Jim Kling

For patients with psoriatic arthritis (PsA) whose condition doesn’t respond adequately to methotrexate, addition of the tumor necrosis factor (TNF) inhibitor adalimumab increased the likelihood of achieving minimum disease activity (MDA), compared with escalation of MTX dose, according to results from a phase 4, open-label study.

The new study is one of only a few to compare treatment protocols in a field that has seen new therapeutic options become available in recent years. That lack of evidence can leave patients and physicians uncertain about the next step if the initial results of treatment are disappointing.

“There are some gaps in our database and our understanding of psoriatic arthritis, compared to rheumatoid arthritis, where we have had many more studies over the years,” Arthur Kavanaugh, MD, told this news organization when asked to comment on the study.

The trial provides one answer, at least. “There was a clear-cut signal that it made more sense to add adalimumab at that early juncture where a person is not quite doing well enough on methotrexate to satisfy our goal of getting the patient to low disease activity. It gives us as clinicians some ammunition to speak to our insurance formulary people on this side of the Atlantic, or [for] people in the U.K. to go to their local regulatory board that approves medicines and be able to show them some actual practically derived evidence about this very common question that comes up in practice,” senior and corresponding author Philip Mease, MD, said in an interview. The study was published online in The Lancet Rheumatology.

“When a clinician and patient are making the decision to move on from methotrexate monotherapy, either because of lack of efficacy or safety issues, tolerability issues, it makes most sense to add on a biologic medication such as a TNF inhibitor at that juncture, rather than intensifying methotrexate therapy,” said Dr. Mease, who is director of rheumatology research at Swedish Medical Center/Providence St. Joseph Health and a clinical professor at the University of Washington, both in Seattle.

Physicians may be tempted to bump up the dose for patients who can tolerate MTX and who may be showing some improvement, but the new study should prompt a different strategy if MDA isn’t achieved, according to Oliver FitzGerald, MD, a professor at the Conway Institute for Biomolecular Research at University College Dublin, who was asked to comment on the study. “This study clearly shows that the early addition of adalimumab is the better choice, and it would change practice. That being said, there are clearly some patients who do respond sufficiently to increasing methotrexate, and it would be useful to be able to predict which patients might do that.” He added that the study focused on adalimumab and that the results might not apply to other biologics.

The study should encourage use of a quantitative treat-to-target measure like MDA, which is a composite measure of patient perspectives, Dr. Mease said. The American College of Rheumatology and National Psoriasis Foundation and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis have recommended the use of MDA as a treat-to-target measure for PsA. The ACR and NPF recommend TNF inhibitors as first-line treatment, and GRAPPA includes it as a first-line option, whereas the European Alliance of Associations for Rheumatology recommends MTX only in the first line.

The study also suggests that there is value to using adalimumab on a weekly basis if an every-other-week schedule doesn’t produce the desired results. This strategy hasn’t been examined in PsA or even RA, according to Dr. Kavanaugh, who is a professor of medicine at the University of California, San Diego. “It did look like raising the dose might be an option for patients who are on every other week and are not doing quite as well as we would have hoped.”

The CONTROL study was a phase 4, two-part, open-label study. It included 245 patients in 14 countries who did not have MDA with MTX. In the first part of the study, patients were randomly assigned to receive weekly 15 mg MTX along with 40 mg adalimumab every other week, or escalation of MTX dose to 20-25 mg/week. MTX could be administered orally or intravenously. After 16 weeks (part 1), for patients who achieved MDA, current therapy was maintained or modified; for patients who did not achieve MDA, therapy was escalated over the following 16 weeks by giving adalimumab every week in the combination group or by adding adalimumab every other week in the MTX escalation arm.

Overall, 95% of the MTX plus adalimumab group completed part 1, as did 90% of the MTX escalation group. A total of 41% of the adalimumab group achieved MDA at 16 weeks versus 13% of the MTX group (P < .0001). The result held after accounting for sex and the interaction between sex and treatment (odds ratio, 4.6; 95% confidence interval, 2.4-8.9).

Among patients who achieved MDA at 16 weeks, 80% in the adalimumab group continued to have MDA at 32 weeks even after MTX had been withdrawn. Of those in the MTX escalation group, 67% continued to have MDA at 32 weeks with continued escalation of MTX.

Of the patients in the MTX escalation group who did not respond, 55% reached MDA following introduction of adalimumab every other week. Of those who did not respond to adalimumab, 30% reached MDA after switching to weekly adalimumab doses.

The study was open label, and patients who received adalimumab may have expected some improvement; that could have skewed the findings, Dr. Kavanaugh said. “I think that’s an important consideration as we interpret the data. The people who got the MTX arm probably had less of an expectation that they were going to do much better than those who switched to the adalimumab, as did the doctors taking care of them.”

The CONTROL study was funded by AbbVie. Dr. Mease has received research grants, consulted for, or received speaker honoraria from AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, Sun Pharma, and UCB. Dr. FitzGerald has received grant support and honoraria from AbbVie. Dr. Kavanaugh has received research support from or consulted for AbbVie, Janssen, Pfizer, Lilly, Novartis, and UCB.

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

For patients with psoriatic arthritis (PsA) whose condition doesn’t respond adequately to methotrexate, addition of the tumor necrosis factor (TNF) inhibitor adalimumab increased the likelihood of achieving minimum disease activity (MDA), compared with escalation of MTX dose, according to results from a phase 4, open-label study.

The new study is one of only a few to compare treatment protocols in a field that has seen new therapeutic options become available in recent years. That lack of evidence can leave patients and physicians uncertain about the next step if the initial results of treatment are disappointing.

“There are some gaps in our database and our understanding of psoriatic arthritis, compared to rheumatoid arthritis, where we have had many more studies over the years,” Arthur Kavanaugh, MD, told this news organization when asked to comment on the study.

The trial provides one answer, at least. “There was a clear-cut signal that it made more sense to add adalimumab at that early juncture where a person is not quite doing well enough on methotrexate to satisfy our goal of getting the patient to low disease activity. It gives us as clinicians some ammunition to speak to our insurance formulary people on this side of the Atlantic, or [for] people in the U.K. to go to their local regulatory board that approves medicines and be able to show them some actual practically derived evidence about this very common question that comes up in practice,” senior and corresponding author Philip Mease, MD, said in an interview. The study was published online in The Lancet Rheumatology.

“When a clinician and patient are making the decision to move on from methotrexate monotherapy, either because of lack of efficacy or safety issues, tolerability issues, it makes most sense to add on a biologic medication such as a TNF inhibitor at that juncture, rather than intensifying methotrexate therapy,” said Dr. Mease, who is director of rheumatology research at Swedish Medical Center/Providence St. Joseph Health and a clinical professor at the University of Washington, both in Seattle.

Physicians may be tempted to bump up the dose for patients who can tolerate MTX and who may be showing some improvement, but the new study should prompt a different strategy if MDA isn’t achieved, according to Oliver FitzGerald, MD, a professor at the Conway Institute for Biomolecular Research at University College Dublin, who was asked to comment on the study. “This study clearly shows that the early addition of adalimumab is the better choice, and it would change practice. That being said, there are clearly some patients who do respond sufficiently to increasing methotrexate, and it would be useful to be able to predict which patients might do that.” He added that the study focused on adalimumab and that the results might not apply to other biologics.

The study should encourage use of a quantitative treat-to-target measure like MDA, which is a composite measure of patient perspectives, Dr. Mease said. The American College of Rheumatology and National Psoriasis Foundation and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis have recommended the use of MDA as a treat-to-target measure for PsA. The ACR and NPF recommend TNF inhibitors as first-line treatment, and GRAPPA includes it as a first-line option, whereas the European Alliance of Associations for Rheumatology recommends MTX only in the first line.

The study also suggests that there is value to using adalimumab on a weekly basis if an every-other-week schedule doesn’t produce the desired results. This strategy hasn’t been examined in PsA or even RA, according to Dr. Kavanaugh, who is a professor of medicine at the University of California, San Diego. “It did look like raising the dose might be an option for patients who are on every other week and are not doing quite as well as we would have hoped.”

The CONTROL study was a phase 4, two-part, open-label study. It included 245 patients in 14 countries who did not have MDA with MTX. In the first part of the study, patients were randomly assigned to receive weekly 15 mg MTX along with 40 mg adalimumab every other week, or escalation of MTX dose to 20-25 mg/week. MTX could be administered orally or intravenously. After 16 weeks (part 1), for patients who achieved MDA, current therapy was maintained or modified; for patients who did not achieve MDA, therapy was escalated over the following 16 weeks by giving adalimumab every week in the combination group or by adding adalimumab every other week in the MTX escalation arm.

Overall, 95% of the MTX plus adalimumab group completed part 1, as did 90% of the MTX escalation group. A total of 41% of the adalimumab group achieved MDA at 16 weeks versus 13% of the MTX group (P < .0001). The result held after accounting for sex and the interaction between sex and treatment (odds ratio, 4.6; 95% confidence interval, 2.4-8.9).

Among patients who achieved MDA at 16 weeks, 80% in the adalimumab group continued to have MDA at 32 weeks even after MTX had been withdrawn. Of those in the MTX escalation group, 67% continued to have MDA at 32 weeks with continued escalation of MTX.

Of the patients in the MTX escalation group who did not respond, 55% reached MDA following introduction of adalimumab every other week. Of those who did not respond to adalimumab, 30% reached MDA after switching to weekly adalimumab doses.

The study was open label, and patients who received adalimumab may have expected some improvement; that could have skewed the findings, Dr. Kavanaugh said. “I think that’s an important consideration as we interpret the data. The people who got the MTX arm probably had less of an expectation that they were going to do much better than those who switched to the adalimumab, as did the doctors taking care of them.”

The CONTROL study was funded by AbbVie. Dr. Mease has received research grants, consulted for, or received speaker honoraria from AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, Sun Pharma, and UCB. Dr. FitzGerald has received grant support and honoraria from AbbVie. Dr. Kavanaugh has received research support from or consulted for AbbVie, Janssen, Pfizer, Lilly, Novartis, and UCB.

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

For patients with psoriatic arthritis (PsA) whose condition doesn’t respond adequately to methotrexate, addition of the tumor necrosis factor (TNF) inhibitor adalimumab increased the likelihood of achieving minimum disease activity (MDA), compared with escalation of MTX dose, according to results from a phase 4, open-label study.

The new study is one of only a few to compare treatment protocols in a field that has seen new therapeutic options become available in recent years. That lack of evidence can leave patients and physicians uncertain about the next step if the initial results of treatment are disappointing.

“There are some gaps in our database and our understanding of psoriatic arthritis, compared to rheumatoid arthritis, where we have had many more studies over the years,” Arthur Kavanaugh, MD, told this news organization when asked to comment on the study.

The trial provides one answer, at least. “There was a clear-cut signal that it made more sense to add adalimumab at that early juncture where a person is not quite doing well enough on methotrexate to satisfy our goal of getting the patient to low disease activity. It gives us as clinicians some ammunition to speak to our insurance formulary people on this side of the Atlantic, or [for] people in the U.K. to go to their local regulatory board that approves medicines and be able to show them some actual practically derived evidence about this very common question that comes up in practice,” senior and corresponding author Philip Mease, MD, said in an interview. The study was published online in The Lancet Rheumatology.

“When a clinician and patient are making the decision to move on from methotrexate monotherapy, either because of lack of efficacy or safety issues, tolerability issues, it makes most sense to add on a biologic medication such as a TNF inhibitor at that juncture, rather than intensifying methotrexate therapy,” said Dr. Mease, who is director of rheumatology research at Swedish Medical Center/Providence St. Joseph Health and a clinical professor at the University of Washington, both in Seattle.

Physicians may be tempted to bump up the dose for patients who can tolerate MTX and who may be showing some improvement, but the new study should prompt a different strategy if MDA isn’t achieved, according to Oliver FitzGerald, MD, a professor at the Conway Institute for Biomolecular Research at University College Dublin, who was asked to comment on the study. “This study clearly shows that the early addition of adalimumab is the better choice, and it would change practice. That being said, there are clearly some patients who do respond sufficiently to increasing methotrexate, and it would be useful to be able to predict which patients might do that.” He added that the study focused on adalimumab and that the results might not apply to other biologics.

The study should encourage use of a quantitative treat-to-target measure like MDA, which is a composite measure of patient perspectives, Dr. Mease said. The American College of Rheumatology and National Psoriasis Foundation and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis have recommended the use of MDA as a treat-to-target measure for PsA. The ACR and NPF recommend TNF inhibitors as first-line treatment, and GRAPPA includes it as a first-line option, whereas the European Alliance of Associations for Rheumatology recommends MTX only in the first line.

The study also suggests that there is value to using adalimumab on a weekly basis if an every-other-week schedule doesn’t produce the desired results. This strategy hasn’t been examined in PsA or even RA, according to Dr. Kavanaugh, who is a professor of medicine at the University of California, San Diego. “It did look like raising the dose might be an option for patients who are on every other week and are not doing quite as well as we would have hoped.”

The CONTROL study was a phase 4, two-part, open-label study. It included 245 patients in 14 countries who did not have MDA with MTX. In the first part of the study, patients were randomly assigned to receive weekly 15 mg MTX along with 40 mg adalimumab every other week, or escalation of MTX dose to 20-25 mg/week. MTX could be administered orally or intravenously. After 16 weeks (part 1), for patients who achieved MDA, current therapy was maintained or modified; for patients who did not achieve MDA, therapy was escalated over the following 16 weeks by giving adalimumab every week in the combination group or by adding adalimumab every other week in the MTX escalation arm.

Overall, 95% of the MTX plus adalimumab group completed part 1, as did 90% of the MTX escalation group. A total of 41% of the adalimumab group achieved MDA at 16 weeks versus 13% of the MTX group (P < .0001). The result held after accounting for sex and the interaction between sex and treatment (odds ratio, 4.6; 95% confidence interval, 2.4-8.9).

Among patients who achieved MDA at 16 weeks, 80% in the adalimumab group continued to have MDA at 32 weeks even after MTX had been withdrawn. Of those in the MTX escalation group, 67% continued to have MDA at 32 weeks with continued escalation of MTX.

Of the patients in the MTX escalation group who did not respond, 55% reached MDA following introduction of adalimumab every other week. Of those who did not respond to adalimumab, 30% reached MDA after switching to weekly adalimumab doses.

The study was open label, and patients who received adalimumab may have expected some improvement; that could have skewed the findings, Dr. Kavanaugh said. “I think that’s an important consideration as we interpret the data. The people who got the MTX arm probably had less of an expectation that they were going to do much better than those who switched to the adalimumab, as did the doctors taking care of them.”

