaggeration of the temporal veins is a common finding.

Most patients with FFA (83%) are postmenopausal women and nearly all (98.6%) have Fitzpatrick skin type 1 or 2 (white skin that burns easily and doesn’t readily tan). Other pertinent findings include the absence of oral lesions, nail changes, or other skin diseases.

A punch biopsy taken from the leading edge of the hair loss confirms the diagnosis of FFA and, ideally, should be reviewed by a dermatopathologist. Histologic examination will reveal a lichenoid lymphocytic infiltrate (predominantly around the hair follicle where the follicular stem cells reside), resulting in fibrosis and scarring. In addition to confirming the diagnosis with histologic examination, the following conditions must be ruled out in the differential: alopecia areata, female pattern hair loss, discoid lupus erythematosus, central centrifugal cicatricial alopecia, and traction alopecia.

Early detection is key. In general, physicians should initiate treatment as soon as possible to prevent disease progression and reduce permanent scarring and hair loss. Intralesional steroids such as triamcinolone acetonide (5-10 mg/cc), as well as high-potency topical steroids, are generally helpful to stabilize the disease. There is also some evidence of benefit from oral dutasteride or finasteride at variable doses. Immunosuppressants such as hydroxychloroquine also may be used as second-line treatments, although the benefit-to-risk ratio needs to be taken into consideration.

This patient was started on a regimen of topical high-potency steroids (clobetasol foam, 0.05%), with targeted, intralesional injection of steroids (10 mg/cc of triamcinolone acetonide) to areas with the most inflammation. She also was advised to use ketoconazole 2% shampoo while showering. These interventions decreased the patient’s symptoms dramatically. Her scalp erythema and scale improved, but the hair did not regrow. One year later, her hairline was clinically stable with no evidence of disease progression. She continued to see a dermatologist annually.

‌

This case was adapted from: Power DV, Disse M, Hordinsky M. Progressive hair loss. J Fam Pract. 2017;66:521-523.

The FP referred the patient to a dermatology clinic that specialized in hair loss. Based on the clinical findings, physicians at the clinic suspected that this was a case of frontal fibrosing alopecia (FFA), a primary lymphocytic cicatricial (scarring) alopecia. A dermatopathologist confirmed the diagnosis via histologic review.

FFA is characterized by symmetric band-like hair loss with evidence of scarring in the frontal and temporal regions of the scalp. (The extent of hair loss can be assessed by retracting the patient’s hair and having the patient raise his or her eyebrows and wrinkle the forehead in a surprised look.) FFA is accompanied by eyebrow loss in 73% to 95% of patients. Mild to severe perifollicular (and possibly more generalized) erythema and scale are usually present. In addition, erythematous or skin-colored papules may appear on the face, and marked exaggeration of the temporal veins is a common finding.

Most patients with FFA (83%) are postmenopausal women and nearly all (98.6%) have Fitzpatrick skin type 1 or 2 (white skin that burns easily and doesn’t readily tan). Other pertinent findings include the absence of oral lesions, nail changes, or other skin diseases.

A punch biopsy taken from the leading edge of the hair loss confirms the diagnosis of FFA and, ideally, should be reviewed by a dermatopathologist. Histologic examination will reveal a lichenoid lymphocytic infiltrate (predominantly around the hair follicle where the follicular stem cells reside), resulting in fibrosis and scarring. In addition to confirming the diagnosis with histologic examination, the following conditions must be ruled out in the differential: alopecia areata, female pattern hair loss, discoid lupus erythematosus, central centrifugal cicatricial alopecia, and traction alopecia.

Early detection is key. In general, physicians should initiate treatment as soon as possible to prevent disease progression and reduce permanent scarring and hair loss. Intralesional steroids such as triamcinolone acetonide (5-10 mg/cc), as well as high-potency topical steroids, are generally helpful to stabilize the disease. There is also some evidence of benefit from oral dutasteride or finasteride at variable doses. Immunosuppressants such as hydroxychloroquine also may be used as second-line treatments, although the benefit-to-risk ratio needs to be taken into consideration.