The CONTROL study was funded by AbbVie. Dr. Mease has received research grants, consulted for, or received speaker honoraria from AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, Sun Pharma, and UCB. Dr. FitzGerald has received grant support and honoraria from AbbVie. Dr. Kavanaugh has received research support from or consulted for AbbVie, Janssen, Pfizer, Lilly, Novartis, and UCB.

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

Screening for conditions like lung cancer has the potential to save lives, but can also lead to diagnoses that have little clinical impact. Such overdiagnosis was illustrated in a recent study from JAMA Internal Medicine of women in Taiwan who were screened for lung cancer using low-dose CT (LDCT).

The study, and the accompanying editorial, pointed out the potential for large databases of routine clinical data to track long-term outcomes, and potentially identify patient subgroups that could benefit from early diagnosis using digital technologies.

The Taiwanese findings echo a similar trend identified in a 2018 post hoc analysis of the Danish Lung Cancer Screening Trial, which estimated that 67.2% of cancers found during that CT screening program for current or former smokers were overdiagnosed. The authors recommended that researchers report rates of overdiagnosis in future screening studies.

The authors of the Taiwan study noted that LDCT is low cost and is frequently offered to individuals who are not considered at high risk of lung cancer, and advertisements in Taiwan often target women, who rarely smoke. The researchers examined data from the Taiwan National Cancer Registry. They looked for evidence of an increased incidence of early-stage detection and reduced incidence of late-stage diagnosis. They found that, from 2004 to 2018, there was an increase of lung cancer incidence from 2.3 to 14.4 per 100,000 (difference, 12.1; 95% confidence interval, 11.3-12.8), but no significant difference in the incidence of late-stage disease (from 18.7 to 19.3 per 100,000; difference, 0.6; 95% CI, –0.5 to 1.7).

“This combination of findings, an additional 12.1 early-stage cancers per 100,000 population and no reduction in late-stage cancers, is strongly suggestive of overdiagnosis,” the authors wrote.

It can be difficult to convince people of the potential harms of overdiagnosis, especially when patients have a nodule removed and remain healthy years later. “It’s very counterintuitive, but it’s a reality, and I think this paper paints the reality very, very clearly,” said Daniel Capurro, MD, PhD, deputy director of the Centre for the Digital Transformation of Health at University of Melbourne, and an author of the editorial.

The issue is that some lung cancers progress so slowly that they may never cause a problem clinically, and their removal can lead to unnecessary cost and risk. And it’s not just cancer. “There are a bunch of other conditions that are defined by specific criteria, but we don’t add the prognosis to that definition. At the individual patient level, we don’t know the prognosis,” Dr. Capurro said.

Dr. Capurro discussed the increasing use of digital technologies like smartphone apps. Machine learning can potentially use such data to diagnose conditions like sleep or mood disorders before they become clinically significant, allowing earlier intervention, but they could also lead to overdiagnosis. Dr. Capurro proposed using longitudinal databases to track patient outcomes, which could be applied to digital screening technologies.

“You might be able to find unknown patterns that help discriminate between these pathological definitions. You should be able to train (digital screens) with the pathological definition plus the disease trajectory as a way to improve that label,” he said.

The study was funded by the Taiwan Ministry of Health and Welfare Clinical Trial Center.

Screening for conditions like lung cancer has the potential to save lives, but can also lead to diagnoses that have little clinical impact. Such overdiagnosis was illustrated in a recent study from JAMA Internal Medicine of women in Taiwan who were screened for lung cancer using low-dose CT (LDCT).

The study, and the accompanying editorial, pointed out the potential for large databases of routine clinical data to track long-term outcomes, and potentially identify patient subgroups that could benefit from early diagnosis using digital technologies.

The Taiwanese findings echo a similar trend identified in a 2018 post hoc analysis of the Danish Lung Cancer Screening Trial, which estimated that 67.2% of cancers found during that CT screening program for current or former smokers were overdiagnosed. The authors recommended that researchers report rates of overdiagnosis in future screening studies.

The authors of the Taiwan study noted that LDCT is low cost and is frequently offered to individuals who are not considered at high risk of lung cancer, and advertisements in Taiwan often target women, who rarely smoke. The researchers examined data from the Taiwan National Cancer Registry. They looked for evidence of an increased incidence of early-stage detection and reduced incidence of late-stage diagnosis. They found that, from 2004 to 2018, there was an increase of lung cancer incidence from 2.3 to 14.4 per 100,000 (difference, 12.1; 95% confidence interval, 11.3-12.8), but no significant difference in the incidence of late-stage disease (from 18.7 to 19.3 per 100,000; difference, 0.6; 95% CI, –0.5 to 1.7).

“This combination of findings, an additional 12.1 early-stage cancers per 100,000 population and no reduction in late-stage cancers, is strongly suggestive of overdiagnosis,” the authors wrote.

It can be difficult to convince people of the potential harms of overdiagnosis, especially when patients have a nodule removed and remain healthy years later. “It’s very counterintuitive, but it’s a reality, and I think this paper paints the reality very, very clearly,” said Daniel Capurro, MD, PhD, deputy director of the Centre for the Digital Transformation of Health at University of Melbourne, and an author of the editorial.

The issue is that some lung cancers progress so slowly that they may never cause a problem clinically, and their removal can lead to unnecessary cost and risk. And it’s not just cancer. “There are a bunch of other conditions that are defined by specific criteria, but we don’t add the prognosis to that definition. At the individual patient level, we don’t know the prognosis,” Dr. Capurro said.

Dr. Capurro discussed the increasing use of digital technologies like smartphone apps. Machine learning can potentially use such data to diagnose conditions like sleep or mood disorders before they become clinically significant, allowing earlier intervention, but they could also lead to overdiagnosis. Dr. Capurro proposed using longitudinal databases to track patient outcomes, which could be applied to digital screening technologies.

“You might be able to find unknown patterns that help discriminate between these pathological definitions. You should be able to train (digital screens) with the pathological definition plus the disease trajectory as a way to improve that label,” he said.

The study was funded by the Taiwan Ministry of Health and Welfare Clinical Trial Center.

Screening for conditions like lung cancer has the potential to save lives, but can also lead to diagnoses that have little clinical impact. Such overdiagnosis was illustrated in a recent study from JAMA Internal Medicine of women in Taiwan who were screened for lung cancer using low-dose CT (LDCT).

The study, and the accompanying editorial, pointed out the potential for large databases of routine clinical data to track long-term outcomes, and potentially identify patient subgroups that could benefit from early diagnosis using digital technologies.

The Taiwanese findings echo a similar trend identified in a 2018 post hoc analysis of the Danish Lung Cancer Screening Trial, which estimated that 67.2% of cancers found during that CT screening program for current or former smokers were overdiagnosed. The authors recommended that researchers report rates of overdiagnosis in future screening studies.

The authors of the Taiwan study noted that LDCT is low cost and is frequently offered to individuals who are not considered at high risk of lung cancer, and advertisements in Taiwan often target women, who rarely smoke. The researchers examined data from the Taiwan National Cancer Registry. They looked for evidence of an increased incidence of early-stage detection and reduced incidence of late-stage diagnosis. They found that, from 2004 to 2018, there was an increase of lung cancer incidence from 2.3 to 14.4 per 100,000 (difference, 12.1; 95% confidence interval, 11.3-12.8), but no significant difference in the incidence of late-stage disease (from 18.7 to 19.3 per 100,000; difference, 0.6; 95% CI, –0.5 to 1.7).

“This combination of findings, an additional 12.1 early-stage cancers per 100,000 population and no reduction in late-stage cancers, is strongly suggestive of overdiagnosis,” the authors wrote.

It can be difficult to convince people of the potential harms of overdiagnosis, especially when patients have a nodule removed and remain healthy years later. “It’s very counterintuitive, but it’s a reality, and I think this paper paints the reality very, very clearly,” said Daniel Capurro, MD, PhD, deputy director of the Centre for the Digital Transformation of Health at University of Melbourne, and an author of the editorial.

The issue is that some lung cancers progress so slowly that they may never cause a problem clinically, and their removal can lead to unnecessary cost and risk. And it’s not just cancer. “There are a bunch of other conditions that are defined by specific criteria, but we don’t add the prognosis to that definition. At the individual patient level, we don’t know the prognosis,” Dr. Capurro said.

Dr. Capurro discussed the increasing use of digital technologies like smartphone apps. Machine learning can potentially use such data to diagnose conditions like sleep or mood disorders before they become clinically significant, allowing earlier intervention, but they could also lead to overdiagnosis. Dr. Capurro proposed using longitudinal databases to track patient outcomes, which could be applied to digital screening technologies.

“You might be able to find unknown patterns that help discriminate between these pathological definitions. You should be able to train (digital screens) with the pathological definition plus the disease trajectory as a way to improve that label,” he said.

The study was funded by the Taiwan Ministry of Health and Welfare Clinical Trial Center.

A topical formulation of fluticasone designed to dissolve and coat the esophagus appears safe and effective for the treatment of eosinophilic esophagitis (EOE), according to new results from a phase 2b study. The results pave the way for phase 3 clinical trials.

Topical steroids are frequently used off-label for EOE. They may be repurposed from nebulizers used for asthma, with patients mixing the drugs themselves or sending them to a pharmacy to be compounded. Patients remove the spacer from a nebulizer in order to swallow the active compound or mix the liquid that would be nebulized with honey or Splenda to thicken it to maximize its contact with the esophagus. “Both of these things are very cumbersome and difficult. I get a lot of complaints from patients [that] it doesn’t taste good. So, the fact that we have a drug that we are already using, but it’s designed for the esophagus, is really exciting,” said Nielsen Fernandez-Becker, MD, PhD, of the department of gastroenterology and hepatology at Stanford (Calif.) University. Dr. Fernandez-Becker referred some patients to the trial and performed some procedures.

javi_indy/ Thinkstock

“I don’t think the findings are unexpected, given what we’ve seen with swallowed inhalers with fluticasone, but I think the real importance of this is that it does look like a dedicated swallow form works. And if this leads to [Food and Drug Administration] approval, then I think that that really becomes a game-changer for this EOE population. Getting something that’s FDA approved to treat this disorder is a key unmet need,” said John Clarke, MD, who was not involved in the study.

He also pointed out that the safety profile of the drug appears good with respect to both candidiasis and adrenal suppression. “It at least seems comparable, if not better than what we’re currently doing with the inhaler,” said Dr. Clarke, a clinical professor of medicine and director of the esophagus program at Stanford University.

Current options for EOE are limited primarily to the use of proton pump inhibitors and food-elimination diets. Oral budesonide is available to patients in Europe and under investigation in the United States.

The new formulation (APT-1011, Ellodi Pharmaceuticals) is meant to be taken without water and dissolves on the tongue and then coats the esophagus.

In the phase 2b study published in Clinical Gastroenterology and Hepatology, researchers randomized 106 adults from six countries with EOE to receive one of four doses of APT-1011, or placebo. Participants had to have current symptoms of dysphagia and active disease after no histologic response from at least 8 weeks of high-dose (20-40 mg/day) proton pump inhibitors. The study included a placebo-controlled, 12-week induction period followed by 40 weeks of maintenance therapy with no placebo arm. The researchers considered a count of fewer than six eosinophils per high-powered field, as measured during an esophageal biopsy, to be a histologic response.

No patients in the placebo group had a response. The response rate was 80% among patients taking a 3-mg dose twice per day; 67% among those taking a 3-mg dose only at bedtime; 86% for those taking 1.5 mg twice per day; and 48% for 1.5 mg only at bedtime (P < .001 for all comparisons to placebo).

After 12 weeks, EOE Endoscopic Reference Score (EREFS) improved from 4.5 to 2.3 in the 3-mg b.i.d. group (5.3-2.1 for bedtime only), and from 4.6 to 1.7 for the 1.5-mg b.i.d. group (5.3-2.9 for 1.5 bedtime only). In the placebo group, the change was from 5.2 to 4.5.

Among those who responded during the induction period, the majority continued to be responders at weeks 26 and 52, including the 3-mg b.i.d. group (88% and 69%, respectively), the 3-mg bedtime-only group (79% and 64%), the 1.5-mg b.i.d. group (89% and 84%), and the 1.5-mg bedtime-only group (70% and 30%).

If approved, the new formulation will likely have a big impact on EOE patients, according to Dr. Fernandez-Becker. “The treatment that we decide on ultimately is through shared decision-making with the physician and the patient. I have many patients who want to go with diet, but it’s very difficult and it takes a long time to tailor the therapy, and many patients are not interested in proton pump inhibitors. So topical steroids are something that I prescribe a lot for patients,” she said.

The fact that the formulation is based on a drug with a known safety record is encouraging, but more research needs to be done. “I don’t expect that this would be any different, but that’s something that’s going to be studied,” said Dr. Fernandez-Becker.

The study was funded by Ellodi Pharmaceuticals. Dr. Clarke has no relevant financial disclosures. Dr. Fernandez-Becker has no relevant financial disclosures but was a participant in the study.

A topical formulation of fluticasone designed to dissolve and coat the esophagus appears safe and effective for the treatment of eosinophilic esophagitis (EOE), according to new results from a phase 2b study. The results pave the way for phase 3 clinical trials.

Topical steroids are frequently used off-label for EOE. They may be repurposed from nebulizers used for asthma, with patients mixing the drugs themselves or sending them to a pharmacy to be compounded. Patients remove the spacer from a nebulizer in order to swallow the active compound or mix the liquid that would be nebulized with honey or Splenda to thicken it to maximize its contact with the esophagus. “Both of these things are very cumbersome and difficult. I get a lot of complaints from patients [that] it doesn’t taste good. So, the fact that we have a drug that we are already using, but it’s designed for the esophagus, is really exciting,” said Nielsen Fernandez-Becker, MD, PhD, of the department of gastroenterology and hepatology at Stanford (Calif.) University. Dr. Fernandez-Becker referred some patients to the trial and performed some procedures.

javi_indy/ Thinkstock

“I don’t think the findings are unexpected, given what we’ve seen with swallowed inhalers with fluticasone, but I think the real importance of this is that it does look like a dedicated swallow form works. And if this leads to [Food and Drug Administration] approval, then I think that that really becomes a game-changer for this EOE population. Getting something that’s FDA approved to treat this disorder is a key unmet need,” said John Clarke, MD, who was not involved in the study.

He also pointed out that the safety profile of the drug appears good with respect to both candidiasis and adrenal suppression. “It at least seems comparable, if not better than what we’re currently doing with the inhaler,” said Dr. Clarke, a clinical professor of medicine and director of the esophagus program at Stanford University.