This patient was started on a regimen of topical high-potency steroids (clobetasol foam, 0.05%), with targeted, intralesional injection of steroids (10 mg/cc of triamcinolone acetonide) to areas with the most inflammation. She also was advised to use ketoconazole 2% shampoo while showering. These interventions decreased the patient’s symptoms dramatically. Her scalp erythema and scale improved, but the hair did not regrow. One year later, her hairline was clinically stable with no evidence of disease progression. She continued to see a dermatologist annually.

‌

This case was adapted from: Power DV, Disse M, Hordinsky M. Progressive hair loss. J Fam Pract. 2017;66:521-523.

The FP referred the patient to a dermatology clinic that specialized in hair loss. Based on the clinical findings, physicians at the clinic suspected that this was a case of frontal fibrosing alopecia (FFA), a primary lymphocytic cicatricial (scarring) alopecia. A dermatopathologist confirmed the diagnosis via histologic review.

FFA is characterized by symmetric band-like hair loss with evidence of scarring in the frontal and temporal regions of the scalp. (The extent of hair loss can be assessed by retracting the patient’s hair and having the patient raise his or her eyebrows and wrinkle the forehead in a surprised look.) FFA is accompanied by eyebrow loss in 73% to 95% of patients. Mild to severe perifollicular (and possibly more generalized) erythema and scale are usually present. In addition, erythematous or skin-colored papules may appear on the face, and marked exaggeration of the temporal veins is a common finding.

Most patients with FFA (83%) are postmenopausal women and nearly all (98.6%) have Fitzpatrick skin type 1 or 2 (white skin that burns easily and doesn’t readily tan). Other pertinent findings include the absence of oral lesions, nail changes, or other skin diseases.

A punch biopsy taken from the leading edge of the hair loss confirms the diagnosis of FFA and, ideally, should be reviewed by a dermatopathologist. Histologic examination will reveal a lichenoid lymphocytic infiltrate (predominantly around the hair follicle where the follicular stem cells reside), resulting in fibrosis and scarring. In addition to confirming the diagnosis with histologic examination, the following conditions must be ruled out in the differential: alopecia areata, female pattern hair loss, discoid lupus erythematosus, central centrifugal cicatricial alopecia, and traction alopecia.

Early detection is key. In general, physicians should initiate treatment as soon as possible to prevent disease progression and reduce permanent scarring and hair loss. Intralesional steroids such as triamcinolone acetonide (5-10 mg/cc), as well as high-potency topical steroids, are generally helpful to stabilize the disease. There is also some evidence of benefit from oral dutasteride or finasteride at variable doses. Immunosuppressants such as hydroxychloroquine also may be used as second-line treatments, although the benefit-to-risk ratio needs to be taken into consideration.

This patient was started on a regimen of topical high-potency steroids (clobetasol foam, 0.05%), with targeted, intralesional injection of steroids (10 mg/cc of triamcinolone acetonide) to areas with the most inflammation. She also was advised to use ketoconazole 2% shampoo while showering. These interventions decreased the patient’s symptoms dramatically. Her scalp erythema and scale improved, but the hair did not regrow. One year later, her hairline was clinically stable with no evidence of disease progression. She continued to see a dermatologist annually.

‌

This case was adapted from: Power DV, Disse M, Hordinsky M. Progressive hair loss. J Fam Pract. 2017;66:521-523.

A 14-year-old boy presents to dermatology for evaluation of an asymptomatic “rash” present on his arms since age 6. The condition has caught the attention of family members and teachers over the years, particularly in regard to possible contagion.

The patient is otherwise reasonably healthy, although he has asthma and seasonal allergies.

EXAMINATION
The "rash" consists of uniformly distributed and sized planar papules. Although they are tiny, averaging only 1 mm wide, they are prominent enough to be noticeable and palpable. They appear slightly lighter than the surrounding skin. Distribution is from the lower deltoid to mid-dorsal forearm, affecting both arms identically. The volar aspects and triceps of both arms are totally spared.

The patient has type IV skin.

What’s the diagnosis?

DISCUSSION
This case is an almost perfect representation of lichen nitidus (LN), in terms of morphology, distribution, and configuration. Close examination of individual lesions revealed that the papules were somewhat planar (ie, flat-topped), giving their surfaces a reflective appearance that the eye interprets as white (particularly contrasted with darker skin).