Current options for EOE are limited primarily to the use of proton pump inhibitors and food-elimination diets. Oral budesonide is available to patients in Europe and under investigation in the United States.

The new formulation (APT-1011, Ellodi Pharmaceuticals) is meant to be taken without water and dissolves on the tongue and then coats the esophagus.

In the phase 2b study published in Clinical Gastroenterology and Hepatology, researchers randomized 106 adults from six countries with EOE to receive one of four doses of APT-1011, or placebo. Participants had to have current symptoms of dysphagia and active disease after no histologic response from at least 8 weeks of high-dose (20-40 mg/day) proton pump inhibitors. The study included a placebo-controlled, 12-week induction period followed by 40 weeks of maintenance therapy with no placebo arm. The researchers considered a count of fewer than six eosinophils per high-powered field, as measured during an esophageal biopsy, to be a histologic response.

No patients in the placebo group had a response. The response rate was 80% among patients taking a 3-mg dose twice per day; 67% among those taking a 3-mg dose only at bedtime; 86% for those taking 1.5 mg twice per day; and 48% for 1.5 mg only at bedtime (P < .001 for all comparisons to placebo).

After 12 weeks, EOE Endoscopic Reference Score (EREFS) improved from 4.5 to 2.3 in the 3-mg b.i.d. group (5.3-2.1 for bedtime only), and from 4.6 to 1.7 for the 1.5-mg b.i.d. group (5.3-2.9 for 1.5 bedtime only). In the placebo group, the change was from 5.2 to 4.5.

Among those who responded during the induction period, the majority continued to be responders at weeks 26 and 52, including the 3-mg b.i.d. group (88% and 69%, respectively), the 3-mg bedtime-only group (79% and 64%), the 1.5-mg b.i.d. group (89% and 84%), and the 1.5-mg bedtime-only group (70% and 30%).

If approved, the new formulation will likely have a big impact on EOE patients, according to Dr. Fernandez-Becker. “The treatment that we decide on ultimately is through shared decision-making with the physician and the patient. I have many patients who want to go with diet, but it’s very difficult and it takes a long time to tailor the therapy, and many patients are not interested in proton pump inhibitors. So topical steroids are something that I prescribe a lot for patients,” she said.

The fact that the formulation is based on a drug with a known safety record is encouraging, but more research needs to be done. “I don’t expect that this would be any different, but that’s something that’s going to be studied,” said Dr. Fernandez-Becker.

The study was funded by Ellodi Pharmaceuticals. Dr. Clarke has no relevant financial disclosures. Dr. Fernandez-Becker has no relevant financial disclosures but was a participant in the study.

A topical formulation of fluticasone designed to dissolve and coat the esophagus appears safe and effective for the treatment of eosinophilic esophagitis (EOE), according to new results from a phase 2b study. The results pave the way for phase 3 clinical trials.

Topical steroids are frequently used off-label for EOE. They may be repurposed from nebulizers used for asthma, with patients mixing the drugs themselves or sending them to a pharmacy to be compounded. Patients remove the spacer from a nebulizer in order to swallow the active compound or mix the liquid that would be nebulized with honey or Splenda to thicken it to maximize its contact with the esophagus. “Both of these things are very cumbersome and difficult. I get a lot of complaints from patients [that] it doesn’t taste good. So, the fact that we have a drug that we are already using, but it’s designed for the esophagus, is really exciting,” said Nielsen Fernandez-Becker, MD, PhD, of the department of gastroenterology and hepatology at Stanford (Calif.) University. Dr. Fernandez-Becker referred some patients to the trial and performed some procedures.

javi_indy/ Thinkstock

“I don’t think the findings are unexpected, given what we’ve seen with swallowed inhalers with fluticasone, but I think the real importance of this is that it does look like a dedicated swallow form works. And if this leads to [Food and Drug Administration] approval, then I think that that really becomes a game-changer for this EOE population. Getting something that’s FDA approved to treat this disorder is a key unmet need,” said John Clarke, MD, who was not involved in the study.

He also pointed out that the safety profile of the drug appears good with respect to both candidiasis and adrenal suppression. “It at least seems comparable, if not better than what we’re currently doing with the inhaler,” said Dr. Clarke, a clinical professor of medicine and director of the esophagus program at Stanford University.

Current options for EOE are limited primarily to the use of proton pump inhibitors and food-elimination diets. Oral budesonide is available to patients in Europe and under investigation in the United States.

The new formulation (APT-1011, Ellodi Pharmaceuticals) is meant to be taken without water and dissolves on the tongue and then coats the esophagus.

In the phase 2b study published in Clinical Gastroenterology and Hepatology, researchers randomized 106 adults from six countries with EOE to receive one of four doses of APT-1011, or placebo. Participants had to have current symptoms of dysphagia and active disease after no histologic response from at least 8 weeks of high-dose (20-40 mg/day) proton pump inhibitors. The study included a placebo-controlled, 12-week induction period followed by 40 weeks of maintenance therapy with no placebo arm. The researchers considered a count of fewer than six eosinophils per high-powered field, as measured during an esophageal biopsy, to be a histologic response.

No patients in the placebo group had a response. The response rate was 80% among patients taking a 3-mg dose twice per day; 67% among those taking a 3-mg dose only at bedtime; 86% for those taking 1.5 mg twice per day; and 48% for 1.5 mg only at bedtime (P < .001 for all comparisons to placebo).

After 12 weeks, EOE Endoscopic Reference Score (EREFS) improved from 4.5 to 2.3 in the 3-mg b.i.d. group (5.3-2.1 for bedtime only), and from 4.6 to 1.7 for the 1.5-mg b.i.d. group (5.3-2.9 for 1.5 bedtime only). In the placebo group, the change was from 5.2 to 4.5.

Among those who responded during the induction period, the majority continued to be responders at weeks 26 and 52, including the 3-mg b.i.d. group (88% and 69%, respectively), the 3-mg bedtime-only group (79% and 64%), the 1.5-mg b.i.d. group (89% and 84%), and the 1.5-mg bedtime-only group (70% and 30%).

If approved, the new formulation will likely have a big impact on EOE patients, according to Dr. Fernandez-Becker. “The treatment that we decide on ultimately is through shared decision-making with the physician and the patient. I have many patients who want to go with diet, but it’s very difficult and it takes a long time to tailor the therapy, and many patients are not interested in proton pump inhibitors. So topical steroids are something that I prescribe a lot for patients,” she said.

The fact that the formulation is based on a drug with a known safety record is encouraging, but more research needs to be done. “I don’t expect that this would be any different, but that’s something that’s going to be studied,” said Dr. Fernandez-Becker.

The study was funded by Ellodi Pharmaceuticals. Dr. Clarke has no relevant financial disclosures. Dr. Fernandez-Becker has no relevant financial disclosures but was a participant in the study.

Among patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD) receiving ocrelizumab or rituximab, B cell depletion appears to last well past the 6-month dosing regimen typically used with these drugs. The results, drawn from a retrospective analysis, provide support for clinical trials to rest longer re-infusion intervals.

The study appeared online Jan. 21 in the journal Multiple Sclerosis and Related Disorders, presented by lead author Mahmoud AbdelRazek, MD, at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Both drugs were approved based on clinical trials that investigated 6-month doses, but previous studies have suggested depletion can last longer, including a range of 9-26 months in the case of rituximab.

The initial rationale for monitoring B cell depletion was to prevent a relapse by re-infusing a patient if B cells levels rise, but the researchers noted a pattern of sustained depletion, especially in patients who had a delayed infusion for some reason – they often still had low B cell counts at the time of the next drug infusion. “That became not an unusual finding,” said Dr. AbdelRazek in an interview. He is an instructor of neurology at Harvard Medical School.

Patients also found the delay appealing, in part because they often felt unwell in the days following an infusion, and delays could mean fewer infections and other adverse effects. “Most of my patients I’ve discussed this with would be very appreciative of that delay,” said Dr. AbdelRazek. “There’s obviously an economic benefit as well,” said Dr. AbdelRazek.
 

The final answer?

The retrospective nature of the study is a key weakness, and the rationale to delay infusions based on continuing B cell depletion assumes that B cell depletion is in fact the mechanism of action for countering MS. “That is a critical question,” said Mark Gudesblatt, MD, who was asked to comment on the study. But if that is indeed the way the drugs work, then it would make sense to identify patients who repopulate B cells more slowly and tailor drug regimens. “It’s not one size fits all and blindly just re-dosing. The upsides are good: You come in less frequently for dosing, the cost to payers is less. But the bad is, maybe there are other markers. This is the putative mechanism, but what we believe may not be the final answer. There may be more to the story,” said Dr. Gutesblatt, who is Medical Director at South Shore Neurologic Associates, Patchogue, New York.

Dr. AbdelRazek also noted the study’s limitation. “I think a clinical trial is going to be warranted to really have this translated into clinical practice,” he said. His group is planning to conduct just such a trial, pending confirmation of a funding source.
 

B cell depletion beyond 6 months

The researchers analyzed data from 178 patients with MS and 10 patients with NMOSD who received ocrelizumab (n = 111) or rituximab (n = 53), or both (n = 24) at two Harvard Medical School teaching hospitals between 2010 and 2020. The data included 800 infusions and 1,054 CD19 measurements.

The researchers defined B cell depletion as an absolute count of 20 cells/uL or less, a B cell percentage of 2% or less, or if B cells were 5% or less of total lymphocytes.

Among the patient population, B cell depletion that met all 3 criteria occurred as long as 13.8 months after an initial ocrelizumab infusion cycle, and 22.8 months after second or more cycles of ocrelizumab. Following rituximab, the researchers noted B cell depletions. Following 500 mg of rituximab, B cell depletion defined by the first, second, or third criteria occurred as far out as 22.3, 26.2, and 28.5 months. For 1,000 mg doses of rituximab, B cell depletion occurred as long as 18.3, 18.3, and 29.1 months after a dose.

Examining 90 B cell measurements conducted at least 8 months after an ocrelizumab infusion, 50% were depleted by the first definition and 54% by the second definition. At 13 months, the figures were 58% and 62% among 26 B-cell measurements. Eight months or more after rituximab, 113 B-cell measurements showed rates of 43% and 52% B-cell depletion by the first two criteria.

Dr. AbdelRazek and Dr. Gudesblatt have no relevant financial disclosures.

Among patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD) receiving ocrelizumab or rituximab, B cell depletion appears to last well past the 6-month dosing regimen typically used with these drugs. The results, drawn from a retrospective analysis, provide support for clinical trials to rest longer re-infusion intervals.

The study appeared online Jan. 21 in the journal Multiple Sclerosis and Related Disorders, presented by lead author Mahmoud AbdelRazek, MD, at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Both drugs were approved based on clinical trials that investigated 6-month doses, but previous studies have suggested depletion can last longer, including a range of 9-26 months in the case of rituximab.

The initial rationale for monitoring B cell depletion was to prevent a relapse by re-infusing a patient if B cells levels rise, but the researchers noted a pattern of sustained depletion, especially in patients who had a delayed infusion for some reason – they often still had low B cell counts at the time of the next drug infusion. “That became not an unusual finding,” said Dr. AbdelRazek in an interview. He is an instructor of neurology at Harvard Medical School.

Patients also found the delay appealing, in part because they often felt unwell in the days following an infusion, and delays could mean fewer infections and other adverse effects. “Most of my patients I’ve discussed this with would be very appreciative of that delay,” said Dr. AbdelRazek. “There’s obviously an economic benefit as well,” said Dr. AbdelRazek.
 

The final answer?

The retrospective nature of the study is a key weakness, and the rationale to delay infusions based on continuing B cell depletion assumes that B cell depletion is in fact the mechanism of action for countering MS. “That is a critical question,” said Mark Gudesblatt, MD, who was asked to comment on the study. But if that is indeed the way the drugs work, then it would make sense to identify patients who repopulate B cells more slowly and tailor drug regimens. “It’s not one size fits all and blindly just re-dosing. The upsides are good: You come in less frequently for dosing, the cost to payers is less. But the bad is, maybe there are other markers. This is the putative mechanism, but what we believe may not be the final answer. There may be more to the story,” said Dr. Gutesblatt, who is Medical Director at South Shore Neurologic Associates, Patchogue, New York.

Dr. AbdelRazek also noted the study’s limitation. “I think a clinical trial is going to be warranted to really have this translated into clinical practice,” he said. His group is planning to conduct just such a trial, pending confirmation of a funding source.
 

B cell depletion beyond 6 months

The researchers analyzed data from 178 patients with MS and 10 patients with NMOSD who received ocrelizumab (n = 111) or rituximab (n = 53), or both (n = 24) at two Harvard Medical School teaching hospitals between 2010 and 2020. The data included 800 infusions and 1,054 CD19 measurements.

The researchers defined B cell depletion as an absolute count of 20 cells/uL or less, a B cell percentage of 2% or less, or if B cells were 5% or less of total lymphocytes.

Among the patient population, B cell depletion that met all 3 criteria occurred as long as 13.8 months after an initial ocrelizumab infusion cycle, and 22.8 months after second or more cycles of ocrelizumab. Following rituximab, the researchers noted B cell depletions. Following 500 mg of rituximab, B cell depletion defined by the first, second, or third criteria occurred as far out as 22.3, 26.2, and 28.5 months. For 1,000 mg doses of rituximab, B cell depletion occurred as long as 18.3, 18.3, and 29.1 months after a dose.

Examining 90 B cell measurements conducted at least 8 months after an ocrelizumab infusion, 50% were depleted by the first definition and 54% by the second definition. At 13 months, the figures were 58% and 62% among 26 B-cell measurements. Eight months or more after rituximab, 113 B-cell measurements showed rates of 43% and 52% B-cell depletion by the first two criteria.

Dr. AbdelRazek and Dr. Gudesblatt have no relevant financial disclosures.

Among patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD) receiving ocrelizumab or rituximab, B cell depletion appears to last well past the 6-month dosing regimen typically used with these drugs. The results, drawn from a retrospective analysis, provide support for clinical trials to rest longer re-infusion intervals.

The study appeared online Jan. 21 in the journal Multiple Sclerosis and Related Disorders, presented by lead author Mahmoud AbdelRazek, MD, at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Both drugs were approved based on clinical trials that investigated 6-month doses, but previous studies have suggested depletion can last longer, including a range of 9-26 months in the case of rituximab.

The initial rationale for monitoring B cell depletion was to prevent a relapse by re-infusing a patient if B cells levels rise, but the researchers noted a pattern of sustained depletion, especially in patients who had a delayed infusion for some reason – they often still had low B cell counts at the time of the next drug infusion. “That became not an unusual finding,” said Dr. AbdelRazek in an interview. He is an instructor of neurology at Harvard Medical School.