LN can occur in anyone, but it is most often seen in those with darker skin. It is also frequently seen in children, many of whom are atopic, with dry, sensitive skin that is prone to eczema.

In terms of distribution, LN typically affects the extensor triceps, elbow, and forearms bilaterally. With its flat-topped and shiny appearance, LN is sometimes called "mini-lichen planus"—a condition that can demonstrate similar features. Fortunately, LN is seldom itchy and shares none of the distinct histologic characteristics of lichen planus.

LN is quite unusual, if not rare. It is also idiopathic and nearly always resolves on its own—although this can take months to years.

Emollients help to make the affected skin smoother and less visible. Class 4 steroid creams (eg, triamcinolone 0.05%) can help with itching.

TAKE-HOME LEARNING POINTS

• Lichen nitidus (LN) is a rare idiopathic skin condition manifesting with patches of tiny planar papules; it typically affects the elbow and dorsal forearm.
• LN has no pathologic implications and is asymptomatic and self-limited.
• The lesions of LN have a “lichenoid” appearance—ie, a shiny, flat-topped look similar to that seen with lichen planus.
• Fortunately, LN rarely requires treatment, aside from relief of mild itching.

A 14-year-old boy presents to dermatology for evaluation of an asymptomatic “rash” present on his arms since age 6. The condition has caught the attention of family members and teachers over the years, particularly in regard to possible contagion.

The patient is otherwise reasonably healthy, although he has asthma and seasonal allergies.

EXAMINATION
The "rash" consists of uniformly distributed and sized planar papules. Although they are tiny, averaging only 1 mm wide, they are prominent enough to be noticeable and palpable. They appear slightly lighter than the surrounding skin. Distribution is from the lower deltoid to mid-dorsal forearm, affecting both arms identically. The volar aspects and triceps of both arms are totally spared.

The patient has type IV skin.

What’s the diagnosis?

DISCUSSION
This case is an almost perfect representation of lichen nitidus (LN), in terms of morphology, distribution, and configuration. Close examination of individual lesions revealed that the papules were somewhat planar (ie, flat-topped), giving their surfaces a reflective appearance that the eye interprets as white (particularly contrasted with darker skin).

LN can occur in anyone, but it is most often seen in those with darker skin. It is also frequently seen in children, many of whom are atopic, with dry, sensitive skin that is prone to eczema.

In terms of distribution, LN typically affects the extensor triceps, elbow, and forearms bilaterally. With its flat-topped and shiny appearance, LN is sometimes called "mini-lichen planus"—a condition that can demonstrate similar features. Fortunately, LN is seldom itchy and shares none of the distinct histologic characteristics of lichen planus.

LN is quite unusual, if not rare. It is also idiopathic and nearly always resolves on its own—although this can take months to years.

Emollients help to make the affected skin smoother and less visible. Class 4 steroid creams (eg, triamcinolone 0.05%) can help with itching.

TAKE-HOME LEARNING POINTS

• Lichen nitidus (LN) is a rare idiopathic skin condition manifesting with patches of tiny planar papules; it typically affects the elbow and dorsal forearm.
• LN has no pathologic implications and is asymptomatic and self-limited.
• The lesions of LN have a “lichenoid” appearance—ie, a shiny, flat-topped look similar to that seen with lichen planus.
• Fortunately, LN rarely requires treatment, aside from relief of mild itching.

A 14-year-old boy presents to dermatology for evaluation of an asymptomatic “rash” present on his arms since age 6. The condition has caught the attention of family members and teachers over the years, particularly in regard to possible contagion.

The patient is otherwise reasonably healthy, although he has asthma and seasonal allergies.

EXAMINATION
The "rash" consists of uniformly distributed and sized planar papules. Although they are tiny, averaging only 1 mm wide, they are prominent enough to be noticeable and palpable. They appear slightly lighter than the surrounding skin. Distribution is from the lower deltoid to mid-dorsal forearm, affecting both arms identically. The volar aspects and triceps of both arms are totally spared.

The patient has type IV skin.

What’s the diagnosis?

DISCUSSION
This case is an almost perfect representation of lichen nitidus (LN), in terms of morphology, distribution, and configuration. Close examination of individual lesions revealed that the papules were somewhat planar (ie, flat-topped), giving their surfaces a reflective appearance that the eye interprets as white (particularly contrasted with darker skin).