Patients also found the delay appealing, in part because they often felt unwell in the days following an infusion, and delays could mean fewer infections and other adverse effects. “Most of my patients I’ve discussed this with would be very appreciative of that delay,” said Dr. AbdelRazek. “There’s obviously an economic benefit as well,” said Dr. AbdelRazek.
 

The final answer?

The retrospective nature of the study is a key weakness, and the rationale to delay infusions based on continuing B cell depletion assumes that B cell depletion is in fact the mechanism of action for countering MS. “That is a critical question,” said Mark Gudesblatt, MD, who was asked to comment on the study. But if that is indeed the way the drugs work, then it would make sense to identify patients who repopulate B cells more slowly and tailor drug regimens. “It’s not one size fits all and blindly just re-dosing. The upsides are good: You come in less frequently for dosing, the cost to payers is less. But the bad is, maybe there are other markers. This is the putative mechanism, but what we believe may not be the final answer. There may be more to the story,” said Dr. Gutesblatt, who is Medical Director at South Shore Neurologic Associates, Patchogue, New York.

Dr. AbdelRazek also noted the study’s limitation. “I think a clinical trial is going to be warranted to really have this translated into clinical practice,” he said. His group is planning to conduct just such a trial, pending confirmation of a funding source.
 

B cell depletion beyond 6 months

The researchers analyzed data from 178 patients with MS and 10 patients with NMOSD who received ocrelizumab (n = 111) or rituximab (n = 53), or both (n = 24) at two Harvard Medical School teaching hospitals between 2010 and 2020. The data included 800 infusions and 1,054 CD19 measurements.

The researchers defined B cell depletion as an absolute count of 20 cells/uL or less, a B cell percentage of 2% or less, or if B cells were 5% or less of total lymphocytes.

Among the patient population, B cell depletion that met all 3 criteria occurred as long as 13.8 months after an initial ocrelizumab infusion cycle, and 22.8 months after second or more cycles of ocrelizumab. Following rituximab, the researchers noted B cell depletions. Following 500 mg of rituximab, B cell depletion defined by the first, second, or third criteria occurred as far out as 22.3, 26.2, and 28.5 months. For 1,000 mg doses of rituximab, B cell depletion occurred as long as 18.3, 18.3, and 29.1 months after a dose.

Examining 90 B cell measurements conducted at least 8 months after an ocrelizumab infusion, 50% were depleted by the first definition and 54% by the second definition. At 13 months, the figures were 58% and 62% among 26 B-cell measurements. Eight months or more after rituximab, 113 B-cell measurements showed rates of 43% and 52% B-cell depletion by the first two criteria.

Dr. AbdelRazek and Dr. Gudesblatt have no relevant financial disclosures.

A new expert commentary from the American Gastroenterological Association focuses on noninvasive screening options for colorectal cancer (CRC), as well as approaches to ensure quality in noninvasive screening programs. The commentary was published in Gastroenterology.

The American Cancer Society reported in its Cancer Facts & Figures 2021 report that lifetime risk of CRC in the United States is 4%, and those with above average risk are recommended to undergo CRC screening at an earlier age, with colonoscopy as a screening modality. Between 75% and 80% of the U.S. population is considered at average risk, and this is the group covered by the expert commentary. In this group, CRC rates jump from 35.1 to 61.2 cases per 100,000 people between the ages of 45-49 years and 50-54 years. Early-onset (before 50) CRC accounts for 12% of all cases and 7% of CRC-related deaths.

The authors noted that the U.S. Preventive Services Task Force made a grade B recommendation for individuals to begin screening at age 45, regardless of screening method, and their modeling suggests that screening initialization at 45 rather than 50 years increases life-years gained by 6.2% at the cost of a 17% increase in colonoscopies.

According to the commentary authors, a hybrid approach combining annual fecal immunochemical testing (FIT) at age 45-49, followed by colonoscopy between ages 50 and 70, could result in substantial gains in life-years while prioritizing colonoscopies for advancing age, which is associated with increased risk of advanced adenomas (AA) and CRC.
 

Exploring options

For stool-based CRC screening, FIT has generally replaced guaiac fecal occult blood testing because of better patient adherence and fewer restrictions on medicine and diet. FIT can produce a quantitative result measured in micrograms of hemoglobin per gram, or qualitatively positive above a threshold of 20 mcg per gram. The MTsDNA (Cologuard) test combines FIT with two DNA methylation markers, KRAS mutation screening, and a measurement of total human DNA, with use of an algorithm of combined results to determine positivity. It is approved only for average-risk individuals aged 45-85.

In cases where MTsDNA tests positive, but colonoscopy reveals no findings, an aerodigestive cancer could be present. However, this is considered rare based on a study that revealed that 2.4% of patients with discordant results developed an aerodigestive cancer during a median 5.4 years of follow-up, compared with 1.1% of cases with negative MTsDNA and negative colonoscopy. The difference was not statistically significant. The commentary authors suggest that no further testing is required after a negative high-quality colonoscopy and that patients can resume screening at normal intervals with any of the recommended tests.

The Septin 9 blood test (Epi proColon) is another screening option, and is FDA approved for average-risk individuals older than 50 years. It detects methylation of the promoter region of the Septin 9 gene. It has a 48% sensitivity and 91.5% specificity for CRC, as well as a sensitivity of 11.2% for AA. One model found that Septin 9 screening every 1 or 2 years could lead to more quality-adjusted life-years gained and prevention of more deaths than annual FIT, but with more colonoscopies. CRC screening guidelines do not endorse Septin 9, but screening studies are in progress to assess its performance.
 

Ensuring quality

“The linchpin for effective noninvasive screening programs is adherence, and several measures of adherence are required,” the authors wrote. To ensure high quality of noninvasive screening programs, it is important to create metrics and employ continuous monitoring of compliance, and to initiate changes when adherence and outcomes lag. Important metrics include patient compliance, rapid reporting of test results, timely implementation of follow-up colonoscopies, and systems put in place to restore patients to appropriate CRC screening intervals.

The authors suggested several specific metrics and attainable performance goals. The ratio of tests completed within 1 year to tests ordered should reach 90% or more. Outreach should be conducted to patients who do not complete testing within 1 month of the order. All patients should be contacted with 2 weeks of test results, and those who test negative should be made aware of the appropriate interval for future screening, along with the method of contact.

At least 80% of patients who receive a positive test should be offered a colonoscopy date within 3 months, and all within 6 months, because delay past that time is associated with greater risk of AA, CRC, and advanced-stage CRC. Within 6 months of a positive noninvasive test, at least 95% of patients should have undergone a colonoscopy, unless they are too ill, have moved, or cannot be reached. “Quality metrics for noninvasive screening programs should be set and program performance should be measured and ideally reported publicly,” the authors summarized. “Poor adherence at any level should trigger review of established protocols and facilitate change to ensure high-quality screening.”

Two authors disclosed relationships with Freenome and/or Check-Cap, but the third disclosed no conflicts.
 

A new expert commentary from the American Gastroenterological Association focuses on noninvasive screening options for colorectal cancer (CRC), as well as approaches to ensure quality in noninvasive screening programs. The commentary was published in Gastroenterology.

The American Cancer Society reported in its Cancer Facts & Figures 2021 report that lifetime risk of CRC in the United States is 4%, and those with above average risk are recommended to undergo CRC screening at an earlier age, with colonoscopy as a screening modality. Between 75% and 80% of the U.S. population is considered at average risk, and this is the group covered by the expert commentary. In this group, CRC rates jump from 35.1 to 61.2 cases per 100,000 people between the ages of 45-49 years and 50-54 years. Early-onset (before 50) CRC accounts for 12% of all cases and 7% of CRC-related deaths.

The authors noted that the U.S. Preventive Services Task Force made a grade B recommendation for individuals to begin screening at age 45, regardless of screening method, and their modeling suggests that screening initialization at 45 rather than 50 years increases life-years gained by 6.2% at the cost of a 17% increase in colonoscopies.

According to the commentary authors, a hybrid approach combining annual fecal immunochemical testing (FIT) at age 45-49, followed by colonoscopy between ages 50 and 70, could result in substantial gains in life-years while prioritizing colonoscopies for advancing age, which is associated with increased risk of advanced adenomas (AA) and CRC.
 

Exploring options

For stool-based CRC screening, FIT has generally replaced guaiac fecal occult blood testing because of better patient adherence and fewer restrictions on medicine and diet. FIT can produce a quantitative result measured in micrograms of hemoglobin per gram, or qualitatively positive above a threshold of 20 mcg per gram. The MTsDNA (Cologuard) test combines FIT with two DNA methylation markers, KRAS mutation screening, and a measurement of total human DNA, with use of an algorithm of combined results to determine positivity. It is approved only for average-risk individuals aged 45-85.

In cases where MTsDNA tests positive, but colonoscopy reveals no findings, an aerodigestive cancer could be present. However, this is considered rare based on a study that revealed that 2.4% of patients with discordant results developed an aerodigestive cancer during a median 5.4 years of follow-up, compared with 1.1% of cases with negative MTsDNA and negative colonoscopy. The difference was not statistically significant. The commentary authors suggest that no further testing is required after a negative high-quality colonoscopy and that patients can resume screening at normal intervals with any of the recommended tests.

The Septin 9 blood test (Epi proColon) is another screening option, and is FDA approved for average-risk individuals older than 50 years. It detects methylation of the promoter region of the Septin 9 gene. It has a 48% sensitivity and 91.5% specificity for CRC, as well as a sensitivity of 11.2% for AA. One model found that Septin 9 screening every 1 or 2 years could lead to more quality-adjusted life-years gained and prevention of more deaths than annual FIT, but with more colonoscopies. CRC screening guidelines do not endorse Septin 9, but screening studies are in progress to assess its performance.
 

Ensuring quality

“The linchpin for effective noninvasive screening programs is adherence, and several measures of adherence are required,” the authors wrote. To ensure high quality of noninvasive screening programs, it is important to create metrics and employ continuous monitoring of compliance, and to initiate changes when adherence and outcomes lag. Important metrics include patient compliance, rapid reporting of test results, timely implementation of follow-up colonoscopies, and systems put in place to restore patients to appropriate CRC screening intervals.

The authors suggested several specific metrics and attainable performance goals. The ratio of tests completed within 1 year to tests ordered should reach 90% or more. Outreach should be conducted to patients who do not complete testing within 1 month of the order. All patients should be contacted with 2 weeks of test results, and those who test negative should be made aware of the appropriate interval for future screening, along with the method of contact.

At least 80% of patients who receive a positive test should be offered a colonoscopy date within 3 months, and all within 6 months, because delay past that time is associated with greater risk of AA, CRC, and advanced-stage CRC. Within 6 months of a positive noninvasive test, at least 95% of patients should have undergone a colonoscopy, unless they are too ill, have moved, or cannot be reached. “Quality metrics for noninvasive screening programs should be set and program performance should be measured and ideally reported publicly,” the authors summarized. “Poor adherence at any level should trigger review of established protocols and facilitate change to ensure high-quality screening.”

Two authors disclosed relationships with Freenome and/or Check-Cap, but the third disclosed no conflicts.
 

A new expert commentary from the American Gastroenterological Association focuses on noninvasive screening options for colorectal cancer (CRC), as well as approaches to ensure quality in noninvasive screening programs. The commentary was published in Gastroenterology.

The American Cancer Society reported in its Cancer Facts & Figures 2021 report that lifetime risk of CRC in the United States is 4%, and those with above average risk are recommended to undergo CRC screening at an earlier age, with colonoscopy as a screening modality. Between 75% and 80% of the U.S. population is considered at average risk, and this is the group covered by the expert commentary. In this group, CRC rates jump from 35.1 to 61.2 cases per 100,000 people between the ages of 45-49 years and 50-54 years. Early-onset (before 50) CRC accounts for 12% of all cases and 7% of CRC-related deaths.

The authors noted that the U.S. Preventive Services Task Force made a grade B recommendation for individuals to begin screening at age 45, regardless of screening method, and their modeling suggests that screening initialization at 45 rather than 50 years increases life-years gained by 6.2% at the cost of a 17% increase in colonoscopies.

According to the commentary authors, a hybrid approach combining annual fecal immunochemical testing (FIT) at age 45-49, followed by colonoscopy between ages 50 and 70, could result in substantial gains in life-years while prioritizing colonoscopies for advancing age, which is associated with increased risk of advanced adenomas (AA) and CRC.
 

Exploring options

For stool-based CRC screening, FIT has generally replaced guaiac fecal occult blood testing because of better patient adherence and fewer restrictions on medicine and diet. FIT can produce a quantitative result measured in micrograms of hemoglobin per gram, or qualitatively positive above a threshold of 20 mcg per gram. The MTsDNA (Cologuard) test combines FIT with two DNA methylation markers, KRAS mutation screening, and a measurement of total human DNA, with use of an algorithm of combined results to determine positivity. It is approved only for average-risk individuals aged 45-85.

In cases where MTsDNA tests positive, but colonoscopy reveals no findings, an aerodigestive cancer could be present. However, this is considered rare based on a study that revealed that 2.4% of patients with discordant results developed an aerodigestive cancer during a median 5.4 years of follow-up, compared with 1.1% of cases with negative MTsDNA and negative colonoscopy. The difference was not statistically significant. The commentary authors suggest that no further testing is required after a negative high-quality colonoscopy and that patients can resume screening at normal intervals with any of the recommended tests.

The Septin 9 blood test (Epi proColon) is another screening option, and is FDA approved for average-risk individuals older than 50 years. It detects methylation of the promoter region of the Septin 9 gene. It has a 48% sensitivity and 91.5% specificity for CRC, as well as a sensitivity of 11.2% for AA. One model found that Septin 9 screening every 1 or 2 years could lead to more quality-adjusted life-years gained and prevention of more deaths than annual FIT, but with more colonoscopies. CRC screening guidelines do not endorse Septin 9, but screening studies are in progress to assess its performance.
 

Ensuring quality

“The linchpin for effective noninvasive screening programs is adherence, and several measures of adherence are required,” the authors wrote. To ensure high quality of noninvasive screening programs, it is important to create metrics and employ continuous monitoring of compliance, and to initiate changes when adherence and outcomes lag. Important metrics include patient compliance, rapid reporting of test results, timely implementation of follow-up colonoscopies, and systems put in place to restore patients to appropriate CRC screening intervals.

The authors suggested several specific metrics and attainable performance goals. The ratio of tests completed within 1 year to tests ordered should reach 90% or more. Outreach should be conducted to patients who do not complete testing within 1 month of the order. All patients should be contacted with 2 weeks of test results, and those who test negative should be made aware of the appropriate interval for future screening, along with the method of contact.