LN can occur in anyone, but it is most often seen in those with darker skin. It is also frequently seen in children, many of whom are atopic, with dry, sensitive skin that is prone to eczema.

In terms of distribution, LN typically affects the extensor triceps, elbow, and forearms bilaterally. With its flat-topped and shiny appearance, LN is sometimes called "mini-lichen planus"—a condition that can demonstrate similar features. Fortunately, LN is seldom itchy and shares none of the distinct histologic characteristics of lichen planus.

LN is quite unusual, if not rare. It is also idiopathic and nearly always resolves on its own—although this can take months to years.

Emollients help to make the affected skin smoother and less visible. Class 4 steroid creams (eg, triamcinolone 0.05%) can help with itching.

TAKE-HOME LEARNING POINTS

• Lichen nitidus (LN) is a rare idiopathic skin condition manifesting with patches of tiny planar papules; it typically affects the elbow and dorsal forearm.
• LN has no pathologic implications and is asymptomatic and self-limited.
• The lesions of LN have a “lichenoid” appearance—ie, a shiny, flat-topped look similar to that seen with lichen planus.
• Fortunately, LN rarely requires treatment, aside from relief of mild itching.

Infants born in a country with no endemic measles no longer received adequate protection against the disease from maternal antibodies when they were aged 6 months, according to new research.

FatCamera/E+/Getty Images

In fact, most of the 196 infants’ maternal measles antibodies had dropped below the protective threshold by 3 months of age – well before the recommended age of 12-15 months for the first dose of MMR vaccine.

The odds of inadequate protection doubled for each additional month of age, Michelle Science, MD, of the University of Toronto and associates reported in Pediatrics.

“The widening gap between loss of maternal antibodies and measles vaccination described in our study leaves infants vulnerable to measles for much of their infancy and highlights the need for further research to support public health policy,” Dr. Science and colleagues wrote.

The findings are not surprising for a setting in which measles has been eliminated and align with results from past research, Huong Q. McLean, PhD, MPH, of the Marshfield (Wis.) Clinic Research Institute and Walter A. Orenstein, MD, of Emory University in Atlanta wrote in an accompanying editorial (Pediatrics. 2019 Nov 21. doi: 10.1542/peds.2019-2541).

However, this susceptibility prior to receiving the MMR has taken on a new significance more recently, Dr. McLean and Dr. Orenstein suggested.

“In light of increasing measles outbreaks during the past year reaching levels not recorded in the United States since 1992 and increased measles elsewhere, coupled with the risk of severe illness in infants, there is increased concern regarding the protection of infants against measles,” the editorialists wrote.

Dr. Science and colleagues tested serum samples from 196 term infants, all under 12 months old, for antibodies against measles. The sera had been previously collected at a single tertiary care center in Ontario for clinical testing and then stored. Measles has been eliminated in Canada since 1998.

The researchers randomly selected 25 samples for each of eight different age groups: up to 30 days old; 1 month (31-60 days); 2 months (61-89 days); 3 months (90-119 days); 4 months; 5 months; 6-9 months; and 9-11 months.

Just over half the babies (56%) were male, and 35% had an underlying condition, but none had conditions that might affect antibody levels. The conditions were primarily a developmental delay or otherwise affecting the central nervous system, liver, or gastrointestinal function. Mean maternal age was 32 years.

To ensure high test sensitivity, the researchers used the plaque-reduction neutralization test (PRNT) to test for measles-neutralizing antibodies instead of using enzyme-linked immunosorbent assay (ELISA) because “ELISA sensitivity decreases as antibody titers decrease,” Dr. Science and colleagues wrote. They used a neutralization titer of less than 192 mIU/mL as the threshold for protection against measles.

When the researchers calculated the predicted standardized mean antibody titer for infants with a mother aged 32 years, they determined their mean to be 541 mIU/mL at 1 month, 142 mIU/mL at 3 months (below the measles threshold of susceptibility of 192 mIU/mL) , and 64 mIU/mL at 6 months. None of the infants had measles antibodies above the protective threshold at 6 months old, the authors noted.

Children’s odds of susceptibility to measles doubled for each additional month of age, after adjustment for infant sex and maternal age (odds ratio, 2.13). Children’s likelihood of susceptibility to measles modestly increased as maternal age increased in 5-year increments from 25 to 40 years.

Children with an underlying conditions had greater susceptibility to measles (83%), compared with those without a comorbidity (68%, P = .03). No difference in susceptibility existed between males and females or based on gestational age at birth (ranging from 37 to 41 weeks).

The Advisory Committee on Immunization Practices permits measles vaccination “as early as 6 months for infants who plan to travel internationally, infants with ongoing risk for exposure during measles outbreaks and as postexposure prophylaxis,” Dr. McLean and Dr. Orenstein noted in their editorial.

They discussed the rationale for various changes in the recommended schedule for measles immunization, based on changes in epidemiology of the disease and improved understanding of the immune response to vaccination since the vaccine became available in 1963. Then they posed the question of whether the recommendation should be revised again.

“Ideally, the schedule should minimize the risk of measles and its complications and optimize vaccine-induced protection,” Dr. McLean and Dr. Orenstein wrote.

They argued that the evidence cannot currently support changing the first MMR dose to a younger age because measles incidence in the United States remains extremely low outside of the extraordinary outbreaks in 2014 and 2019. Further, infants under 12 months of age make up less than 15% of measles cases during outbreaks, and unvaccinated people make up more than 70% of cases.

Rather, they stated, this new study emphasizes the importance of following the current schedule, with consideration of an earlier schedule only warranted during outbreaks.

“Health care providers must work to maintain high levels of coverage with 2 doses of MMR among vaccine-eligible populations and minimize pockets of susceptibility to prevent transmission to infants and prevent reestablishment of endemic transmission,” they concluded.

The research was funded by the Public Health Ontario Project Initiation Fund. The authors had no relevant financial disclosures. The editorialists had no external funding and no relevant financial disclosures.

SOURCE: Science M et al. Pediatrics. 2019 Nov 21. doi: 10.1542/peds.2019-0630.

Infants born in a country with no endemic measles no longer received adequate protection against the disease from maternal antibodies when they were aged 6 months, according to new research.

FatCamera/E+/Getty Images

In fact, most of the 196 infants’ maternal measles antibodies had dropped below the protective threshold by 3 months of age – well before the recommended age of 12-15 months for the first dose of MMR vaccine.

The odds of inadequate protection doubled for each additional month of age, Michelle Science, MD, of the University of Toronto and associates reported in Pediatrics.

“The widening gap between loss of maternal antibodies and measles vaccination described in our study leaves infants vulnerable to measles for much of their infancy and highlights the need for further research to support public health policy,” Dr. Science and colleagues wrote.

The findings are not surprising for a setting in which measles has been eliminated and align with results from past research, Huong Q. McLean, PhD, MPH, of the Marshfield (Wis.) Clinic Research Institute and Walter A. Orenstein, MD, of Emory University in Atlanta wrote in an accompanying editorial (Pediatrics. 2019 Nov 21. doi: 10.1542/peds.2019-2541).

However, this susceptibility prior to receiving the MMR has taken on a new significance more recently, Dr. McLean and Dr. Orenstein suggested.

“In light of increasing measles outbreaks during the past year reaching levels not recorded in the United States since 1992 and increased measles elsewhere, coupled with the risk of severe illness in infants, there is increased concern regarding the protection of infants against measles,” the editorialists wrote.

Dr. Science and colleagues tested serum samples from 196 term infants, all under 12 months old, for antibodies against measles. The sera had been previously collected at a single tertiary care center in Ontario for clinical testing and then stored. Measles has been eliminated in Canada since 1998.

The researchers randomly selected 25 samples for each of eight different age groups: up to 30 days old; 1 month (31-60 days); 2 months (61-89 days); 3 months (90-119 days); 4 months; 5 months; 6-9 months; and 9-11 months.

Just over half the babies (56%) were male, and 35% had an underlying condition, but none had conditions that might affect antibody levels. The conditions were primarily a developmental delay or otherwise affecting the central nervous system, liver, or gastrointestinal function. Mean maternal age was 32 years.