At least 80% of patients who receive a positive test should be offered a colonoscopy date within 3 months, and all within 6 months, because delay past that time is associated with greater risk of AA, CRC, and advanced-stage CRC. Within 6 months of a positive noninvasive test, at least 95% of patients should have undergone a colonoscopy, unless they are too ill, have moved, or cannot be reached. “Quality metrics for noninvasive screening programs should be set and program performance should be measured and ideally reported publicly,” the authors summarized. “Poor adherence at any level should trigger review of established protocols and facilitate change to ensure high-quality screening.”

Two authors disclosed relationships with Freenome and/or Check-Cap, but the third disclosed no conflicts.
 

The risk of cardiovascular (CV) events in patients with psoriatic disease rises with higher levels of two cardiac biomarkers in a manner independent of risk calculated by the Framingham Risk Score (FRS), a longitudinal cohort study has shown. But researchers who conducted the study note that neither of the two biomarkers identified in the study – cardiac troponin I (cTnI) and N-terminal pro-brain-type natriuretic peptide (NT-proBNP) – led to an improvement in predictive performance when combined with the FRS, despite their association with carotid plaque burden.

Psoriasis and psoriatic arthritis are both associated with greater risk of CV morbidity and mortality, partly because of systemic inflammation that leads to atherogenesis. Measures of CV risk such as the FRS rely on traditional measures of CV risk and thus are likely to underestimate the CV event risk of people with psoriatic disease, according to the authors of the new study, published online in Arthritis & Rheumatology. The effort was led by Keith Colaço, MSc; Lihi Eder, MD, PhD; and other researchers affiliated with the University of Toronto.

Alexander Raths/ThinkStock

“We are desperately in need of biomarker science advancement in psoriatic arthritis for a variety of places of guidance: How to choose a medication more accurately for the patient in front of us – that is, getting to be more like oncologists who use biomarkers to pick the best treatment or combination. That’s an important need. A second important need is how to guide clinicians regarding risk prediction for things like persistent, severe disease activity, progressive structural damage from disease, and, in this case, predicting a very common comorbidity that occurs in [psoriasis and] psoriatic arthritis patients,” Philip J. Mease, MD, told this news organization when asked to comment on the study.

Such biomarkers could assist with patient counseling, according to Dr. Mease, who is director of rheumatology research at Swedish Medical Center/Providence St. Joseph Health and is a clinical professor at the University of Washington, both in Seattle. Some patients may struggle with advice to lose weight or adopt lifestyle measures to limit CV risk, and more accurate predictions of risk may serve as further motivation. “It could well be that if you have a biomarker that accurately predicts a coming cataclysm, that it will lead you to redouble your efforts to do whatever it takes to reduce cardiovascular risk,” he said.

Both cTnI and NT-proBNP have been linked to increased CV risk in the general population, but little work has been done in the context of rheumatologic diseases.

The researchers analyzed data from 358 patients seen at the University of Toronto. The mean follow-up was 3.69 years. After adjustment for CV risk factors, lipid-lowering therapy, and creatinine levels, there was an association between cTnI levels and total carotid plaque area (adjusted beta coefficient, 0.21; 95% confidence interval, 0-0.41), but not for levels of NT-proBNP.

Atherosclerosis progressed in 89 participants overall, but multivariate adjustment revealed no significant relationship between progression and cTnI or NT-proBNP levels.

Separately, the researchers analyzed 1,000 individuals with psoriatic arthritis (n = 648) or with psoriasis and no arthritis (n = 352) whom they followed for a mean of 7.1 years after the patients underwent evaluation during 2002-2019. After adjustment for FRS, there was an association between the risk of a CV event and each 1–standard deviation increase in both cTnI (hazard ratio, 3.02; 95% CI, 1.12-8.16) and NT-proBNP (HR, 2.02; 95% CI, 1.28-3.18).

The combination of both biomarkers with the FRS predicted higher CV risk (HR, 1.91; 95% CI, 1.23-2.97). Neither biomarker made a statistically significant difference in changing CV risk prediction when added individually to FRS, although cTnI trended toward significance (HR, 2.60; 95% CI, 0.98-6.87).

Instead of the carotid plaque burden, Dr. Mease would have liked to have seen the authors evaluate calcium scores in coronary arteries as measured by CT. “I would have loved to have seen the researchers using that in addition to the carotid plaque assessment, to see what that would show us about these patients,” he said.

Only a small number of patients experienced CV events during the study period, which will likely make it necessary to conduct larger studies to identify a clear relationship. “You need a registry-type study with probably many hundreds if not thousands of patients in order to identify whether or not adding troponin could be useful to what we typically measure with patients when we’re trying to assess their risk,” Dr. Mease said.

The study was supported in part by the National Psoriasis Foundation and the Arthritis Society. Individual researchers have received support from a range of sources, including the Enid Walker Estate, the Women’s College Research Institute, the Arthritis Society, the National Psoriasis Foundation, the Edward Dunlop Foundation, the Ontario Ministry of Science and Innovation, and a Pfizer Chair Research Award. Some of the researchers have financial relationships with pharmaceutical companies that market drugs for psoriasis and psoriatic arthritis.

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

The risk of cardiovascular (CV) events in patients with psoriatic disease rises with higher levels of two cardiac biomarkers in a manner independent of risk calculated by the Framingham Risk Score (FRS), a longitudinal cohort study has shown. But researchers who conducted the study note that neither of the two biomarkers identified in the study – cardiac troponin I (cTnI) and N-terminal pro-brain-type natriuretic peptide (NT-proBNP) – led to an improvement in predictive performance when combined with the FRS, despite their association with carotid plaque burden.

Psoriasis and psoriatic arthritis are both associated with greater risk of CV morbidity and mortality, partly because of systemic inflammation that leads to atherogenesis. Measures of CV risk such as the FRS rely on traditional measures of CV risk and thus are likely to underestimate the CV event risk of people with psoriatic disease, according to the authors of the new study, published online in Arthritis & Rheumatology. The effort was led by Keith Colaço, MSc; Lihi Eder, MD, PhD; and other researchers affiliated with the University of Toronto.

Alexander Raths/ThinkStock

“We are desperately in need of biomarker science advancement in psoriatic arthritis for a variety of places of guidance: How to choose a medication more accurately for the patient in front of us – that is, getting to be more like oncologists who use biomarkers to pick the best treatment or combination. That’s an important need. A second important need is how to guide clinicians regarding risk prediction for things like persistent, severe disease activity, progressive structural damage from disease, and, in this case, predicting a very common comorbidity that occurs in [psoriasis and] psoriatic arthritis patients,” Philip J. Mease, MD, told this news organization when asked to comment on the study.

Such biomarkers could assist with patient counseling, according to Dr. Mease, who is director of rheumatology research at Swedish Medical Center/Providence St. Joseph Health and is a clinical professor at the University of Washington, both in Seattle. Some patients may struggle with advice to lose weight or adopt lifestyle measures to limit CV risk, and more accurate predictions of risk may serve as further motivation. “It could well be that if you have a biomarker that accurately predicts a coming cataclysm, that it will lead you to redouble your efforts to do whatever it takes to reduce cardiovascular risk,” he said.

Both cTnI and NT-proBNP have been linked to increased CV risk in the general population, but little work has been done in the context of rheumatologic diseases.

The researchers analyzed data from 358 patients seen at the University of Toronto. The mean follow-up was 3.69 years. After adjustment for CV risk factors, lipid-lowering therapy, and creatinine levels, there was an association between cTnI levels and total carotid plaque area (adjusted beta coefficient, 0.21; 95% confidence interval, 0-0.41), but not for levels of NT-proBNP.

Atherosclerosis progressed in 89 participants overall, but multivariate adjustment revealed no significant relationship between progression and cTnI or NT-proBNP levels.

Separately, the researchers analyzed 1,000 individuals with psoriatic arthritis (n = 648) or with psoriasis and no arthritis (n = 352) whom they followed for a mean of 7.1 years after the patients underwent evaluation during 2002-2019. After adjustment for FRS, there was an association between the risk of a CV event and each 1–standard deviation increase in both cTnI (hazard ratio, 3.02; 95% CI, 1.12-8.16) and NT-proBNP (HR, 2.02; 95% CI, 1.28-3.18).

The combination of both biomarkers with the FRS predicted higher CV risk (HR, 1.91; 95% CI, 1.23-2.97). Neither biomarker made a statistically significant difference in changing CV risk prediction when added individually to FRS, although cTnI trended toward significance (HR, 2.60; 95% CI, 0.98-6.87).

Instead of the carotid plaque burden, Dr. Mease would have liked to have seen the authors evaluate calcium scores in coronary arteries as measured by CT. “I would have loved to have seen the researchers using that in addition to the carotid plaque assessment, to see what that would show us about these patients,” he said.

Only a small number of patients experienced CV events during the study period, which will likely make it necessary to conduct larger studies to identify a clear relationship. “You need a registry-type study with probably many hundreds if not thousands of patients in order to identify whether or not adding troponin could be useful to what we typically measure with patients when we’re trying to assess their risk,” Dr. Mease said.

The study was supported in part by the National Psoriasis Foundation and the Arthritis Society. Individual researchers have received support from a range of sources, including the Enid Walker Estate, the Women’s College Research Institute, the Arthritis Society, the National Psoriasis Foundation, the Edward Dunlop Foundation, the Ontario Ministry of Science and Innovation, and a Pfizer Chair Research Award. Some of the researchers have financial relationships with pharmaceutical companies that market drugs for psoriasis and psoriatic arthritis.

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

The risk of cardiovascular (CV) events in patients with psoriatic disease rises with higher levels of two cardiac biomarkers in a manner independent of risk calculated by the Framingham Risk Score (FRS), a longitudinal cohort study has shown. But researchers who conducted the study note that neither of the two biomarkers identified in the study – cardiac troponin I (cTnI) and N-terminal pro-brain-type natriuretic peptide (NT-proBNP) – led to an improvement in predictive performance when combined with the FRS, despite their association with carotid plaque burden.

Psoriasis and psoriatic arthritis are both associated with greater risk of CV morbidity and mortality, partly because of systemic inflammation that leads to atherogenesis. Measures of CV risk such as the FRS rely on traditional measures of CV risk and thus are likely to underestimate the CV event risk of people with psoriatic disease, according to the authors of the new study, published online in Arthritis & Rheumatology. The effort was led by Keith Colaço, MSc; Lihi Eder, MD, PhD; and other researchers affiliated with the University of Toronto.

Alexander Raths/ThinkStock

“We are desperately in need of biomarker science advancement in psoriatic arthritis for a variety of places of guidance: How to choose a medication more accurately for the patient in front of us – that is, getting to be more like oncologists who use biomarkers to pick the best treatment or combination. That’s an important need. A second important need is how to guide clinicians regarding risk prediction for things like persistent, severe disease activity, progressive structural damage from disease, and, in this case, predicting a very common comorbidity that occurs in [psoriasis and] psoriatic arthritis patients,” Philip J. Mease, MD, told this news organization when asked to comment on the study.

Such biomarkers could assist with patient counseling, according to Dr. Mease, who is director of rheumatology research at Swedish Medical Center/Providence St. Joseph Health and is a clinical professor at the University of Washington, both in Seattle. Some patients may struggle with advice to lose weight or adopt lifestyle measures to limit CV risk, and more accurate predictions of risk may serve as further motivation. “It could well be that if you have a biomarker that accurately predicts a coming cataclysm, that it will lead you to redouble your efforts to do whatever it takes to reduce cardiovascular risk,” he said.

Both cTnI and NT-proBNP have been linked to increased CV risk in the general population, but little work has been done in the context of rheumatologic diseases.

The researchers analyzed data from 358 patients seen at the University of Toronto. The mean follow-up was 3.69 years. After adjustment for CV risk factors, lipid-lowering therapy, and creatinine levels, there was an association between cTnI levels and total carotid plaque area (adjusted beta coefficient, 0.21; 95% confidence interval, 0-0.41), but not for levels of NT-proBNP.

Atherosclerosis progressed in 89 participants overall, but multivariate adjustment revealed no significant relationship between progression and cTnI or NT-proBNP levels.

Separately, the researchers analyzed 1,000 individuals with psoriatic arthritis (n = 648) or with psoriasis and no arthritis (n = 352) whom they followed for a mean of 7.1 years after the patients underwent evaluation during 2002-2019. After adjustment for FRS, there was an association between the risk of a CV event and each 1–standard deviation increase in both cTnI (hazard ratio, 3.02; 95% CI, 1.12-8.16) and NT-proBNP (HR, 2.02; 95% CI, 1.28-3.18).

The combination of both biomarkers with the FRS predicted higher CV risk (HR, 1.91; 95% CI, 1.23-2.97). Neither biomarker made a statistically significant difference in changing CV risk prediction when added individually to FRS, although cTnI trended toward significance (HR, 2.60; 95% CI, 0.98-6.87).

Instead of the carotid plaque burden, Dr. Mease would have liked to have seen the authors evaluate calcium scores in coronary arteries as measured by CT. “I would have loved to have seen the researchers using that in addition to the carotid plaque assessment, to see what that would show us about these patients,” he said.

Only a small number of patients experienced CV events during the study period, which will likely make it necessary to conduct larger studies to identify a clear relationship. “You need a registry-type study with probably many hundreds if not thousands of patients in order to identify whether or not adding troponin could be useful to what we typically measure with patients when we’re trying to assess their risk,” Dr. Mease said.

The study was supported in part by the National Psoriasis Foundation and the Arthritis Society. Individual researchers have received support from a range of sources, including the Enid Walker Estate, the Women’s College Research Institute, the Arthritis Society, the National Psoriasis Foundation, the Edward Dunlop Foundation, the Ontario Ministry of Science and Innovation, and a Pfizer Chair Research Award. Some of the researchers have financial relationships with pharmaceutical companies that market drugs for psoriasis and psoriatic arthritis.

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

New recommendations from the American Gastroenterological Association focus on choice of systemic therapy in hepatocellular carcinoma (HCC) patients. The guideline authors point out that prognosis and treatment decisions are both heavily dependent on a combination of the severity of underlying disease and biological characteristics of the tumor.

The document includes options for patients who are ineligible for locoregional therapy or resection, patients with metastatic disease and preserved liver function, patients with poor liver function, and patients receiving adjuvant therapy following surgery or locoregional therapy (LRT).