To ensure high test sensitivity, the researchers used the plaque-reduction neutralization test (PRNT) to test for measles-neutralizing antibodies instead of using enzyme-linked immunosorbent assay (ELISA) because “ELISA sensitivity decreases as antibody titers decrease,” Dr. Science and colleagues wrote. They used a neutralization titer of less than 192 mIU/mL as the threshold for protection against measles.

When the researchers calculated the predicted standardized mean antibody titer for infants with a mother aged 32 years, they determined their mean to be 541 mIU/mL at 1 month, 142 mIU/mL at 3 months (below the measles threshold of susceptibility of 192 mIU/mL) , and 64 mIU/mL at 6 months. None of the infants had measles antibodies above the protective threshold at 6 months old, the authors noted.

Children’s odds of susceptibility to measles doubled for each additional month of age, after adjustment for infant sex and maternal age (odds ratio, 2.13). Children’s likelihood of susceptibility to measles modestly increased as maternal age increased in 5-year increments from 25 to 40 years.

Children with an underlying conditions had greater susceptibility to measles (83%), compared with those without a comorbidity (68%, P = .03). No difference in susceptibility existed between males and females or based on gestational age at birth (ranging from 37 to 41 weeks).

The Advisory Committee on Immunization Practices permits measles vaccination “as early as 6 months for infants who plan to travel internationally, infants with ongoing risk for exposure during measles outbreaks and as postexposure prophylaxis,” Dr. McLean and Dr. Orenstein noted in their editorial.

They discussed the rationale for various changes in the recommended schedule for measles immunization, based on changes in epidemiology of the disease and improved understanding of the immune response to vaccination since the vaccine became available in 1963. Then they posed the question of whether the recommendation should be revised again.

“Ideally, the schedule should minimize the risk of measles and its complications and optimize vaccine-induced protection,” Dr. McLean and Dr. Orenstein wrote.

They argued that the evidence cannot currently support changing the first MMR dose to a younger age because measles incidence in the United States remains extremely low outside of the extraordinary outbreaks in 2014 and 2019. Further, infants under 12 months of age make up less than 15% of measles cases during outbreaks, and unvaccinated people make up more than 70% of cases.

Rather, they stated, this new study emphasizes the importance of following the current schedule, with consideration of an earlier schedule only warranted during outbreaks.

“Health care providers must work to maintain high levels of coverage with 2 doses of MMR among vaccine-eligible populations and minimize pockets of susceptibility to prevent transmission to infants and prevent reestablishment of endemic transmission,” they concluded.

The research was funded by the Public Health Ontario Project Initiation Fund. The authors had no relevant financial disclosures. The editorialists had no external funding and no relevant financial disclosures.

SOURCE: Science M et al. Pediatrics. 2019 Nov 21. doi: 10.1542/peds.2019-0630.

Infants born in a country with no endemic measles no longer received adequate protection against the disease from maternal antibodies when they were aged 6 months, according to new research.

FatCamera/E+/Getty Images

In fact, most of the 196 infants’ maternal measles antibodies had dropped below the protective threshold by 3 months of age – well before the recommended age of 12-15 months for the first dose of MMR vaccine.

The odds of inadequate protection doubled for each additional month of age, Michelle Science, MD, of the University of Toronto and associates reported in Pediatrics.

“The widening gap between loss of maternal antibodies and measles vaccination described in our study leaves infants vulnerable to measles for much of their infancy and highlights the need for further research to support public health policy,” Dr. Science and colleagues wrote.

The findings are not surprising for a setting in which measles has been eliminated and align with results from past research, Huong Q. McLean, PhD, MPH, of the Marshfield (Wis.) Clinic Research Institute and Walter A. Orenstein, MD, of Emory University in Atlanta wrote in an accompanying editorial (Pediatrics. 2019 Nov 21. doi: 10.1542/peds.2019-2541).

However, this susceptibility prior to receiving the MMR has taken on a new significance more recently, Dr. McLean and Dr. Orenstein suggested.

“In light of increasing measles outbreaks during the past year reaching levels not recorded in the United States since 1992 and increased measles elsewhere, coupled with the risk of severe illness in infants, there is increased concern regarding the protection of infants against measles,” the editorialists wrote.