Intermediate or advanced tumor stage is common among HCC patients, and curative options such as surgery and ablation are generally limited to early-stage disease. LRTs – including transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and systemic therapy – may be employed against advanced or metastatic HCC, according to the authors, led by Grace L. Su, MD, of the division of gastroenterology and hepatology at the University of Michigan, Ann Arbor, and the Veterans Affairs Ann Arbor Healthcare System.

In 2007, the Food and Drug Administration approved the multikinase inhibitor sorafenib as the first systemic therapy for HCC. The new guideline comes in the wake of new systemic therapeutic options that have arrived in the years since, including molecularly targeted therapy and immunotherapy. The authors of the guidance, published in Gastroenterology, include advice on both first- and second-line therapies.

Certainty of evidence for the recommendations ranges from low to very low, indicating limited or very little confidence in the effect estimated, and the true effect is likely to be considerably different than predicted by best current estimates. Accordingly, the recommendations are conditional, and decisions should be made with the values and preferences of the individual patient in mind.

In patients with preserved liver function who are ineligible for LRT or resection, or who have metastatic disease, the authors suggest that first-line treatment should be the combination of atezolizumab and bevacizumab rather than sorafenib. Bevacizumab comes with a bleeding risk, so patients should first be evaluated endoscopically and treated for esophageal varices. For patients who are ineligible for bevacizumab, alternatives are lenvatinib or sorafenib. Patients who are more concerned about disease progression than adverse events may want to consider lenvatinib rather than sorafenib, while those concerned about blood pressure control and who are less concerned about adverse skin reactions may choose sorafenib.

Options for second-line therapy after sorafenib include cabozantinib (mortality reduction, 2.2 months) and pembrolizumab (mortality reduction, 3.3 months). Patients with alpha-fetoprotein levels higher than 400 ng/mL may be candidates for treatment with ramucirumab (mortality reduction, 1.2 months). Another option is regorafenib (mortality reduction, 2.8 months). Patients who are more concerned about adverse effects than a potential survival benefit with any of these therapies may reasonably choose no systemic therapy.

For HCC patients with poor liver function, who are not eligible for LRT or resection, or with metastatic disease, the guidelines recommend against routine use of sorafenib.

In the setting of adjuvant therapy following curative surgical resection, curative local ablation, or TACE LRT, the guidelines recommend against the use of sorafenib. The authors also recommended against the use of bevacizumab following TACE LRT.

The authors noted that there is no high-quality comparative evidence in the second-line setting for atezolizumab plus bevacizumab, sorafenib, or lenvatinib. There is a dearth of evidence and few biomarkers to guide personalization of therapies, which places the emphasis on patient preferences, risks, and benefits.

The authors disclosed no conflicts.

New recommendations from the American Gastroenterological Association focus on choice of systemic therapy in hepatocellular carcinoma (HCC) patients. The guideline authors point out that prognosis and treatment decisions are both heavily dependent on a combination of the severity of underlying disease and biological characteristics of the tumor.

The document includes options for patients who are ineligible for locoregional therapy or resection, patients with metastatic disease and preserved liver function, patients with poor liver function, and patients receiving adjuvant therapy following surgery or locoregional therapy (LRT).

Intermediate or advanced tumor stage is common among HCC patients, and curative options such as surgery and ablation are generally limited to early-stage disease. LRTs – including transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and systemic therapy – may be employed against advanced or metastatic HCC, according to the authors, led by Grace L. Su, MD, of the division of gastroenterology and hepatology at the University of Michigan, Ann Arbor, and the Veterans Affairs Ann Arbor Healthcare System.

In 2007, the Food and Drug Administration approved the multikinase inhibitor sorafenib as the first systemic therapy for HCC. The new guideline comes in the wake of new systemic therapeutic options that have arrived in the years since, including molecularly targeted therapy and immunotherapy. The authors of the guidance, published in Gastroenterology, include advice on both first- and second-line therapies.

Certainty of evidence for the recommendations ranges from low to very low, indicating limited or very little confidence in the effect estimated, and the true effect is likely to be considerably different than predicted by best current estimates. Accordingly, the recommendations are conditional, and decisions should be made with the values and preferences of the individual patient in mind.

In patients with preserved liver function who are ineligible for LRT or resection, or who have metastatic disease, the authors suggest that first-line treatment should be the combination of atezolizumab and bevacizumab rather than sorafenib. Bevacizumab comes with a bleeding risk, so patients should first be evaluated endoscopically and treated for esophageal varices. For patients who are ineligible for bevacizumab, alternatives are lenvatinib or sorafenib. Patients who are more concerned about disease progression than adverse events may want to consider lenvatinib rather than sorafenib, while those concerned about blood pressure control and who are less concerned about adverse skin reactions may choose sorafenib.

Options for second-line therapy after sorafenib include cabozantinib (mortality reduction, 2.2 months) and pembrolizumab (mortality reduction, 3.3 months). Patients with alpha-fetoprotein levels higher than 400 ng/mL may be candidates for treatment with ramucirumab (mortality reduction, 1.2 months). Another option is regorafenib (mortality reduction, 2.8 months). Patients who are more concerned about adverse effects than a potential survival benefit with any of these therapies may reasonably choose no systemic therapy.

For HCC patients with poor liver function, who are not eligible for LRT or resection, or with metastatic disease, the guidelines recommend against routine use of sorafenib.

In the setting of adjuvant therapy following curative surgical resection, curative local ablation, or TACE LRT, the guidelines recommend against the use of sorafenib. The authors also recommended against the use of bevacizumab following TACE LRT.

The authors noted that there is no high-quality comparative evidence in the second-line setting for atezolizumab plus bevacizumab, sorafenib, or lenvatinib. There is a dearth of evidence and few biomarkers to guide personalization of therapies, which places the emphasis on patient preferences, risks, and benefits.

The authors disclosed no conflicts.

New recommendations from the American Gastroenterological Association focus on choice of systemic therapy in hepatocellular carcinoma (HCC) patients. The guideline authors point out that prognosis and treatment decisions are both heavily dependent on a combination of the severity of underlying disease and biological characteristics of the tumor.

The document includes options for patients who are ineligible for locoregional therapy or resection, patients with metastatic disease and preserved liver function, patients with poor liver function, and patients receiving adjuvant therapy following surgery or locoregional therapy (LRT).

Intermediate or advanced tumor stage is common among HCC patients, and curative options such as surgery and ablation are generally limited to early-stage disease. LRTs – including transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and systemic therapy – may be employed against advanced or metastatic HCC, according to the authors, led by Grace L. Su, MD, of the division of gastroenterology and hepatology at the University of Michigan, Ann Arbor, and the Veterans Affairs Ann Arbor Healthcare System.

In 2007, the Food and Drug Administration approved the multikinase inhibitor sorafenib as the first systemic therapy for HCC. The new guideline comes in the wake of new systemic therapeutic options that have arrived in the years since, including molecularly targeted therapy and immunotherapy. The authors of the guidance, published in Gastroenterology, include advice on both first- and second-line therapies.

Certainty of evidence for the recommendations ranges from low to very low, indicating limited or very little confidence in the effect estimated, and the true effect is likely to be considerably different than predicted by best current estimates. Accordingly, the recommendations are conditional, and decisions should be made with the values and preferences of the individual patient in mind.

In patients with preserved liver function who are ineligible for LRT or resection, or who have metastatic disease, the authors suggest that first-line treatment should be the combination of atezolizumab and bevacizumab rather than sorafenib. Bevacizumab comes with a bleeding risk, so patients should first be evaluated endoscopically and treated for esophageal varices. For patients who are ineligible for bevacizumab, alternatives are lenvatinib or sorafenib. Patients who are more concerned about disease progression than adverse events may want to consider lenvatinib rather than sorafenib, while those concerned about blood pressure control and who are less concerned about adverse skin reactions may choose sorafenib.

Options for second-line therapy after sorafenib include cabozantinib (mortality reduction, 2.2 months) and pembrolizumab (mortality reduction, 3.3 months). Patients with alpha-fetoprotein levels higher than 400 ng/mL may be candidates for treatment with ramucirumab (mortality reduction, 1.2 months). Another option is regorafenib (mortality reduction, 2.8 months). Patients who are more concerned about adverse effects than a potential survival benefit with any of these therapies may reasonably choose no systemic therapy.

For HCC patients with poor liver function, who are not eligible for LRT or resection, or with metastatic disease, the guidelines recommend against routine use of sorafenib.

In the setting of adjuvant therapy following curative surgical resection, curative local ablation, or TACE LRT, the guidelines recommend against the use of sorafenib. The authors also recommended against the use of bevacizumab following TACE LRT.

The authors noted that there is no high-quality comparative evidence in the second-line setting for atezolizumab plus bevacizumab, sorafenib, or lenvatinib. There is a dearth of evidence and few biomarkers to guide personalization of therapies, which places the emphasis on patient preferences, risks, and benefits.

The authors disclosed no conflicts.

A randomized, controlled trial of transcranial direct current stimulation (tDCS) in patients with multiple sclerosis (MS) showed improvement in a secondary outcome measure – cognition – and provided evidence that the technique can be employed outside of a physician’s office.

The primary outcome of the sham-controlled trial was fatigue, but the findings presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) focused on a secondary cognitive measure, called the Brief International Cognitive Assessment for MS (BICAMS).

The intervention may still be a work in progress as far as a treatment technique “but the more important point is that there is a path to remote cognitive rehab interventions which, as a concept, is important,” said Mark Gudesblatt, MD, medical director at South Shore Neurologic Associates in Patchogue, N.Y., who was asked to comment on the study.
 

Adaptive mechanisms

The study grew out of work done with BrainHQ, which is a brain-training program available commercially through Posit Science. It employs an algorithm to recommend and tailor exercises for participants and to adjust the difficulty of the exercises in order to maintain engagement. “We believe the key ingredient is really the adaptive mechanisms that adjust to users in real time, for instance slowing down when the user slows down or speeding up to drive the learning to maintain a level of engagement. The games are designed to target processing speed that then has a transfer effect to other aspects of cognitive function,” Leigh Charvet, PhD, said during her presentation of the study results. Dr. Charvet is director of MS research and a professor of neurology at New York University.

The researchers previously conducted a large trial in patients with MS and showed that the adaptive mechanism, used for 60 hours over 12 weeks, could improve cognitive functioning. “We had two learnings from that trial: One that the brain training in at least a very intense dose was beneficial for cognitive functioning, and the second was that at-home treatments are very popular,” said Dr. Charvet.

In the most recent trial, the researchers turned to tDCS in an effort to boost the effect of brain training. “The idea is that if you can stimulate the region of the brain that is engaged with the training activity, you can boost or potentiate the outcomes of the training,” said Dr. Charvet. The tDCS treatment applies 1.0-4.0 mA current to the scalp, where it can be placed to specifically affect a brain region of interest. The study targeted the dorsolateral prefrontal cortex, which is a key region for executive function and cognitive flexibility.

The team developed a protocol that would allow the intervention to be conducted at home, with live supervision via HIPAA-compliant teleconferencing and technology that was designed for ease of use. The tDCS devices were preprogrammed and operated on an unlock code, which initiated active or sham tDCS. “We replicated onsite lab standards, but delivered it to people at home,” said Dr. Charvet.

In the new study, 106 patients with MS who had fatigue, but not depression, underwent 30 20-minute training sessions over a 6-week period, with active or sham tDCS. The participants were tested before and after treatment using the BICAMS. The sham group had a mean change of –0.17 in the BICAMS z score, compared with a mean of +0.05 in the tDCS group (P = .027).

One of the tests that make up the BICAMS battery, the single digit modalities test (SDMT), showed a trend toward improvement in the tDCS group (z sore, +0.09 versus –0.19; P = .058). There was no significant difference between the groups In the Rey’s Auditory Verbal Learning Test or the Brief Visuospatial Memory Test–Revised.
 

What about fatigue?

The emphasis on a secondary outcome drew some criticism. “It’s odd, because the primary outcome was fatigue. They didn’t report the primary outcome, they focused on a secondary outcome of cognitive measure,” said Patricia Coyle, MD, who was asked to comment on the study.

“I think the most important finding in this study was that they were able to deliver the transcranial direct current stimulation at home, via computer. They were able to do this study by computer with their patients at home, and it was a fairly large number. You could consider it broadly as a proof of principle that this can be done,” said Dr. Coyle, professor of neurology and director of Stony Brook MS Comprehensive Care Center.

The study was funded by the National MS Society. Dr. Gudesblatt has no relevant financial disclosures. Dr. Coyle has consulted or received speaker fees from Accord-ant, Alexion, Biogen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mylan, Novartis, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Dr. Coyle has received research funding from Actelion, Alker-mes, Celgene, CorEvitas LLC, Genentech/Roche, MedDay, Novartis, and Sanofi Genzyme.

A randomized, controlled trial of transcranial direct current stimulation (tDCS) in patients with multiple sclerosis (MS) showed improvement in a secondary outcome measure – cognition – and provided evidence that the technique can be employed outside of a physician’s office.

The primary outcome of the sham-controlled trial was fatigue, but the findings presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) focused on a secondary cognitive measure, called the Brief International Cognitive Assessment for MS (BICAMS).

The intervention may still be a work in progress as far as a treatment technique “but the more important point is that there is a path to remote cognitive rehab interventions which, as a concept, is important,” said Mark Gudesblatt, MD, medical director at South Shore Neurologic Associates in Patchogue, N.Y., who was asked to comment on the study.
 

Adaptive mechanisms

The study grew out of work done with BrainHQ, which is a brain-training program available commercially through Posit Science. It employs an algorithm to recommend and tailor exercises for participants and to adjust the difficulty of the exercises in order to maintain engagement. “We believe the key ingredient is really the adaptive mechanisms that adjust to users in real time, for instance slowing down when the user slows down or speeding up to drive the learning to maintain a level of engagement. The games are designed to target processing speed that then has a transfer effect to other aspects of cognitive function,” Leigh Charvet, PhD, said during her presentation of the study results. Dr. Charvet is director of MS research and a professor of neurology at New York University.

The researchers previously conducted a large trial in patients with MS and showed that the adaptive mechanism, used for 60 hours over 12 weeks, could improve cognitive functioning. “We had two learnings from that trial: One that the brain training in at least a very intense dose was beneficial for cognitive functioning, and the second was that at-home treatments are very popular,” said Dr. Charvet.

In the most recent trial, the researchers turned to tDCS in an effort to boost the effect of brain training. “The idea is that if you can stimulate the region of the brain that is engaged with the training activity, you can boost or potentiate the outcomes of the training,” said Dr. Charvet. The tDCS treatment applies 1.0-4.0 mA current to the scalp, where it can be placed to specifically affect a brain region of interest. The study targeted the dorsolateral prefrontal cortex, which is a key region for executive function and cognitive flexibility.