Dr. Science and colleagues tested serum samples from 196 term infants, all under 12 months old, for antibodies against measles. The sera had been previously collected at a single tertiary care center in Ontario for clinical testing and then stored. Measles has been eliminated in Canada since 1998.

The researchers randomly selected 25 samples for each of eight different age groups: up to 30 days old; 1 month (31-60 days); 2 months (61-89 days); 3 months (90-119 days); 4 months; 5 months; 6-9 months; and 9-11 months.

Just over half the babies (56%) were male, and 35% had an underlying condition, but none had conditions that might affect antibody levels. The conditions were primarily a developmental delay or otherwise affecting the central nervous system, liver, or gastrointestinal function. Mean maternal age was 32 years.

To ensure high test sensitivity, the researchers used the plaque-reduction neutralization test (PRNT) to test for measles-neutralizing antibodies instead of using enzyme-linked immunosorbent assay (ELISA) because “ELISA sensitivity decreases as antibody titers decrease,” Dr. Science and colleagues wrote. They used a neutralization titer of less than 192 mIU/mL as the threshold for protection against measles.

When the researchers calculated the predicted standardized mean antibody titer for infants with a mother aged 32 years, they determined their mean to be 541 mIU/mL at 1 month, 142 mIU/mL at 3 months (below the measles threshold of susceptibility of 192 mIU/mL) , and 64 mIU/mL at 6 months. None of the infants had measles antibodies above the protective threshold at 6 months old, the authors noted.

Children’s odds of susceptibility to measles doubled for each additional month of age, after adjustment for infant sex and maternal age (odds ratio, 2.13). Children’s likelihood of susceptibility to measles modestly increased as maternal age increased in 5-year increments from 25 to 40 years.

Children with an underlying conditions had greater susceptibility to measles (83%), compared with those without a comorbidity (68%, P = .03). No difference in susceptibility existed between males and females or based on gestational age at birth (ranging from 37 to 41 weeks).

The Advisory Committee on Immunization Practices permits measles vaccination “as early as 6 months for infants who plan to travel internationally, infants with ongoing risk for exposure during measles outbreaks and as postexposure prophylaxis,” Dr. McLean and Dr. Orenstein noted in their editorial.

They discussed the rationale for various changes in the recommended schedule for measles immunization, based on changes in epidemiology of the disease and improved understanding of the immune response to vaccination since the vaccine became available in 1963. Then they posed the question of whether the recommendation should be revised again.

“Ideally, the schedule should minimize the risk of measles and its complications and optimize vaccine-induced protection,” Dr. McLean and Dr. Orenstein wrote.

They argued that the evidence cannot currently support changing the first MMR dose to a younger age because measles incidence in the United States remains extremely low outside of the extraordinary outbreaks in 2014 and 2019. Further, infants under 12 months of age make up less than 15% of measles cases during outbreaks, and unvaccinated people make up more than 70% of cases.

Rather, they stated, this new study emphasizes the importance of following the current schedule, with consideration of an earlier schedule only warranted during outbreaks.

“Health care providers must work to maintain high levels of coverage with 2 doses of MMR among vaccine-eligible populations and minimize pockets of susceptibility to prevent transmission to infants and prevent reestablishment of endemic transmission,” they concluded.

The research was funded by the Public Health Ontario Project Initiation Fund. The authors had no relevant financial disclosures. The editorialists had no external funding and no relevant financial disclosures.

SOURCE: Science M et al. Pediatrics. 2019 Nov 21. doi: 10.1542/peds.2019-0630.

The clinical features were consistent with a filiform wart, which is caused by human papillomavirus and common on the face. Filiform warts may occur on mucosal surfaces, including the nasal mucosa, lips, or eyelids. Most are benign and resolve within 2 years without treatment, but others can be symptomatic. Larger filiform warts may develop the clinical features of a cutaneous horn and mimic a squamous cell carcinoma.

Patients often want the wart removed for functional or cosmetic reasons. Although, there are many treatments available for warts, none have success rates that exceed about 70%. The most common options for treatment include topical salicylic acid in a liquid or plaster, cryotherapy, intralesional immunotherapy with candida antigen, excision, and topical acid.