The team developed a protocol that would allow the intervention to be conducted at home, with live supervision via HIPAA-compliant teleconferencing and technology that was designed for ease of use. The tDCS devices were preprogrammed and operated on an unlock code, which initiated active or sham tDCS. “We replicated onsite lab standards, but delivered it to people at home,” said Dr. Charvet.

In the new study, 106 patients with MS who had fatigue, but not depression, underwent 30 20-minute training sessions over a 6-week period, with active or sham tDCS. The participants were tested before and after treatment using the BICAMS. The sham group had a mean change of –0.17 in the BICAMS z score, compared with a mean of +0.05 in the tDCS group (P = .027).

One of the tests that make up the BICAMS battery, the single digit modalities test (SDMT), showed a trend toward improvement in the tDCS group (z sore, +0.09 versus –0.19; P = .058). There was no significant difference between the groups In the Rey’s Auditory Verbal Learning Test or the Brief Visuospatial Memory Test–Revised.
 

What about fatigue?

The emphasis on a secondary outcome drew some criticism. “It’s odd, because the primary outcome was fatigue. They didn’t report the primary outcome, they focused on a secondary outcome of cognitive measure,” said Patricia Coyle, MD, who was asked to comment on the study.

“I think the most important finding in this study was that they were able to deliver the transcranial direct current stimulation at home, via computer. They were able to do this study by computer with their patients at home, and it was a fairly large number. You could consider it broadly as a proof of principle that this can be done,” said Dr. Coyle, professor of neurology and director of Stony Brook MS Comprehensive Care Center.

The study was funded by the National MS Society. Dr. Gudesblatt has no relevant financial disclosures. Dr. Coyle has consulted or received speaker fees from Accord-ant, Alexion, Biogen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mylan, Novartis, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Dr. Coyle has received research funding from Actelion, Alker-mes, Celgene, CorEvitas LLC, Genentech/Roche, MedDay, Novartis, and Sanofi Genzyme.

A randomized, controlled trial of transcranial direct current stimulation (tDCS) in patients with multiple sclerosis (MS) showed improvement in a secondary outcome measure – cognition – and provided evidence that the technique can be employed outside of a physician’s office.

The primary outcome of the sham-controlled trial was fatigue, but the findings presented at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) focused on a secondary cognitive measure, called the Brief International Cognitive Assessment for MS (BICAMS).

The intervention may still be a work in progress as far as a treatment technique “but the more important point is that there is a path to remote cognitive rehab interventions which, as a concept, is important,” said Mark Gudesblatt, MD, medical director at South Shore Neurologic Associates in Patchogue, N.Y., who was asked to comment on the study.
 

Adaptive mechanisms

The study grew out of work done with BrainHQ, which is a brain-training program available commercially through Posit Science. It employs an algorithm to recommend and tailor exercises for participants and to adjust the difficulty of the exercises in order to maintain engagement. “We believe the key ingredient is really the adaptive mechanisms that adjust to users in real time, for instance slowing down when the user slows down or speeding up to drive the learning to maintain a level of engagement. The games are designed to target processing speed that then has a transfer effect to other aspects of cognitive function,” Leigh Charvet, PhD, said during her presentation of the study results. Dr. Charvet is director of MS research and a professor of neurology at New York University.

The researchers previously conducted a large trial in patients with MS and showed that the adaptive mechanism, used for 60 hours over 12 weeks, could improve cognitive functioning. “We had two learnings from that trial: One that the brain training in at least a very intense dose was beneficial for cognitive functioning, and the second was that at-home treatments are very popular,” said Dr. Charvet.

In the most recent trial, the researchers turned to tDCS in an effort to boost the effect of brain training. “The idea is that if you can stimulate the region of the brain that is engaged with the training activity, you can boost or potentiate the outcomes of the training,” said Dr. Charvet. The tDCS treatment applies 1.0-4.0 mA current to the scalp, where it can be placed to specifically affect a brain region of interest. The study targeted the dorsolateral prefrontal cortex, which is a key region for executive function and cognitive flexibility.

The team developed a protocol that would allow the intervention to be conducted at home, with live supervision via HIPAA-compliant teleconferencing and technology that was designed for ease of use. The tDCS devices were preprogrammed and operated on an unlock code, which initiated active or sham tDCS. “We replicated onsite lab standards, but delivered it to people at home,” said Dr. Charvet.

In the new study, 106 patients with MS who had fatigue, but not depression, underwent 30 20-minute training sessions over a 6-week period, with active or sham tDCS. The participants were tested before and after treatment using the BICAMS. The sham group had a mean change of –0.17 in the BICAMS z score, compared with a mean of +0.05 in the tDCS group (P = .027).

One of the tests that make up the BICAMS battery, the single digit modalities test (SDMT), showed a trend toward improvement in the tDCS group (z sore, +0.09 versus –0.19; P = .058). There was no significant difference between the groups In the Rey’s Auditory Verbal Learning Test or the Brief Visuospatial Memory Test–Revised.
 

What about fatigue?

The emphasis on a secondary outcome drew some criticism. “It’s odd, because the primary outcome was fatigue. They didn’t report the primary outcome, they focused on a secondary outcome of cognitive measure,” said Patricia Coyle, MD, who was asked to comment on the study.

“I think the most important finding in this study was that they were able to deliver the transcranial direct current stimulation at home, via computer. They were able to do this study by computer with their patients at home, and it was a fairly large number. You could consider it broadly as a proof of principle that this can be done,” said Dr. Coyle, professor of neurology and director of Stony Brook MS Comprehensive Care Center.

The study was funded by the National MS Society. Dr. Gudesblatt has no relevant financial disclosures. Dr. Coyle has consulted or received speaker fees from Accord-ant, Alexion, Biogen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Horizon Therapeutics, Janssen, Mylan, Novartis, Sanofi Genzyme, TG Therapeutics, and Viela Bio. Dr. Coyle has received research funding from Actelion, Alker-mes, Celgene, CorEvitas LLC, Genentech/Roche, MedDay, Novartis, and Sanofi Genzyme.

Multiple sclerosis (MS) remains a challenging disease to diagnose, but recent advances in magnetic resonance imaging (MRI) have the potential to improve both the sensitivity and specificity of diagnosis. One method involves use of MRI to detect central vein sign (CVS) in MRI images. The CVS is a hypointense vessel at the center of a hyperintense focal lesion, and various retrospective analyses have revealed an association between a greater percentage of lesions being CVS and a diagnosis of MS.

“This is a very frequent finding in MS patients, but it’s a very infrequent finding in non-MS patients, specifically radiological mimics or clinical mimics that are typically confused with MS at the time of clinical diagnosis, and could lead to misdiagnosis. The idea here of a central vein sign is to use it diagnostically as early as possible in the evaluation of the MS, and use it as complementary to the existing McDonald criteria to improve sensitivity and specificity,” Pascal Sati, PhD, said in an interview. Dr. Sati presented an overview of the topic at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). He is associate professor of neurology at Cedars Sinai Medical Center in Los Angeles and the director of the neuroimaging program in the department of neurology at Cedars Sinai.

The findings could address an important issue in MS. “Misdiagnosis is a big problem in multiple sclerosis, and it has been for a long time. There are recent surveys of physicians that show that something like 95% of MS physicians have seen a case of misdiagnosis in the last year,” Kevin Patel, MD, said in an interview. Dr. Patel is assistant professor of neurology at the University of California, Los Angeles, and moderated the session where Dr. Sati presented.
 

What is the diagnostic threshold of CVS positivity?

A key question is what percentage of lesions should be CVS positive (CVS+) to predict a diagnosis of MS. One meta-analysis found that an average of 73% CVS positivity in MS patients, but levels below 40% in conditions that can mimic MS, such as migraine (22%), cerebral small vessel disease (28.5%), and neuromyelitis optica spectrum disorder (33.5%). However, both biological and technical effects can influence that percentage. The percentage is lower among older patients with MS, and those with vascular comorbidities, likely due to noninflammatory or ischemic plaques, or other lesion types, said Dr. Sati.

On the technical side, lower field strengths tend to reveal a lower proportion of CVS than higher field strengths, which are more sensitive. However, the choice of MRI technique can influence sensitivity, and the optimized T2* EPI and FLAIR* techniques have been shown to reveal higher percentages of CVS, even at lower field strengths like the commonly available 3-T.

Forty percent CVS positivity has been suggested as a diagnostic for MS, but this can be time consuming to determine in patients with large numbers of lesions. An alternative is to analyze a subset of lesions and make a diagnosis if these lesions display the CVS. For example, ‘Select 3*’ would establish an MS diagnosis if at least 3 brain lesions have the CVS, or the ‘6-lesion rule’ would establish an MS diagnosis if at least 6 out 10 brain lesions have the CVS. Recent retrospective studies have supported these simplified diagnostic criteria, suggesting that these approaches perform similarly to the 40% rule.
 

What will change clinical practice?

However, retrospective studies aren’t enough to change international diagnostic guidelines and clinical practice. Dr. Sati is part of a group of investigators from the North American Imaging in MS (NAIMS) Cooperative that is conducting a large prospective diagnostic study (CAVS-MS) with a $7.2 million grant from the National Institutes of Health, which is currently recruiting 400 patients being evaluated for MS. The MRI protocol will use the optimized T2* EPI/FLAIR* techniques developed by Dr. Sati on 3-T scanners. “It’s a twofold goal: First the evaluation of the diagnostic power of the central vein sign in a real-world cohort, and then the validation of the advanced MRI technology that we’re developing to image the central vein sign clinically,” said Dr. Sati.

Neurologists generally are becoming more aware of these techniques, according to Dr. Patel, but they aren’t yet widely used outside of research settings.

“We haven’t collected enough evidence to really warrant wide implementation. I suspect that that’s one of the major reasons why it is that we don’t see this deployed more widely. I think there’ll be a bit of time before this is integrated to the standard sequences that are done for evaluation of multiple sclerosis,” said Dr. Patel.

The technique must contend with comorbid factors, especially vascular comorbidities such as hypertension, diabetes, or high cholesterol, that can cause white matter hyperintensities as individuals age. “This can create difficulties with using this procedure, because if you have small vessel disease at the same time you have MS, you have much more T2 lesion volume. It becomes a little bit more difficult to suss out whether the person has MS. So there’s a little bit of work that needs to be done along those lines as well,” said Dr. Patel.

With more research, the technology has the potential to improve MS diagnosis, both among community neurologists and even among specialists, according to Dr. Patel. “There are definitely cases that are rather ambiguous that even though they present at a major academic center, it’s sometimes very difficult for us to determine as to whether the person has multiple sclerosis or not. And this sort of technique can potentially help us in distinguishing those cases. Sometimes even after they see folks at tertiary centers, folks still don’t have a definitive diagnosis,” said Dr. Patel.

Dr. Sati and Dr. Patel have no relevant financial disclosures.

Multiple sclerosis (MS) remains a challenging disease to diagnose, but recent advances in magnetic resonance imaging (MRI) have the potential to improve both the sensitivity and specificity of diagnosis. One method involves use of MRI to detect central vein sign (CVS) in MRI images. The CVS is a hypointense vessel at the center of a hyperintense focal lesion, and various retrospective analyses have revealed an association between a greater percentage of lesions being CVS and a diagnosis of MS.

“This is a very frequent finding in MS patients, but it’s a very infrequent finding in non-MS patients, specifically radiological mimics or clinical mimics that are typically confused with MS at the time of clinical diagnosis, and could lead to misdiagnosis. The idea here of a central vein sign is to use it diagnostically as early as possible in the evaluation of the MS, and use it as complementary to the existing McDonald criteria to improve sensitivity and specificity,” Pascal Sati, PhD, said in an interview. Dr. Sati presented an overview of the topic at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). He is associate professor of neurology at Cedars Sinai Medical Center in Los Angeles and the director of the neuroimaging program in the department of neurology at Cedars Sinai.

The findings could address an important issue in MS. “Misdiagnosis is a big problem in multiple sclerosis, and it has been for a long time. There are recent surveys of physicians that show that something like 95% of MS physicians have seen a case of misdiagnosis in the last year,” Kevin Patel, MD, said in an interview. Dr. Patel is assistant professor of neurology at the University of California, Los Angeles, and moderated the session where Dr. Sati presented.
 

What is the diagnostic threshold of CVS positivity?

A key question is what percentage of lesions should be CVS positive (CVS+) to predict a diagnosis of MS. One meta-analysis found that an average of 73% CVS positivity in MS patients, but levels below 40% in conditions that can mimic MS, such as migraine (22%), cerebral small vessel disease (28.5%), and neuromyelitis optica spectrum disorder (33.5%). However, both biological and technical effects can influence that percentage. The percentage is lower among older patients with MS, and those with vascular comorbidities, likely due to noninflammatory or ischemic plaques, or other lesion types, said Dr. Sati.

On the technical side, lower field strengths tend to reveal a lower proportion of CVS than higher field strengths, which are more sensitive. However, the choice of MRI technique can influence sensitivity, and the optimized T2* EPI and FLAIR* techniques have been shown to reveal higher percentages of CVS, even at lower field strengths like the commonly available 3-T.

Forty percent CVS positivity has been suggested as a diagnostic for MS, but this can be time consuming to determine in patients with large numbers of lesions. An alternative is to analyze a subset of lesions and make a diagnosis if these lesions display the CVS. For example, ‘Select 3*’ would establish an MS diagnosis if at least 3 brain lesions have the CVS, or the ‘6-lesion rule’ would establish an MS diagnosis if at least 6 out 10 brain lesions have the CVS. Recent retrospective studies have supported these simplified diagnostic criteria, suggesting that these approaches perform similarly to the 40% rule.
 

What will change clinical practice?

However, retrospective studies aren’t enough to change international diagnostic guidelines and clinical practice. Dr. Sati is part of a group of investigators from the North American Imaging in MS (NAIMS) Cooperative that is conducting a large prospective diagnostic study (CAVS-MS) with a $7.2 million grant from the National Institutes of Health, which is currently recruiting 400 patients being evaluated for MS. The MRI protocol will use the optimized T2* EPI/FLAIR* techniques developed by Dr. Sati on 3-T scanners. “It’s a twofold goal: First the evaluation of the diagnostic power of the central vein sign in a real-world cohort, and then the validation of the advanced MRI technology that we’re developing to image the central vein sign clinically,” said Dr. Sati.

Neurologists generally are becoming more aware of these techniques, according to Dr. Patel, but they aren’t yet widely used outside of research settings.

“We haven’t collected enough evidence to really warrant wide implementation. I suspect that that’s one of the major reasons why it is that we don’t see this deployed more widely. I think there’ll be a bit of time before this is integrated to the standard sequences that are done for evaluation of multiple sclerosis,” said Dr. Patel.

The technique must contend with comorbid factors, especially vascular comorbidities such as hypertension, diabetes, or high cholesterol, that can cause white matter hyperintensities as individuals age. “This can create difficulties with using this procedure, because if you have small vessel disease at the same time you have MS, you have much more T2 lesion volume. It becomes a little bit more difficult to suss out whether the person has MS. So there’s a little bit of work that needs to be done along those lines as well,” said Dr. Patel.

With more research, the technology has the potential to improve MS diagnosis, both among community neurologists and even among specialists, according to Dr. Patel. “There are definitely cases that are rather ambiguous that even though they present at a major academic center, it’s sometimes very difficult for us to determine as to whether the person has multiple sclerosis or not. And this sort of technique can potentially help us in distinguishing those cases. Sometimes even after they see folks at tertiary centers, folks still don’t have a definitive diagnosis,” said Dr. Patel.

Dr. Sati and Dr. Patel have no relevant financial disclosures.

Multiple sclerosis (MS) remains a challenging disease to diagnose, but recent advances in magnetic resonance imaging (MRI) have the potential to improve both the sensitivity and specificity of diagnosis. One method involves use of MRI to detect central vein sign (CVS) in MRI images. The CVS is a hypointense vessel at the center of a hyperintense focal lesion, and various retrospective analyses have revealed an association between a greater percentage of lesions being CVS and a diagnosis of MS.

“This is a very frequent finding in MS patients, but it’s a very infrequent finding in non-MS patients, specifically radiological mimics or clinical mimics that are typically confused with MS at the time of clinical diagnosis, and could lead to misdiagnosis. The idea here of a central vein sign is to use it diagnostically as early as possible in the evaluation of the MS, and use it as complementary to the existing McDonald criteria to improve sensitivity and specificity,” Pascal Sati, PhD, said in an interview. Dr. Sati presented an overview of the topic at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS). He is associate professor of neurology at Cedars Sinai Medical Center in Los Angeles and the director of the neuroimaging program in the department of neurology at Cedars Sinai.

The findings could address an important issue in MS. “Misdiagnosis is a big problem in multiple sclerosis, and it has been for a long time. There are recent surveys of physicians that show that something like 95% of MS physicians have seen a case of misdiagnosis in the last year,” Kevin Patel, MD, said in an interview. Dr. Patel is assistant professor of neurology at the University of California, Los Angeles, and moderated the session where Dr. Sati presented.
 

What is the diagnostic threshold of CVS positivity?

A key question is what percentage of lesions should be CVS positive (CVS+) to predict a diagnosis of MS. One meta-analysis found that an average of 73% CVS positivity in MS patients, but levels below 40% in conditions that can mimic MS, such as migraine (22%), cerebral small vessel disease (28.5%), and neuromyelitis optica spectrum disorder (33.5%). However, both biological and technical effects can influence that percentage. The percentage is lower among older patients with MS, and those with vascular comorbidities, likely due to noninflammatory or ischemic plaques, or other lesion types, said Dr. Sati.

On the technical side, lower field strengths tend to reveal a lower proportion of CVS than higher field strengths, which are more sensitive. However, the choice of MRI technique can influence sensitivity, and the optimized T2* EPI and FLAIR* techniques have been shown to reveal higher percentages of CVS, even at lower field strengths like the commonly available 3-T.

Forty percent CVS positivity has been suggested as a diagnostic for MS, but this can be time consuming to determine in patients with large numbers of lesions. An alternative is to analyze a subset of lesions and make a diagnosis if these lesions display the CVS. For example, ‘Select 3*’ would establish an MS diagnosis if at least 3 brain lesions have the CVS, or the ‘6-lesion rule’ would establish an MS diagnosis if at least 6 out 10 brain lesions have the CVS. Recent retrospective studies have supported these simplified diagnostic criteria, suggesting that these approaches perform similarly to the 40% rule.
 

What will change clinical practice?

However, retrospective studies aren’t enough to change international diagnostic guidelines and clinical practice. Dr. Sati is part of a group of investigators from the North American Imaging in MS (NAIMS) Cooperative that is conducting a large prospective diagnostic study (CAVS-MS) with a $7.2 million grant from the National Institutes of Health, which is currently recruiting 400 patients being evaluated for MS. The MRI protocol will use the optimized T2* EPI/FLAIR* techniques developed by Dr. Sati on 3-T scanners. “It’s a twofold goal: First the evaluation of the diagnostic power of the central vein sign in a real-world cohort, and then the validation of the advanced MRI technology that we’re developing to image the central vein sign clinically,” said Dr. Sati.

Neurologists generally are becoming more aware of these techniques, according to Dr. Patel, but they aren’t yet widely used outside of research settings.

“We haven’t collected enough evidence to really warrant wide implementation. I suspect that that’s one of the major reasons why it is that we don’t see this deployed more widely. I think there’ll be a bit of time before this is integrated to the standard sequences that are done for evaluation of multiple sclerosis,” said Dr. Patel.

The technique must contend with comorbid factors, especially vascular comorbidities such as hypertension, diabetes, or high cholesterol, that can cause white matter hyperintensities as individuals age. “This can create difficulties with using this procedure, because if you have small vessel disease at the same time you have MS, you have much more T2 lesion volume. It becomes a little bit more difficult to suss out whether the person has MS. So there’s a little bit of work that needs to be done along those lines as well,” said Dr. Patel.

With more research, the technology has the potential to improve MS diagnosis, both among community neurologists and even among specialists, according to Dr. Patel. “There are definitely cases that are rather ambiguous that even though they present at a major academic center, it’s sometimes very difficult for us to determine as to whether the person has multiple sclerosis or not. And this sort of technique can potentially help us in distinguishing those cases. Sometimes even after they see folks at tertiary centers, folks still don’t have a definitive diagnosis,” said Dr. Patel.

Dr. Sati and Dr. Patel have no relevant financial disclosures.

Among women with ATM, CHEK2, or PALB2 pathogenic variants, annual MRI screening beginning at age 30 or 35, followed by concomitant MRI and mammography at age 40, could significantly reduce breast cancer mortality, according to a new model.

Adjunct screening with MRI is already recommended among women with the BRCA1 or BRCA2 mutations. ATM, CHEK2, and PALB2 are the most common of a more recently discovered group of pathogenic variants that confer a moderate to high risk of breast cancer.

In a study published online Feb. 17, 2022, in JAMA Oncology, researchers used two simulation models and risk estimates from the Cancer Risk Estimates Related to Susceptibility Consortium to predict that MRI screening at age 35 would produce a 54.4%-57.6% reduction in breast cancer mortality, with an estimated 4,661-5,001 false positive screenings and 1,280-1,368 benign biopsies per 1,000 women. At age 30, the model predicted 55.4-59.5% reduction in risk, 5,075-5,415 false positives, and 1,439-1,528 benign biopsies. Annual mammography at age 40 alone could reduce risk by 36%-39%.

The false positives and benign biopsies represent cumulative lifetime results.

“We’ve known for a long time that mammography is less sensitive in younger women than in older women and, of course, when women have a genetic predisposition, we’re very concerned about early-onset cancer. We’ve also known that when you do MRI at the same time as mammography, you find a lot more cancers. [There are] more false positives, but there is clearly a greater yield of cancer in that setting, and the cancers are found earlier,” senior author Mark Robson, MD, said in an interview.

The model showed that mammography screening in women under 40 added no survival benefit, and led to additional false positives and benign biopsies.

“We know that MRI’s detection rate for cancers in a head-to-head comparison with mammography is extremely high, and so I’m not surprised that there was such a difference from a mammography strategy. What I was excited by is just how impactful the MRI screen was in terms of projected reduction in the risk of death. I thought that great,” said Dr. Robson, who is chief of the breast medicine service at Memorial Sloan Kettering Cancer Center, New York.

The balance of mortality reduction versus false positives and benign biopsies will need to be weighed by others. “We didn’t feel like we could make those judgments, but what we were presenting was for people who do make these kinds of policies. The reason that we said 30-35 years (for MRI initiation) is because at that point, the false positive versus life-years gained curve starts to plateau. For instance, when we look at strategies of starting MRI at 25, you we don’t get significantly more life years gained, but we do get more false positives,” Dr. Robson said.

The researchers did not conduct a former cost-benefit analysis for initiating MRI screening at age 30-35.

The study “reinforces the value of MRI for women with these variants that are really just entering the clinical consciousness, and affirms that we need to be doing that in young women to help prevent death from breast cancer. I also think that we need to look at really what mammogram is adding in young women and consider whether or not we really need it at the policy level,” he said.

The study was funded by the National Cancer Institute and the Breast Cancer Research Foundation. Dr. Robson has conducted clinical trials with AstraZeneca, Merck, and Pfizer.

Among women with ATM, CHEK2, or PALB2 pathogenic variants, annual MRI screening beginning at age 30 or 35, followed by concomitant MRI and mammography at age 40, could significantly reduce breast cancer mortality, according to a new model.

Adjunct screening with MRI is already recommended among women with the BRCA1 or BRCA2 mutations. ATM, CHEK2, and PALB2 are the most common of a more recently discovered group of pathogenic variants that confer a moderate to high risk of breast cancer.

In a study published online Feb. 17, 2022, in JAMA Oncology, researchers used two simulation models and risk estimates from the Cancer Risk Estimates Related to Susceptibility Consortium to predict that MRI screening at age 35 would produce a 54.4%-57.6% reduction in breast cancer mortality, with an estimated 4,661-5,001 false positive screenings and 1,280-1,368 benign biopsies per 1,000 women. At age 30, the model predicted 55.4-59.5% reduction in risk, 5,075-5,415 false positives, and 1,439-1,528 benign biopsies. Annual mammography at age 40 alone could reduce risk by 36%-39%.

The false positives and benign biopsies represent cumulative lifetime results.

“We’ve known for a long time that mammography is less sensitive in younger women than in older women and, of course, when women have a genetic predisposition, we’re very concerned about early-onset cancer. We’ve also known that when you do MRI at the same time as mammography, you find a lot more cancers. [There are] more false positives, but there is clearly a greater yield of cancer in that setting, and the cancers are found earlier,” senior author Mark Robson, MD, said in an interview.

The model showed that mammography screening in women under 40 added no survival benefit, and led to additional false positives and benign biopsies.

“We know that MRI’s detection rate for cancers in a head-to-head comparison with mammography is extremely high, and so I’m not surprised that there was such a difference from a mammography strategy. What I was excited by is just how impactful the MRI screen was in terms of projected reduction in the risk of death. I thought that great,” said Dr. Robson, who is chief of the breast medicine service at Memorial Sloan Kettering Cancer Center, New York.

The balance of mortality reduction versus false positives and benign biopsies will need to be weighed by others. “We didn’t feel like we could make those judgments, but what we were presenting was for people who do make these kinds of policies. The reason that we said 30-35 years (for MRI initiation) is because at that point, the false positive versus life-years gained curve starts to plateau. For instance, when we look at strategies of starting MRI at 25, you we don’t get significantly more life years gained, but we do get more false positives,” Dr. Robson said.

The researchers did not conduct a former cost-benefit analysis for initiating MRI screening at age 30-35.

The study “reinforces the value of MRI for women with these variants that are really just entering the clinical consciousness, and affirms that we need to be doing that in young women to help prevent death from breast cancer. I also think that we need to look at really what mammogram is adding in young women and consider whether or not we really need it at the policy level,” he said.

The study was funded by the National Cancer Institute and the Breast Cancer Research Foundation. Dr. Robson has conducted clinical trials with AstraZeneca, Merck, and Pfizer.

Among women with ATM, CHEK2, or PALB2 pathogenic variants, annual MRI screening beginning at age 30 or 35, followed by concomitant MRI and mammography at age 40, could significantly reduce breast cancer mortality, according to a new model.

Adjunct screening with MRI is already recommended among women with the BRCA1 or BRCA2 mutations. ATM, CHEK2, and PALB2 are the most common of a more recently discovered group of pathogenic variants that confer a moderate to high risk of breast cancer.

In a study published online Feb. 17, 2022, in JAMA Oncology, researchers used two simulation models and risk estimates from the Cancer Risk Estimates Related to Susceptibility Consortium to predict that MRI screening at age 35 would produce a 54.4%-57.6% reduction in breast cancer mortality, with an estimated 4,661-5,001 false positive screenings and 1,280-1,368 benign biopsies per 1,000 women. At age 30, the model predicted 55.4-59.5% reduction in risk, 5,075-5,415 false positives, and 1,439-1,528 benign biopsies. Annual mammography at age 40 alone could reduce risk by 36%-39%.

The false positives and benign biopsies represent cumulative lifetime results.

“We’ve known for a long time that mammography is less sensitive in younger women than in older women and, of course, when women have a genetic predisposition, we’re very concerned about early-onset cancer. We’ve also known that when you do MRI at the same time as mammography, you find a lot more cancers. [There are] more false positives, but there is clearly a greater yield of cancer in that setting, and the cancers are found earlier,” senior author Mark Robson, MD, said in an interview.

The model showed that mammography screening in women under 40 added no survival benefit, and led to additional false positives and benign biopsies.

“We know that MRI’s detection rate for cancers in a head-to-head comparison with mammography is extremely high, and so I’m not surprised that there was such a difference from a mammography strategy. What I was excited by is just how impactful the MRI screen was in terms of projected reduction in the risk of death. I thought that great,” said Dr. Robson, who is chief of the breast medicine service at Memorial Sloan Kettering Cancer Center, New York.

The balance of mortality reduction versus false positives and benign biopsies will need to be weighed by others. “We didn’t feel like we could make those judgments, but what we were presenting was for people who do make these kinds of policies. The reason that we said 30-35 years (for MRI initiation) is because at that point, the false positive versus life-years gained curve starts to plateau. For instance, when we look at strategies of starting MRI at 25, you we don’t get significantly more life years gained, but we do get more false positives,” Dr. Robson said.

The researchers did not conduct a former cost-benefit analysis for initiating MRI screening at age 30-35.

The study “reinforces the value of MRI for women with these variants that are really just entering the clinical consciousness, and affirms that we need to be doing that in young women to help prevent death from breast cancer. I also think that we need to look at really what mammogram is adding in young women and consider whether or not we really need it at the policy level,” he said.

The study was funded by the National Cancer Institute and the Breast Cancer Research Foundation. Dr. Robson has conducted clinical trials with AstraZeneca, Merck, and Pfizer.