The location of this patient’s wart limited the treatment options to cryotherapy or snip excision and cautery. The patient opted for cryotherapy. In this process, a hemostat or heavy gauge tweezer is dipped in liquid nitrogen and allowed to cool. Then, without anesthesia, the clinician pinches the lesion gently with the instrument and holds it until the freeze horizon extends to the base. This is then repeated. Each cycle may take 10 and 15 seconds. A benefit of this technique (which is also useful for skin tags and lesions close to the eye) is the ability to avoid overspray of liquid nitrogen and thus, minimize collateral tissue damage. It is also quick and bloodless.

The FP performed cryotherapy on the wart and advised the patient to expect the lesion to become more inflamed over the next 2 to 3 days and then peel off within 1 to 2 weeks. The FP also instructed the patient to return in a week or 2 so that the FP could evaluate whether additional treatment would be necessary. In general, non-genital warts require 2 to 3 individual treatments to clear, but a smaller and pedunculated wart like the one seen in this case tend to clear more easily.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained).

The clinical features were consistent with a filiform wart, which is caused by human papillomavirus and common on the face. Filiform warts may occur on mucosal surfaces, including the nasal mucosa, lips, or eyelids. Most are benign and resolve within 2 years without treatment, but others can be symptomatic. Larger filiform warts may develop the clinical features of a cutaneous horn and mimic a squamous cell carcinoma.

Patients often want the wart removed for functional or cosmetic reasons. Although, there are many treatments available for warts, none have success rates that exceed about 70%. The most common options for treatment include topical salicylic acid in a liquid or plaster, cryotherapy, intralesional immunotherapy with candida antigen, excision, and topical acid.

The location of this patient’s wart limited the treatment options to cryotherapy or snip excision and cautery. The patient opted for cryotherapy. In this process, a hemostat or heavy gauge tweezer is dipped in liquid nitrogen and allowed to cool. Then, without anesthesia, the clinician pinches the lesion gently with the instrument and holds it until the freeze horizon extends to the base. This is then repeated. Each cycle may take 10 and 15 seconds. A benefit of this technique (which is also useful for skin tags and lesions close to the eye) is the ability to avoid overspray of liquid nitrogen and thus, minimize collateral tissue damage. It is also quick and bloodless.

The FP performed cryotherapy on the wart and advised the patient to expect the lesion to become more inflamed over the next 2 to 3 days and then peel off within 1 to 2 weeks. The FP also instructed the patient to return in a week or 2 so that the FP could evaluate whether additional treatment would be necessary. In general, non-genital warts require 2 to 3 individual treatments to clear, but a smaller and pedunculated wart like the one seen in this case tend to clear more easily.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained).

The clinical features were consistent with a filiform wart, which is caused by human papillomavirus and common on the face. Filiform warts may occur on mucosal surfaces, including the nasal mucosa, lips, or eyelids. Most are benign and resolve within 2 years without treatment, but others can be symptomatic. Larger filiform warts may develop the clinical features of a cutaneous horn and mimic a squamous cell carcinoma.

Patients often want the wart removed for functional or cosmetic reasons. Although, there are many treatments available for warts, none have success rates that exceed about 70%. The most common options for treatment include topical salicylic acid in a liquid or plaster, cryotherapy, intralesional immunotherapy with candida antigen, excision, and topical acid.

The location of this patient’s wart limited the treatment options to cryotherapy or snip excision and cautery. The patient opted for cryotherapy. In this process, a hemostat or heavy gauge tweezer is dipped in liquid nitrogen and allowed to cool. Then, without anesthesia, the clinician pinches the lesion gently with the instrument and holds it until the freeze horizon extends to the base. This is then repeated. Each cycle may take 10 and 15 seconds. A benefit of this technique (which is also useful for skin tags and lesions close to the eye) is the ability to avoid overspray of liquid nitrogen and thus, minimize collateral tissue damage. It is also quick and bloodless.

The FP performed cryotherapy on the wart and advised the patient to expect the lesion to become more inflamed over the next 2 to 3 days and then peel off within 1 to 2 weeks. The FP also instructed the patient to return in a week or 2 so that the FP could evaluate whether additional treatment would be necessary. In general, non-genital warts require 2 to 3 individual treatments to clear, but a smaller and pedunculated wart like the one seen in this case tend to clear more easily.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained).