Patients with rheumatoid arthritis have steadily made their initial clinical presentation with shorter and shorter symptom durations and less severe inflammation from the early 1990s into the 2010s, but this paradoxically has coincided with gradual increases in the severity of patient-reported outcome measures, according to findings from the Leiden Early Arthritis Cohort.

For 1,406 patients who met 2010 European League Against Rheumatism/American College of Rheumatology rheumatoid arthritis (RA) criteria during 1993-2015, investigators led by Wouter P. Nieuwenhuis, MD, of the department of rheumatology at Leiden (the Netherlands) University Medical Center found that the symptom duration at initial presentation declined significantly from a median 138 days during 1993-1996 to 97 days during 2011-2015. Although the frequency of autoantibodies at presentation did not change significantly, the median number of swollen joints decreased from 12 to 6, median tender joints declined from 21 to 10, and median C-reactive protein levels dropped from 24 mg/L to 10 mg/L (all P values less than .001). All these measures declined steadily during the five time periods analyzed (1993-1996, 1997-2000, 2001-2005, 2006-2010, 2011-2015). Median scores on the Health Assessment Questionnaire, which measures functional disability, stayed the same in all five time periods.

©kgtoh/Thinkstock

In contrast, patient-reported outcomes measures (PROMs) on visual analog scales for pain, fatigue, and disease activity all rose significantly from 1993-1996 to 2011-2015.

“Presumably, the present findings are not specific for RA, but reflect a general increase in societal pressure posed upon the individual over the years (i.e., society has become more demanding), whereby smaller health problems, which might be less visible, could be experienced as more disabling. In parallel, patients may also have higher health expectations themselves. Both phenomena likely contribute to a shift of reference when reporting outcomes,” the researchers wrote.

They added that the current findings, in light of previous studies that found that PROMs are not responsive to changes in the severity of inflammation, “raise the question if it is known what PROMs actually measure. Furthermore, this may have consequences for the monitoring of RA using PROMs or composite scores (e.g., Disease Activity Score or Simple Disease Activity Index) for defining remission.”

Read the full study in Annals of the Rheumatic Diseases (Ann Rheum Dis. 2016 Aug 24. doi: 10.1136/annrheumdis-2016-209949).

[email protected]

Patients with rheumatoid arthritis have steadily made their initial clinical presentation with shorter and shorter symptom durations and less severe inflammation from the early 1990s into the 2010s, but this paradoxically has coincided with gradual increases in the severity of patient-reported outcome measures, according to findings from the Leiden Early Arthritis Cohort.

For 1,406 patients who met 2010 European League Against Rheumatism/American College of Rheumatology rheumatoid arthritis (RA) criteria during 1993-2015, investigators led by Wouter P. Nieuwenhuis, MD, of the department of rheumatology at Leiden (the Netherlands) University Medical Center found that the symptom duration at initial presentation declined significantly from a median 138 days during 1993-1996 to 97 days during 2011-2015. Although the frequency of autoantibodies at presentation did not change significantly, the median number of swollen joints decreased from 12 to 6, median tender joints declined from 21 to 10, and median C-reactive protein levels dropped from 24 mg/L to 10 mg/L (all P values less than .001). All these measures declined steadily during the five time periods analyzed (1993-1996, 1997-2000, 2001-2005, 2006-2010, 2011-2015). Median scores on the Health Assessment Questionnaire, which measures functional disability, stayed the same in all five time periods.

©kgtoh/Thinkstock

In contrast, patient-reported outcomes measures (PROMs) on visual analog scales for pain, fatigue, and disease activity all rose significantly from 1993-1996 to 2011-2015.

“Presumably, the present findings are not specific for RA, but reflect a general increase in societal pressure posed upon the individual over the years (i.e., society has become more demanding), whereby smaller health problems, which might be less visible, could be experienced as more disabling. In parallel, patients may also have higher health expectations themselves. Both phenomena likely contribute to a shift of reference when reporting outcomes,” the researchers wrote.

They added that the current findings, in light of previous studies that found that PROMs are not responsive to changes in the severity of inflammation, “raise the question if it is known what PROMs actually measure. Furthermore, this may have consequences for the monitoring of RA using PROMs or composite scores (e.g., Disease Activity Score or Simple Disease Activity Index) for defining remission.”

Read the full study in Annals of the Rheumatic Diseases (Ann Rheum Dis. 2016 Aug 24. doi: 10.1136/annrheumdis-2016-209949).

[email protected]

Patients with rheumatoid arthritis have steadily made their initial clinical presentation with shorter and shorter symptom durations and less severe inflammation from the early 1990s into the 2010s, but this paradoxically has coincided with gradual increases in the severity of patient-reported outcome measures, according to findings from the Leiden Early Arthritis Cohort.

For 1,406 patients who met 2010 European League Against Rheumatism/American College of Rheumatology rheumatoid arthritis (RA) criteria during 1993-2015, investigators led by Wouter P. Nieuwenhuis, MD, of the department of rheumatology at Leiden (the Netherlands) University Medical Center found that the symptom duration at initial presentation declined significantly from a median 138 days during 1993-1996 to 97 days during 2011-2015. Although the frequency of autoantibodies at presentation did not change significantly, the median number of swollen joints decreased from 12 to 6, median tender joints declined from 21 to 10, and median C-reactive protein levels dropped from 24 mg/L to 10 mg/L (all P values less than .001). All these measures declined steadily during the five time periods analyzed (1993-1996, 1997-2000, 2001-2005, 2006-2010, 2011-2015). Median scores on the Health Assessment Questionnaire, which measures functional disability, stayed the same in all five time periods.

©kgtoh/Thinkstock

In contrast, patient-reported outcomes measures (PROMs) on visual analog scales for pain, fatigue, and disease activity all rose significantly from 1993-1996 to 2011-2015.

“Presumably, the present findings are not specific for RA, but reflect a general increase in societal pressure posed upon the individual over the years (i.e., society has become more demanding), whereby smaller health problems, which might be less visible, could be experienced as more disabling. In parallel, patients may also have higher health expectations themselves. Both phenomena likely contribute to a shift of reference when reporting outcomes,” the researchers wrote.

They added that the current findings, in light of previous studies that found that PROMs are not responsive to changes in the severity of inflammation, “raise the question if it is known what PROMs actually measure. Furthermore, this may have consequences for the monitoring of RA using PROMs or composite scores (e.g., Disease Activity Score or Simple Disease Activity Index) for defining remission.”

Read the full study in Annals of the Rheumatic Diseases (Ann Rheum Dis. 2016 Aug 24. doi: 10.1136/annrheumdis-2016-209949).

[email protected]

TORONTO—Impairment in odor identification is a strong predictor of the transition to dementia, according to data described at the Alzheimer's Association International Conference. Entorhinal cortical thickness also predicts the transition to dementia, albeit to a lesser degree.

In addition, impaired odor identification, but not entorhinal cortical thickness, appears to predict cognitive decline. These results may provide indirect evidence that olfactory impairment precedes entorhinal cortical thinning, said Seonjoo Lee, PhD, Assistant Professor of Clinical Biostatistics in Psychiatry at Columbia University Mailman School of Public Health in New York.

The olfactory system undergoes structural and functional changes in the early stage of Alzheimer's disease. Dr. Lee and colleagues examined participants in the Washington Heights Community Aging Project II to determine whether the University of Pennsylvania Smell Identification Test (UPSIT) score predicts transition to dementia or cognitive decline. The investigators also sought to compare UPSIT score as a biomarker with entorhinal cortical thickness. Eligible participants were older than 65, did not have dementia, and underwent MRI and UPSIT at baseline. The researchers enrolled 397 subjects in the study and followed them for four years.

In all, 50 participants developed dementia during follow-up, including 49 people who developed Alzheimer's disease. Dr. Lee and colleagues measured average entorhinal cortical thickness using FreeSurfer and tested UPSIT and its interaction with entorhinal cortical thickness as the main effects.

The researchers measured participants' cognition by evaluating memory, language, and visuospatial cognition. They defined cognitive decline as a decline of one or more standard deviations in any of these cognitive domains during the four-year follow-up. In the examinations of incident dementia and cognitive decline, Dr. Lee and colleagues adjusted the data for age, gender, years of education, functional status, intracranial volume, and language of UPSIT administration.

UPSIT score, entorhinal cortical thickness, and these factors' interactions significantly predicted the transition to dementia. As UPSIT score declined, subjects were more likely to develop dementia. The same association was found for entorhinal cortical thickness. Among participants with olfactory impairment, thinning in the entorhinal cortex increased the risk of incident dementia.

In contrast, only UPSIT was a strong predictor of cognitive decline. Dr. Lee also found that entorhinal cortical thickness was significantly associated with UPSIT score only among subjects who transitioned to dementia. "This [result] confirmed that those two biomarkers are associated with each other for dementia," she said. The correlation also indicates that odor identification deficits are related to neurodegenerative changes in the entorhinal cortex during the progression of Alzheimer's disease, she added.

—Erik Greb

TORONTO—Impairment in odor identification is a strong predictor of the transition to dementia, according to data described at the Alzheimer's Association International Conference. Entorhinal cortical thickness also predicts the transition to dementia, albeit to a lesser degree.

In addition, impaired odor identification, but not entorhinal cortical thickness, appears to predict cognitive decline. These results may provide indirect evidence that olfactory impairment precedes entorhinal cortical thinning, said Seonjoo Lee, PhD, Assistant Professor of Clinical Biostatistics in Psychiatry at Columbia University Mailman School of Public Health in New York.

The olfactory system undergoes structural and functional changes in the early stage of Alzheimer's disease. Dr. Lee and colleagues examined participants in the Washington Heights Community Aging Project II to determine whether the University of Pennsylvania Smell Identification Test (UPSIT) score predicts transition to dementia or cognitive decline. The investigators also sought to compare UPSIT score as a biomarker with entorhinal cortical thickness. Eligible participants were older than 65, did not have dementia, and underwent MRI and UPSIT at baseline. The researchers enrolled 397 subjects in the study and followed them for four years.

In all, 50 participants developed dementia during follow-up, including 49 people who developed Alzheimer's disease. Dr. Lee and colleagues measured average entorhinal cortical thickness using FreeSurfer and tested UPSIT and its interaction with entorhinal cortical thickness as the main effects.

The researchers measured participants' cognition by evaluating memory, language, and visuospatial cognition. They defined cognitive decline as a decline of one or more standard deviations in any of these cognitive domains during the four-year follow-up. In the examinations of incident dementia and cognitive decline, Dr. Lee and colleagues adjusted the data for age, gender, years of education, functional status, intracranial volume, and language of UPSIT administration.

UPSIT score, entorhinal cortical thickness, and these factors' interactions significantly predicted the transition to dementia. As UPSIT score declined, subjects were more likely to develop dementia. The same association was found for entorhinal cortical thickness. Among participants with olfactory impairment, thinning in the entorhinal cortex increased the risk of incident dementia.

In contrast, only UPSIT was a strong predictor of cognitive decline. Dr. Lee also found that entorhinal cortical thickness was significantly associated with UPSIT score only among subjects who transitioned to dementia. "This [result] confirmed that those two biomarkers are associated with each other for dementia," she said. The correlation also indicates that odor identification deficits are related to neurodegenerative changes in the entorhinal cortex during the progression of Alzheimer's disease, she added.

—Erik Greb

TORONTO—Impairment in odor identification is a strong predictor of the transition to dementia, according to data described at the Alzheimer's Association International Conference. Entorhinal cortical thickness also predicts the transition to dementia, albeit to a lesser degree.

In addition, impaired odor identification, but not entorhinal cortical thickness, appears to predict cognitive decline. These results may provide indirect evidence that olfactory impairment precedes entorhinal cortical thinning, said Seonjoo Lee, PhD, Assistant Professor of Clinical Biostatistics in Psychiatry at Columbia University Mailman School of Public Health in New York.

The olfactory system undergoes structural and functional changes in the early stage of Alzheimer's disease. Dr. Lee and colleagues examined participants in the Washington Heights Community Aging Project II to determine whether the University of Pennsylvania Smell Identification Test (UPSIT) score predicts transition to dementia or cognitive decline. The investigators also sought to compare UPSIT score as a biomarker with entorhinal cortical thickness. Eligible participants were older than 65, did not have dementia, and underwent MRI and UPSIT at baseline. The researchers enrolled 397 subjects in the study and followed them for four years.

In all, 50 participants developed dementia during follow-up, including 49 people who developed Alzheimer's disease. Dr. Lee and colleagues measured average entorhinal cortical thickness using FreeSurfer and tested UPSIT and its interaction with entorhinal cortical thickness as the main effects.

The researchers measured participants' cognition by evaluating memory, language, and visuospatial cognition. They defined cognitive decline as a decline of one or more standard deviations in any of these cognitive domains during the four-year follow-up. In the examinations of incident dementia and cognitive decline, Dr. Lee and colleagues adjusted the data for age, gender, years of education, functional status, intracranial volume, and language of UPSIT administration.

UPSIT score, entorhinal cortical thickness, and these factors' interactions significantly predicted the transition to dementia. As UPSIT score declined, subjects were more likely to develop dementia. The same association was found for entorhinal cortical thickness. Among participants with olfactory impairment, thinning in the entorhinal cortex increased the risk of incident dementia.

In contrast, only UPSIT was a strong predictor of cognitive decline. Dr. Lee also found that entorhinal cortical thickness was significantly associated with UPSIT score only among subjects who transitioned to dementia. "This [result] confirmed that those two biomarkers are associated with each other for dementia," she said. The correlation also indicates that odor identification deficits are related to neurodegenerative changes in the entorhinal cortex during the progression of Alzheimer's disease, she added.

—Erik Greb

CHICAGO – A new model of gastroesophageal reflux disease (GERD) paints it as a disease caused by inflammatory molecules, rather than a reaction to an acid-inflicted wound.

And rather than esophagitis due to GERD being a top-down process, from surface epithelium to submucosa, multiple lines of evidence now suggest it is a bottom-up phenomenon sparked by activation of a hypoxia-inducible factor that occurs when esophageal epithelium is exposed to acidic bile salts, Rhonda Souza, MD, said at the meeting sponsored by the American Gastroenterological Association.

Michele G. Sullivan/Frontline Medical News

“We’re proposing that reflux is a cytokine-mediated injury,” said Dr. Souza of the University of Texas Southwestern Medical Center, Dallas, and the Dallas VA Medical Center. “The reflux of acid and bile doesn’t destroy the epithelial cells directly, but induces them to produce proinflammatory cytokines. These cytokines attract lymphocytes first, which induce the basal cell proliferation characteristic of GERD. Ultimately, it’s these inflammatory cells that mediate the epithelial injury – not the direct caustic effects of gastric acid.”

Dr. Souza and her colleagues, including Dr. Stuart Spechler and Dr. Kerry Dunbar, also of UT Southwestern and the Dallas VA Medical Center, have been building this case for several years, beginning with a surgical rat model of GERD. Their histologic findings in this model have been recapitulated in human cell lines and, most recently, in a clinical trial of 12 patients (JAMA. 2016. doi:10.1001/jama.2016.5657).

The rat model, published in 2009 (Gastroenterology. 2009. doi:10.1053/j.gastro.2009.07.055) provided one of the first very early looks at the pathogenesis of acute GERD.

Rats underwent esophagoduodenostomy, a procedure that left the stomach in place so that both gastric and duodenal contents could reflux into the esophagus, thus ensuring immediate esophageal exposure to acid and bile acids. But the investigators were puzzled as to why it took weeks to see changes in the esophageal surface. “The epithelial mucosa stayed intact for far longer than it should have – up to 3 weeks – if acid simply caused a caustic injury as the mechanism of cell death and replacement,” Dr. Souza said.

What she did see, however, was a rapid migration of T cells into the submucosa. “By postoperative week 3, we observed profound basal cell and papillary hyperplasia, but the surface cells were still intact, so this hyperplasia was not due to the death of surface cells.”

The team proceeded to an in vitro model using esophageal squamous cell lines established from endoscopic biopsies obtained from GERD patients. When the squamous cells were exposed in culture to acidic bile salts, the cells ramped up their production of several proinflammatory cytokines, including interleukin-8 and interleukin-1b. The production of proinflammatory cytokines released into the surrounding media were potent recruitment signals for lymphocytes.

The researchers saw this same signaling response in their rat model. “We saw a dramatic increase in IL-8 by postoperative week 2. It was in the intracellular spaces between cells at the epithelial surface and in the cell cytoplasm, and we also saw it in the submucosa and in the lamina propria.”

Acute reflux esophagitis has been almost impossible to observe in humans, Dr. Souza said, because most patients don’t seek medical attention until they’ve had months or years of acid reflux symptoms. By then, the injury response to gastroesophageal reflux has become chronic and well established.

The human study, published in May, confirmed the findings in the rat model. It comprised 12 patients with severe GERD who had been on twice-daily proton pump inhibitor (PPI) therapy for at least 1 month. Successful PPI treatment heals reflux esophagitis rapidly, and healing was endoscopically confirmed at baseline in all these patients. Then, however, they gave up their medication so that the damage would begin again. Dr. Souza and her colleagues could travel back in time, clinically speaking, and track the histopatholgic changes as they occurred. Within 2 weeks, esophagitis had reappeared in every patient: Three had the least-severe LA (Los Angeles) grade A, four had LA grade B, and five had LA grade C esophagitis, with extensive mucosal breaks.

“We know from older studies that within 6 months of going off of PPIs, most patients with reflux esophagitis develop it again, but we weren’t sure we would get this response within 2 weeks. It was surprising that not only did everyone get it, but that a few were so severe,” Dr. Souza said.

Biopsies at weeks 1 and 2 showed the same kind of inflammatory signaling seen in the rats. Again, the responding cells were almost exclusively lymphocytes; neutrophils and eosinophils were very rare or absent in all specimens. The team also observed basal cell and papillary hyperplasia and areas of spongiosis, even though the surface cells were still intact.

The lymphocyte-predominant response is the key to this new pathogenic theory, Dr. Souza wrote in her JAMA paper.

“If the traditional notion were true, that acute GERD is caused by refluxed acid directly inflicting lethal, chemical injury to surface epithelial cells, then basal cell and papillary hyperplasia would have been expected only in areas with surface erosions, and the infiltrating inflammatory cells would have been granulocytes primarily.”

She also suggested that PPIs may be healing esophagitis not simply by preventing acid reflux, but by exerting anti-inflammatory properties.

“Cytokines like IL-8 may also have proliferative effects which might have contributed to esophageal basal cell and papillary hyperplasia observed in the absence of surface erosions. In esophageal epithelial cells in culture, PPIs inhibit secretion of IL-8 through acid-independent mechanisms. This observation raises the interesting possibility that anti-inflammatory PPI effects, independent of their effects on acid inhibition, might contribute to GERD healing by PPIs.”

Dr. Souza said she continues to investigate, focusing now on how the initial insult of acidic bile salts on esophageal epithelium stimulates this inflammatory response. The key may be in a small protein called hypoxia-inducible factor-2 alpha (HIF-2a), one of a family of transcription factors that enable cells to respond to hypoxic stress.

Under normal oxygen conditions, HIF proteins are low, their levels regulated by an enzyme called prolyl hydroxylase. This enzyme is inactivated under hypoxic conditions, or in the presence of reactive oxygen species. HIF factors then rise and, among other functions, stimulate a strong inflammatory response. Inflamed tissues like those seen in esophagitis are frequently hypoxic, Dr. Souza said, and this state could be activating HIFs.

She examined HIF levels in her 12-patient cohort. These results were presented earlier this year at the Digestive Disease Weekmeeting in San Diego.

“At weeks 1 and 2, we found large associations between HIF-2a and increases in a number of proinflammatory cytokines including IL-8 and intercellular adhesion molecule–1,” a protein that facilitates leukocyte migration. Preliminary studies of HIF-2a inhibition in esophageal squamous cells in culture exposed to acidic bile salts show promising results as a potential therapeutic strategy to reduce proinflammatory cytokine expression. It is conceivable that anti-inflammatory therapies directed at HIF-2a may be on the horizon for the prevention and treatment of reflux esophagitis, she added.

Neither Dr. Souza nor her colleagues had any relevant financial disclosures.

[email protected]

On Twitter @Alz_Gal

CHICAGO – A new model of gastroesophageal reflux disease (GERD) paints it as a disease caused by inflammatory molecules, rather than a reaction to an acid-inflicted wound.

And rather than esophagitis due to GERD being a top-down process, from surface epithelium to submucosa, multiple lines of evidence now suggest it is a bottom-up phenomenon sparked by activation of a hypoxia-inducible factor that occurs when esophageal epithelium is exposed to acidic bile salts, Rhonda Souza, MD, said at the meeting sponsored by the American Gastroenterological Association.

Michele G. Sullivan/Frontline Medical News

“We’re proposing that reflux is a cytokine-mediated injury,” said Dr. Souza of the University of Texas Southwestern Medical Center, Dallas, and the Dallas VA Medical Center. “The reflux of acid and bile doesn’t destroy the epithelial cells directly, but induces them to produce proinflammatory cytokines. These cytokines attract lymphocytes first, which induce the basal cell proliferation characteristic of GERD. Ultimately, it’s these inflammatory cells that mediate the epithelial injury – not the direct caustic effects of gastric acid.”

Dr. Souza and her colleagues, including Dr. Stuart Spechler and Dr. Kerry Dunbar, also of UT Southwestern and the Dallas VA Medical Center, have been building this case for several years, beginning with a surgical rat model of GERD. Their histologic findings in this model have been recapitulated in human cell lines and, most recently, in a clinical trial of 12 patients (JAMA. 2016. doi:10.1001/jama.2016.5657).

The rat model, published in 2009 (Gastroenterology. 2009. doi:10.1053/j.gastro.2009.07.055) provided one of the first very early looks at the pathogenesis of acute GERD.

Rats underwent esophagoduodenostomy, a procedure that left the stomach in place so that both gastric and duodenal contents could reflux into the esophagus, thus ensuring immediate esophageal exposure to acid and bile acids. But the investigators were puzzled as to why it took weeks to see changes in the esophageal surface. “The epithelial mucosa stayed intact for far longer than it should have – up to 3 weeks – if acid simply caused a caustic injury as the mechanism of cell death and replacement,” Dr. Souza said.

What she did see, however, was a rapid migration of T cells into the submucosa. “By postoperative week 3, we observed profound basal cell and papillary hyperplasia, but the surface cells were still intact, so this hyperplasia was not due to the death of surface cells.”

The team proceeded to an in vitro model using esophageal squamous cell lines established from endoscopic biopsies obtained from GERD patients. When the squamous cells were exposed in culture to acidic bile salts, the cells ramped up their production of several proinflammatory cytokines, including interleukin-8 and interleukin-1b. The production of proinflammatory cytokines released into the surrounding media were potent recruitment signals for lymphocytes.

The researchers saw this same signaling response in their rat model. “We saw a dramatic increase in IL-8 by postoperative week 2. It was in the intracellular spaces between cells at the epithelial surface and in the cell cytoplasm, and we also saw it in the submucosa and in the lamina propria.”

Acute reflux esophagitis has been almost impossible to observe in humans, Dr. Souza said, because most patients don’t seek medical attention until they’ve had months or years of acid reflux symptoms. By then, the injury response to gastroesophageal reflux has become chronic and well established.

The human study, published in May, confirmed the findings in the rat model. It comprised 12 patients with severe GERD who had been on twice-daily proton pump inhibitor (PPI) therapy for at least 1 month. Successful PPI treatment heals reflux esophagitis rapidly, and healing was endoscopically confirmed at baseline in all these patients. Then, however, they gave up their medication so that the damage would begin again. Dr. Souza and her colleagues could travel back in time, clinically speaking, and track the histopatholgic changes as they occurred. Within 2 weeks, esophagitis had reappeared in every patient: Three had the least-severe LA (Los Angeles) grade A, four had LA grade B, and five had LA grade C esophagitis, with extensive mucosal breaks.

“We know from older studies that within 6 months of going off of PPIs, most patients with reflux esophagitis develop it again, but we weren’t sure we would get this response within 2 weeks. It was surprising that not only did everyone get it, but that a few were so severe,” Dr. Souza said.

Biopsies at weeks 1 and 2 showed the same kind of inflammatory signaling seen in the rats. Again, the responding cells were almost exclusively lymphocytes; neutrophils and eosinophils were very rare or absent in all specimens. The team also observed basal cell and papillary hyperplasia and areas of spongiosis, even though the surface cells were still intact.

The lymphocyte-predominant response is the key to this new pathogenic theory, Dr. Souza wrote in her JAMA paper.

“If the traditional notion were true, that acute GERD is caused by refluxed acid directly inflicting lethal, chemical injury to surface epithelial cells, then basal cell and papillary hyperplasia would have been expected only in areas with surface erosions, and the infiltrating inflammatory cells would have been granulocytes primarily.”

She also suggested that PPIs may be healing esophagitis not simply by preventing acid reflux, but by exerting anti-inflammatory properties.

“Cytokines like IL-8 may also have proliferative effects which might have contributed to esophageal basal cell and papillary hyperplasia observed in the absence of surface erosions. In esophageal epithelial cells in culture, PPIs inhibit secretion of IL-8 through acid-independent mechanisms. This observation raises the interesting possibility that anti-inflammatory PPI effects, independent of their effects on acid inhibition, might contribute to GERD healing by PPIs.”

Dr. Souza said she continues to investigate, focusing now on how the initial insult of acidic bile salts on esophageal epithelium stimulates this inflammatory response. The key may be in a small protein called hypoxia-inducible factor-2 alpha (HIF-2a), one of a family of transcription factors that enable cells to respond to hypoxic stress.

Under normal oxygen conditions, HIF proteins are low, their levels regulated by an enzyme called prolyl hydroxylase. This enzyme is inactivated under hypoxic conditions, or in the presence of reactive oxygen species. HIF factors then rise and, among other functions, stimulate a strong inflammatory response. Inflamed tissues like those seen in esophagitis are frequently hypoxic, Dr. Souza said, and this state could be activating HIFs.

She examined HIF levels in her 12-patient cohort. These results were presented earlier this year at the Digestive Disease Weekmeeting in San Diego.

“At weeks 1 and 2, we found large associations between HIF-2a and increases in a number of proinflammatory cytokines including IL-8 and intercellular adhesion molecule–1,” a protein that facilitates leukocyte migration. Preliminary studies of HIF-2a inhibition in esophageal squamous cells in culture exposed to acidic bile salts show promising results as a potential therapeutic strategy to reduce proinflammatory cytokine expression. It is conceivable that anti-inflammatory therapies directed at HIF-2a may be on the horizon for the prevention and treatment of reflux esophagitis, she added.

Neither Dr. Souza nor her colleagues had any relevant financial disclosures.

[email protected]

On Twitter @Alz_Gal

CHICAGO – A new model of gastroesophageal reflux disease (GERD) paints it as a disease caused by inflammatory molecules, rather than a reaction to an acid-inflicted wound.

And rather than esophagitis due to GERD being a top-down process, from surface epithelium to submucosa, multiple lines of evidence now suggest it is a bottom-up phenomenon sparked by activation of a hypoxia-inducible factor that occurs when esophageal epithelium is exposed to acidic bile salts, Rhonda Souza, MD, said at the meeting sponsored by the American Gastroenterological Association.

Michele G. Sullivan/Frontline Medical News

“We’re proposing that reflux is a cytokine-mediated injury,” said Dr. Souza of the University of Texas Southwestern Medical Center, Dallas, and the Dallas VA Medical Center. “The reflux of acid and bile doesn’t destroy the epithelial cells directly, but induces them to produce proinflammatory cytokines. These cytokines attract lymphocytes first, which induce the basal cell proliferation characteristic of GERD. Ultimately, it’s these inflammatory cells that mediate the epithelial injury – not the direct caustic effects of gastric acid.”

Dr. Souza and her colleagues, including Dr. Stuart Spechler and Dr. Kerry Dunbar, also of UT Southwestern and the Dallas VA Medical Center, have been building this case for several years, beginning with a surgical rat model of GERD. Their histologic findings in this model have been recapitulated in human cell lines and, most recently, in a clinical trial of 12 patients (JAMA. 2016. doi:10.1001/jama.2016.5657).

The rat model, published in 2009 (Gastroenterology. 2009. doi:10.1053/j.gastro.2009.07.055) provided one of the first very early looks at the pathogenesis of acute GERD.

Rats underwent esophagoduodenostomy, a procedure that left the stomach in place so that both gastric and duodenal contents could reflux into the esophagus, thus ensuring immediate esophageal exposure to acid and bile acids. But the investigators were puzzled as to why it took weeks to see changes in the esophageal surface. “The epithelial mucosa stayed intact for far longer than it should have – up to 3 weeks – if acid simply caused a caustic injury as the mechanism of cell death and replacement,” Dr. Souza said.

What she did see, however, was a rapid migration of T cells into the submucosa. “By postoperative week 3, we observed profound basal cell and papillary hyperplasia, but the surface cells were still intact, so this hyperplasia was not due to the death of surface cells.”

The team proceeded to an in vitro model using esophageal squamous cell lines established from endoscopic biopsies obtained from GERD patients. When the squamous cells were exposed in culture to acidic bile salts, the cells ramped up their production of several proinflammatory cytokines, including interleukin-8 and interleukin-1b. The production of proinflammatory cytokines released into the surrounding media were potent recruitment signals for lymphocytes.

The researchers saw this same signaling response in their rat model. “We saw a dramatic increase in IL-8 by postoperative week 2. It was in the intracellular spaces between cells at the epithelial surface and in the cell cytoplasm, and we also saw it in the submucosa and in the lamina propria.”

Acute reflux esophagitis has been almost impossible to observe in humans, Dr. Souza said, because most patients don’t seek medical attention until they’ve had months or years of acid reflux symptoms. By then, the injury response to gastroesophageal reflux has become chronic and well established.

The human study, published in May, confirmed the findings in the rat model. It comprised 12 patients with severe GERD who had been on twice-daily proton pump inhibitor (PPI) therapy for at least 1 month. Successful PPI treatment heals reflux esophagitis rapidly, and healing was endoscopically confirmed at baseline in all these patients. Then, however, they gave up their medication so that the damage would begin again. Dr. Souza and her colleagues could travel back in time, clinically speaking, and track the histopatholgic changes as they occurred. Within 2 weeks, esophagitis had reappeared in every patient: Three had the least-severe LA (Los Angeles) grade A, four had LA grade B, and five had LA grade C esophagitis, with extensive mucosal breaks.

“We know from older studies that within 6 months of going off of PPIs, most patients with reflux esophagitis develop it again, but we weren’t sure we would get this response within 2 weeks. It was surprising that not only did everyone get it, but that a few were so severe,” Dr. Souza said.

Biopsies at weeks 1 and 2 showed the same kind of inflammatory signaling seen in the rats. Again, the responding cells were almost exclusively lymphocytes; neutrophils and eosinophils were very rare or absent in all specimens. The team also observed basal cell and papillary hyperplasia and areas of spongiosis, even though the surface cells were still intact.

The lymphocyte-predominant response is the key to this new pathogenic theory, Dr. Souza wrote in her JAMA paper.

“If the traditional notion were true, that acute GERD is caused by refluxed acid directly inflicting lethal, chemical injury to surface epithelial cells, then basal cell and papillary hyperplasia would have been expected only in areas with surface erosions, and the infiltrating inflammatory cells would have been granulocytes primarily.”

She also suggested that PPIs may be healing esophagitis not simply by preventing acid reflux, but by exerting anti-inflammatory properties.

“Cytokines like IL-8 may also have proliferative effects which might have contributed to esophageal basal cell and papillary hyperplasia observed in the absence of surface erosions. In esophageal epithelial cells in culture, PPIs inhibit secretion of IL-8 through acid-independent mechanisms. This observation raises the interesting possibility that anti-inflammatory PPI effects, independent of their effects on acid inhibition, might contribute to GERD healing by PPIs.”

Dr. Souza said she continues to investigate, focusing now on how the initial insult of acidic bile salts on esophageal epithelium stimulates this inflammatory response. The key may be in a small protein called hypoxia-inducible factor-2 alpha (HIF-2a), one of a family of transcription factors that enable cells to respond to hypoxic stress.

Under normal oxygen conditions, HIF proteins are low, their levels regulated by an enzyme called prolyl hydroxylase. This enzyme is inactivated under hypoxic conditions, or in the presence of reactive oxygen species. HIF factors then rise and, among other functions, stimulate a strong inflammatory response. Inflamed tissues like those seen in esophagitis are frequently hypoxic, Dr. Souza said, and this state could be activating HIFs.

She examined HIF levels in her 12-patient cohort. These results were presented earlier this year at the Digestive Disease Weekmeeting in San Diego.

“At weeks 1 and 2, we found large associations between HIF-2a and increases in a number of proinflammatory cytokines including IL-8 and intercellular adhesion molecule–1,” a protein that facilitates leukocyte migration. Preliminary studies of HIF-2a inhibition in esophageal squamous cells in culture exposed to acidic bile salts show promising results as a potential therapeutic strategy to reduce proinflammatory cytokine expression. It is conceivable that anti-inflammatory therapies directed at HIF-2a may be on the horizon for the prevention and treatment of reflux esophagitis, she added.

Neither Dr. Souza nor her colleagues had any relevant financial disclosures.

[email protected]

On Twitter @Alz_Gal

Researchers have found a correlation between multiple sclerosis (MS) and changes in the human gut microbiome, according to data published June 28 in Nature Communications. "There are a number of ways that the microbiome could play a role in MS, and this opens up a whole new world of looking at the disease in a way that it's never been looked at before," said Howard L. Weiner, MD, Director of the Partners MS Center and Codirector of the Ann Romney Center for Neurologic Disease at Brigham and Women's Hospital in Boston.

Previous studies have suggested a connection between bacteria in the gut and MS, as well as inflammatory bowel disease, type 1 diabetes, and rheumatoid arthritis. In one study of 20 patients with MS and 40 healthy controls, researchers found decreased numbers of Faecalibacterium, Prevotella, and Anaerostipes in patients with MS. The connection between microbiota, treatment, and changes in immunity, however, was not investigated. Because the gut microbiome plays a vital role in immune function and autoimmune disease, Dr. Weiner and his colleagues conducted research to detect changes in the intestinal microbiota in patients with MS, compared with controls. "If further studies demonstrate that these candidate microorganisms play an active role in either contributing to or ameliorating MS, then there is potential to develop new diagnostics and therapies to combat the disease," said Dr. Weiner.

The investigators examined data and collected stool samples from 60 untreated and treated patients with relapsing-remitting MS and 43 healthy control subjects. Subjects were part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis study. None of the patients had an active relapse at the time of study enrollment. For the study, microbial DNA was removed from fecal samples, and gene sequencing was performed with two platforms using primers targeting the V3-5 or the V4 variable regions. Investigators also collected breath samples from a second cohort of 41 patients with MS and 32 controls after they participated in an overnight fast.

Patients with MS had microbial changes in the gut that were associated with the activity of genes that play a role in the immune system. Specifically, researchers found that the gut microbiome in patients with MS contained higher levels of Methanobrevibacter and Akkermansia, and lower levels of Butyricimonas, compared with healthy controls. Increased levels of Methanobrevibacter in patients with MS resulted in higher levels of methane in their breath samples, said the researchers. In addition, patients with MS on disease-modifying treatment had increased abundances of Prevotella and Sutterella, and decreased levels of Sarcina, compared with untreated patients with MS.

"This work provides a window into how the gut can affect the immune system, which can then affect the brain. Characterizing the gut microbiome in those with MS may provide new opportunities to diagnose MS and point us toward new interventions to help prevent disease development in those who are risk," said Dr. Weiner.

The researchers plan to continue studying the connection between gut bacteria and the immune system in hopes of developing improved treatment strategies. "In addition, characterization of the gut microbiome in MS may provide biomarkers for assessing disease activity and could theoretically be an avenue to prevent MS in young at-risk populations," said Dr. Weiner.

—Erica Robinson

Researchers have found a correlation between multiple sclerosis (MS) and changes in the human gut microbiome, according to data published June 28 in Nature Communications. "There are a number of ways that the microbiome could play a role in MS, and this opens up a whole new world of looking at the disease in a way that it's never been looked at before," said Howard L. Weiner, MD, Director of the Partners MS Center and Codirector of the Ann Romney Center for Neurologic Disease at Brigham and Women's Hospital in Boston.

Previous studies have suggested a connection between bacteria in the gut and MS, as well as inflammatory bowel disease, type 1 diabetes, and rheumatoid arthritis. In one study of 20 patients with MS and 40 healthy controls, researchers found decreased numbers of Faecalibacterium, Prevotella, and Anaerostipes in patients with MS. The connection between microbiota, treatment, and changes in immunity, however, was not investigated. Because the gut microbiome plays a vital role in immune function and autoimmune disease, Dr. Weiner and his colleagues conducted research to detect changes in the intestinal microbiota in patients with MS, compared with controls. "If further studies demonstrate that these candidate microorganisms play an active role in either contributing to or ameliorating MS, then there is potential to develop new diagnostics and therapies to combat the disease," said Dr. Weiner.

The investigators examined data and collected stool samples from 60 untreated and treated patients with relapsing-remitting MS and 43 healthy control subjects. Subjects were part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis study. None of the patients had an active relapse at the time of study enrollment. For the study, microbial DNA was removed from fecal samples, and gene sequencing was performed with two platforms using primers targeting the V3-5 or the V4 variable regions. Investigators also collected breath samples from a second cohort of 41 patients with MS and 32 controls after they participated in an overnight fast.

Patients with MS had microbial changes in the gut that were associated with the activity of genes that play a role in the immune system. Specifically, researchers found that the gut microbiome in patients with MS contained higher levels of Methanobrevibacter and Akkermansia, and lower levels of Butyricimonas, compared with healthy controls. Increased levels of Methanobrevibacter in patients with MS resulted in higher levels of methane in their breath samples, said the researchers. In addition, patients with MS on disease-modifying treatment had increased abundances of Prevotella and Sutterella, and decreased levels of Sarcina, compared with untreated patients with MS.

"This work provides a window into how the gut can affect the immune system, which can then affect the brain. Characterizing the gut microbiome in those with MS may provide new opportunities to diagnose MS and point us toward new interventions to help prevent disease development in those who are risk," said Dr. Weiner.

The researchers plan to continue studying the connection between gut bacteria and the immune system in hopes of developing improved treatment strategies. "In addition, characterization of the gut microbiome in MS may provide biomarkers for assessing disease activity and could theoretically be an avenue to prevent MS in young at-risk populations," said Dr. Weiner.

—Erica Robinson

Researchers have found a correlation between multiple sclerosis (MS) and changes in the human gut microbiome, according to data published June 28 in Nature Communications. "There are a number of ways that the microbiome could play a role in MS, and this opens up a whole new world of looking at the disease in a way that it's never been looked at before," said Howard L. Weiner, MD, Director of the Partners MS Center and Codirector of the Ann Romney Center for Neurologic Disease at Brigham and Women's Hospital in Boston.

Previous studies have suggested a connection between bacteria in the gut and MS, as well as inflammatory bowel disease, type 1 diabetes, and rheumatoid arthritis. In one study of 20 patients with MS and 40 healthy controls, researchers found decreased numbers of Faecalibacterium, Prevotella, and Anaerostipes in patients with MS. The connection between microbiota, treatment, and changes in immunity, however, was not investigated. Because the gut microbiome plays a vital role in immune function and autoimmune disease, Dr. Weiner and his colleagues conducted research to detect changes in the intestinal microbiota in patients with MS, compared with controls. "If further studies demonstrate that these candidate microorganisms play an active role in either contributing to or ameliorating MS, then there is potential to develop new diagnostics and therapies to combat the disease," said Dr. Weiner.

The investigators examined data and collected stool samples from 60 untreated and treated patients with relapsing-remitting MS and 43 healthy control subjects. Subjects were part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis study. None of the patients had an active relapse at the time of study enrollment. For the study, microbial DNA was removed from fecal samples, and gene sequencing was performed with two platforms using primers targeting the V3-5 or the V4 variable regions. Investigators also collected breath samples from a second cohort of 41 patients with MS and 32 controls after they participated in an overnight fast.

Patients with MS had microbial changes in the gut that were associated with the activity of genes that play a role in the immune system. Specifically, researchers found that the gut microbiome in patients with MS contained higher levels of Methanobrevibacter and Akkermansia, and lower levels of Butyricimonas, compared with healthy controls. Increased levels of Methanobrevibacter in patients with MS resulted in higher levels of methane in their breath samples, said the researchers. In addition, patients with MS on disease-modifying treatment had increased abundances of Prevotella and Sutterella, and decreased levels of Sarcina, compared with untreated patients with MS.

"This work provides a window into how the gut can affect the immune system, which can then affect the brain. Characterizing the gut microbiome in those with MS may provide new opportunities to diagnose MS and point us toward new interventions to help prevent disease development in those who are risk," said Dr. Weiner.

The researchers plan to continue studying the connection between gut bacteria and the immune system in hopes of developing improved treatment strategies. "In addition, characterization of the gut microbiome in MS may provide biomarkers for assessing disease activity and could theoretically be an avenue to prevent MS in young at-risk populations," said Dr. Weiner.

—Erica Robinson

Abatacept does not reduce the number of new gadolinium-enhancing lesions on MRI in patients with relapsing-remitting multiple sclerosis (MS), according to results from the double-blind, randomized, placebo-controlled phase II ACCLAIM study published online ahead of print August 1 in Multiple Sclerosis.

In the ACCLAIM (A Cooperative Clinical Study of Abatacept in MS) study, 42 patients who received abatacept (Orencia) developed a mean of 0.43 new gadolinium-enhancing lesions by week 24, compared with 1.66 lesions for 20 placebo-treated patients. None of the secondary MRI end points (ie, lesion volume change and percent brain volume change) and clinical end points (ie, changes in MS Functional Composite score, Expanded Disability Status Scale [EDSS], and annualized relapse rate) at 24 weeks differed significantly between the groups. The rate of patients who met criteria for no evidence of disease activity or its components (ie, no EDSS progression, no clinical exacerbations, and no new gadolinium-enhancing MRI lesion) from week 8 and before week 28 did not differ between the groups.

During a 28-week extension phase in which the groups switched treatments, patients who switched from abatacept to placebo had a greater number of gadolinium-enhancing lesions than did those who switched from placebo to abatacept (1.25 vs 0.60, respectively), but the difference was not statistically significant.

Abatacept, which is approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis, is a CTLA4 immunoglobulin fusion protein that inhibits the activation of T lymphocytes by blocking the CD28-B7 costimulatory pathway. It was thought to have potential to reduce immune-mediated disease activity in relapsing-remitting MS because T lymphocytes have been implicated in its pathogenesis.

The investigators closed enrollment for the trial early because of slow accrual. The 65 patients who were enrolled in the trial were about half of the population considered to be required (ie, 123) to demonstrate a treatment effect of 50% reduction of new gadolinium-enhancing MRI lesions.

—Jeff Evans

Abatacept does not reduce the number of new gadolinium-enhancing lesions on MRI in patients with relapsing-remitting multiple sclerosis (MS), according to results from the double-blind, randomized, placebo-controlled phase II ACCLAIM study published online ahead of print August 1 in Multiple Sclerosis.

In the ACCLAIM (A Cooperative Clinical Study of Abatacept in MS) study, 42 patients who received abatacept (Orencia) developed a mean of 0.43 new gadolinium-enhancing lesions by week 24, compared with 1.66 lesions for 20 placebo-treated patients. None of the secondary MRI end points (ie, lesion volume change and percent brain volume change) and clinical end points (ie, changes in MS Functional Composite score, Expanded Disability Status Scale [EDSS], and annualized relapse rate) at 24 weeks differed significantly between the groups. The rate of patients who met criteria for no evidence of disease activity or its components (ie, no EDSS progression, no clinical exacerbations, and no new gadolinium-enhancing MRI lesion) from week 8 and before week 28 did not differ between the groups.

During a 28-week extension phase in which the groups switched treatments, patients who switched from abatacept to placebo had a greater number of gadolinium-enhancing lesions than did those who switched from placebo to abatacept (1.25 vs 0.60, respectively), but the difference was not statistically significant.

Abatacept, which is approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis, is a CTLA4 immunoglobulin fusion protein that inhibits the activation of T lymphocytes by blocking the CD28-B7 costimulatory pathway. It was thought to have potential to reduce immune-mediated disease activity in relapsing-remitting MS because T lymphocytes have been implicated in its pathogenesis.

The investigators closed enrollment for the trial early because of slow accrual. The 65 patients who were enrolled in the trial were about half of the population considered to be required (ie, 123) to demonstrate a treatment effect of 50% reduction of new gadolinium-enhancing MRI lesions.

—Jeff Evans

Abatacept does not reduce the number of new gadolinium-enhancing lesions on MRI in patients with relapsing-remitting multiple sclerosis (MS), according to results from the double-blind, randomized, placebo-controlled phase II ACCLAIM study published online ahead of print August 1 in Multiple Sclerosis.

In the ACCLAIM (A Cooperative Clinical Study of Abatacept in MS) study, 42 patients who received abatacept (Orencia) developed a mean of 0.43 new gadolinium-enhancing lesions by week 24, compared with 1.66 lesions for 20 placebo-treated patients. None of the secondary MRI end points (ie, lesion volume change and percent brain volume change) and clinical end points (ie, changes in MS Functional Composite score, Expanded Disability Status Scale [EDSS], and annualized relapse rate) at 24 weeks differed significantly between the groups. The rate of patients who met criteria for no evidence of disease activity or its components (ie, no EDSS progression, no clinical exacerbations, and no new gadolinium-enhancing MRI lesion) from week 8 and before week 28 did not differ between the groups.

During a 28-week extension phase in which the groups switched treatments, patients who switched from abatacept to placebo had a greater number of gadolinium-enhancing lesions than did those who switched from placebo to abatacept (1.25 vs 0.60, respectively), but the difference was not statistically significant.

Abatacept, which is approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis, is a CTLA4 immunoglobulin fusion protein that inhibits the activation of T lymphocytes by blocking the CD28-B7 costimulatory pathway. It was thought to have potential to reduce immune-mediated disease activity in relapsing-remitting MS because T lymphocytes have been implicated in its pathogenesis.

The investigators closed enrollment for the trial early because of slow accrual. The 65 patients who were enrolled in the trial were about half of the population considered to be required (ie, 123) to demonstrate a treatment effect of 50% reduction of new gadolinium-enhancing MRI lesions.

—Jeff Evans

Boston – Shared medical appointments can work well for patients undergoing solid organ transplants and for the clinical staff treating them – serving as an efficient way to educate several patients in a common setting and giving them the opportunity to interact with others going through a similar experience.

“Having those shared medical appointments where they’re sitting next to somebody who’s going through the same thought process and information gathering ... and the ability to talk with similar folks is a huge benefit for those patients,” said Allison Vidimos, MD, chair of the department of dermatology at the Cleveland Clinic. Dr. Vidimos and her colleagues have been so focused on skin cancer diagnosis and treatment in this group of patients that “we’ve kind of lost sight of the human aspect of it and the fear that these patients have,” she added.

These shared medical appointments at the Cleveland Clinic also provide the dermatology staff an efficient means to educate a group of patients about the risks of developing skin cancers and benign conditions associated with immunosuppressive treatments. They also discuss sun protection and avoidance practices, and how to perform skin self exams, all of which are “really important for their well being after their transplant,” Dr. Vidimos said during an interview at the American Academy of Dermatology summer meeting.

Patients learn how frequently they will need a clinical skin exam post-transplant, depending on the occurrence of skin cancers, and that biopsies may be necessary at times.

Dr. Vidimos said it is up to the transplant surgeons to discuss with patients the very low risk of transmission of malignancies from the donor to the recipient. In her presentation at the meeting, she cited a 1.4% risk of an undetected skin or internal malignancy in a donor being transmitted to the recipient.

Because of changes in criteria, patients who have relatively low risk skin cancers or higher risk skin cancers and have been treated, and are at “a defined interval post-treatment where we feel it’s safe to do that transplant,” may be considered a transplant candidate, she said noting that previously, such patients would be excluded from a transplant.

The appropriate time intervals to wait for a transplant for candidates with a history of cutaneous squamous cell carcinoma, malignant melanoma, or Merkel cell carcinoma are spelled out in a recently published consensus paper Dr. Vidimos coauthored with other members of the International Transplant Skin Cancer Collaborative (Am J Transplant. 2016 Feb;16[2]:407-13).

Dr. Vidimos said she is sometimes called to the bedside to perform a skin exam in a pretransplant patient who is very ill. The most common scenario is a liver transplant candidate awaiting transport to the operating room, who has not had a skin exam and needs to be cleared by a dermatologist to rule out a melanoma or another type of skin cancer that could be “fertilized” by postoperative immunosuppressant therapy.

After a transplant, patients need to be seen frequently enough to detect malignant transformation of precancerous skin lesions. Dermatologists should have a low threshold for biopsying any suspicious lesions early. “A lot of times we get biopsies back of skin cancer that do not match ... the clinical picture,” Dr. Vidimos said. Patients should be referred when the dermatologist feels that he or she can not deliver the appropriate treatment.

As transplants have become fairly routine and patients are living longer, community dermatologists will most likely be seeing solid organ transplant recipients more frequently. With longer lifespans, those patients will have more opportunity to develop more skin cancers.

Dr. Vidimos disclosed having received grants and research funding from Genentech.

Boston – Shared medical appointments can work well for patients undergoing solid organ transplants and for the clinical staff treating them – serving as an efficient way to educate several patients in a common setting and giving them the opportunity to interact with others going through a similar experience.

“Having those shared medical appointments where they’re sitting next to somebody who’s going through the same thought process and information gathering ... and the ability to talk with similar folks is a huge benefit for those patients,” said Allison Vidimos, MD, chair of the department of dermatology at the Cleveland Clinic. Dr. Vidimos and her colleagues have been so focused on skin cancer diagnosis and treatment in this group of patients that “we’ve kind of lost sight of the human aspect of it and the fear that these patients have,” she added.

These shared medical appointments at the Cleveland Clinic also provide the dermatology staff an efficient means to educate a group of patients about the risks of developing skin cancers and benign conditions associated with immunosuppressive treatments. They also discuss sun protection and avoidance practices, and how to perform skin self exams, all of which are “really important for their well being after their transplant,” Dr. Vidimos said during an interview at the American Academy of Dermatology summer meeting.

Patients learn how frequently they will need a clinical skin exam post-transplant, depending on the occurrence of skin cancers, and that biopsies may be necessary at times.

Dr. Vidimos said it is up to the transplant surgeons to discuss with patients the very low risk of transmission of malignancies from the donor to the recipient. In her presentation at the meeting, she cited a 1.4% risk of an undetected skin or internal malignancy in a donor being transmitted to the recipient.

Because of changes in criteria, patients who have relatively low risk skin cancers or higher risk skin cancers and have been treated, and are at “a defined interval post-treatment where we feel it’s safe to do that transplant,” may be considered a transplant candidate, she said noting that previously, such patients would be excluded from a transplant.

The appropriate time intervals to wait for a transplant for candidates with a history of cutaneous squamous cell carcinoma, malignant melanoma, or Merkel cell carcinoma are spelled out in a recently published consensus paper Dr. Vidimos coauthored with other members of the International Transplant Skin Cancer Collaborative (Am J Transplant. 2016 Feb;16[2]:407-13).

Dr. Vidimos said she is sometimes called to the bedside to perform a skin exam in a pretransplant patient who is very ill. The most common scenario is a liver transplant candidate awaiting transport to the operating room, who has not had a skin exam and needs to be cleared by a dermatologist to rule out a melanoma or another type of skin cancer that could be “fertilized” by postoperative immunosuppressant therapy.

After a transplant, patients need to be seen frequently enough to detect malignant transformation of precancerous skin lesions. Dermatologists should have a low threshold for biopsying any suspicious lesions early. “A lot of times we get biopsies back of skin cancer that do not match ... the clinical picture,” Dr. Vidimos said. Patients should be referred when the dermatologist feels that he or she can not deliver the appropriate treatment.

As transplants have become fairly routine and patients are living longer, community dermatologists will most likely be seeing solid organ transplant recipients more frequently. With longer lifespans, those patients will have more opportunity to develop more skin cancers.

Dr. Vidimos disclosed having received grants and research funding from Genentech.

Boston – Shared medical appointments can work well for patients undergoing solid organ transplants and for the clinical staff treating them – serving as an efficient way to educate several patients in a common setting and giving them the opportunity to interact with others going through a similar experience.

“Having those shared medical appointments where they’re sitting next to somebody who’s going through the same thought process and information gathering ... and the ability to talk with similar folks is a huge benefit for those patients,” said Allison Vidimos, MD, chair of the department of dermatology at the Cleveland Clinic. Dr. Vidimos and her colleagues have been so focused on skin cancer diagnosis and treatment in this group of patients that “we’ve kind of lost sight of the human aspect of it and the fear that these patients have,” she added.

These shared medical appointments at the Cleveland Clinic also provide the dermatology staff an efficient means to educate a group of patients about the risks of developing skin cancers and benign conditions associated with immunosuppressive treatments. They also discuss sun protection and avoidance practices, and how to perform skin self exams, all of which are “really important for their well being after their transplant,” Dr. Vidimos said during an interview at the American Academy of Dermatology summer meeting.

Patients learn how frequently they will need a clinical skin exam post-transplant, depending on the occurrence of skin cancers, and that biopsies may be necessary at times.

Dr. Vidimos said it is up to the transplant surgeons to discuss with patients the very low risk of transmission of malignancies from the donor to the recipient. In her presentation at the meeting, she cited a 1.4% risk of an undetected skin or internal malignancy in a donor being transmitted to the recipient.

Because of changes in criteria, patients who have relatively low risk skin cancers or higher risk skin cancers and have been treated, and are at “a defined interval post-treatment where we feel it’s safe to do that transplant,” may be considered a transplant candidate, she said noting that previously, such patients would be excluded from a transplant.

The appropriate time intervals to wait for a transplant for candidates with a history of cutaneous squamous cell carcinoma, malignant melanoma, or Merkel cell carcinoma are spelled out in a recently published consensus paper Dr. Vidimos coauthored with other members of the International Transplant Skin Cancer Collaborative (Am J Transplant. 2016 Feb;16[2]:407-13).

Dr. Vidimos said she is sometimes called to the bedside to perform a skin exam in a pretransplant patient who is very ill. The most common scenario is a liver transplant candidate awaiting transport to the operating room, who has not had a skin exam and needs to be cleared by a dermatologist to rule out a melanoma or another type of skin cancer that could be “fertilized” by postoperative immunosuppressant therapy.

After a transplant, patients need to be seen frequently enough to detect malignant transformation of precancerous skin lesions. Dermatologists should have a low threshold for biopsying any suspicious lesions early. “A lot of times we get biopsies back of skin cancer that do not match ... the clinical picture,” Dr. Vidimos said. Patients should be referred when the dermatologist feels that he or she can not deliver the appropriate treatment.

As transplants have become fairly routine and patients are living longer, community dermatologists will most likely be seeing solid organ transplant recipients more frequently. With longer lifespans, those patients will have more opportunity to develop more skin cancers.

Dr. Vidimos disclosed having received grants and research funding from Genentech.

SAN DIEGO – How much damage could a diabetes app do? Plenty. That was the word from a Food and Drug Administration official and a technology guru who spoke to a crowd of diabetes educators about the dangers lurking in apps that promise to track things like insulin dosing.

An app could jeopardize the safety of a patient and provide inaccurate data, advised Molly McElwee, RN, CDE, head of Patient Engagement at TypeZero Technologies. “Vet the app that your patient is using or wants to use. Really vet your apps for these patients.”

© Jupiterimages/Thinkstockphotos.com

Ms. McElwee told an audience at the annual meeting of the American Association of Diabetes Educators that more than 84 “bolus calculator” apps are available for iPhone and Android. But only one, the Accu-Check Connect app, is cleared by the FDA for use with a prescription, she confirmed in an interview. Some app makers claim that their technology has been cleared in their countries of origin, but that raises questions about whether the technology has gone through proper vetting, she said.

“The idea you’d let someone with no medical experience just design [an app], put it out there for you, and then tell you how to dose seems a bit odd,” but that’s the way things work in the “murky, uncharted territory” of apps, she said.

Why is there a need for diabetes apps in the first place? As Ms. McElwee noted, many diabetes patients make crucial decisions about their insulin injections each day. “There aren’t a lot of other diseases where you’re dosing something that could kill you if you dose it incorrectly.” That is exactly why “people look for things like an app that can help them,” she noted.

The FDA does indeed regulate medical apps but far from all of them. It doesn’t regulate apps such as calorie counters and exercise trackers because they’re considered to be low risk, said Courtney Lias, PhD, director of the FDA’s Division of Chemistry and Toxicology Devices. “They don’t give advice or tell patients what action to take,” she said. Nor does the FDA regulate apps that retrospectively analyze data from insulin pumps, she said.

The FDA regulates apps such as insulin-dosing calculators and those used to calculate the levels of insulin injections via a pump, she said. But Apple’s App Store and Google’s Google Play, both of which sell apps, aren’t required to take down apps that don’t comply with FDA regulations, according to Ms. McElwee. Indeed, the FDA says it doesn’t regulate app stores, nor does it regulate manufacturers of devices such as smartphones, although the stores may set their own policies. Instead, “the onus is on the company, the developer, to take the correct regulatory pathway,” Ms. McElwee said.

What’s next? Dr. Lias noted that the FDA will monitor apps that command and control insulin pumps, especially as automated insulin delivery systems loom on the horizon. But there are a variety of technical challenges. How will operating systems be updated? What will happen to critical functions when a phone call interrupts the operation of a diabetes app? What about warnings when the phone is muted? Dr. Lias wondered.

One thing is clear, she said: “The explosion of apps is directly related to how much they’re needed.”

Ms. McElwee and Dr. Lias reported having no relevant financial disclosures.

SAN DIEGO – How much damage could a diabetes app do? Plenty. That was the word from a Food and Drug Administration official and a technology guru who spoke to a crowd of diabetes educators about the dangers lurking in apps that promise to track things like insulin dosing.

An app could jeopardize the safety of a patient and provide inaccurate data, advised Molly McElwee, RN, CDE, head of Patient Engagement at TypeZero Technologies. “Vet the app that your patient is using or wants to use. Really vet your apps for these patients.”

© Jupiterimages/Thinkstockphotos.com

Ms. McElwee told an audience at the annual meeting of the American Association of Diabetes Educators that more than 84 “bolus calculator” apps are available for iPhone and Android. But only one, the Accu-Check Connect app, is cleared by the FDA for use with a prescription, she confirmed in an interview. Some app makers claim that their technology has been cleared in their countries of origin, but that raises questions about whether the technology has gone through proper vetting, she said.

“The idea you’d let someone with no medical experience just design [an app], put it out there for you, and then tell you how to dose seems a bit odd,” but that’s the way things work in the “murky, uncharted territory” of apps, she said.

Why is there a need for diabetes apps in the first place? As Ms. McElwee noted, many diabetes patients make crucial decisions about their insulin injections each day. “There aren’t a lot of other diseases where you’re dosing something that could kill you if you dose it incorrectly.” That is exactly why “people look for things like an app that can help them,” she noted.

The FDA does indeed regulate medical apps but far from all of them. It doesn’t regulate apps such as calorie counters and exercise trackers because they’re considered to be low risk, said Courtney Lias, PhD, director of the FDA’s Division of Chemistry and Toxicology Devices. “They don’t give advice or tell patients what action to take,” she said. Nor does the FDA regulate apps that retrospectively analyze data from insulin pumps, she said.

The FDA regulates apps such as insulin-dosing calculators and those used to calculate the levels of insulin injections via a pump, she said. But Apple’s App Store and Google’s Google Play, both of which sell apps, aren’t required to take down apps that don’t comply with FDA regulations, according to Ms. McElwee. Indeed, the FDA says it doesn’t regulate app stores, nor does it regulate manufacturers of devices such as smartphones, although the stores may set their own policies. Instead, “the onus is on the company, the developer, to take the correct regulatory pathway,” Ms. McElwee said.

What’s next? Dr. Lias noted that the FDA will monitor apps that command and control insulin pumps, especially as automated insulin delivery systems loom on the horizon. But there are a variety of technical challenges. How will operating systems be updated? What will happen to critical functions when a phone call interrupts the operation of a diabetes app? What about warnings when the phone is muted? Dr. Lias wondered.

One thing is clear, she said: “The explosion of apps is directly related to how much they’re needed.”

Ms. McElwee and Dr. Lias reported having no relevant financial disclosures.

SAN DIEGO – How much damage could a diabetes app do? Plenty. That was the word from a Food and Drug Administration official and a technology guru who spoke to a crowd of diabetes educators about the dangers lurking in apps that promise to track things like insulin dosing.

An app could jeopardize the safety of a patient and provide inaccurate data, advised Molly McElwee, RN, CDE, head of Patient Engagement at TypeZero Technologies. “Vet the app that your patient is using or wants to use. Really vet your apps for these patients.”

© Jupiterimages/Thinkstockphotos.com

Ms. McElwee told an audience at the annual meeting of the American Association of Diabetes Educators that more than 84 “bolus calculator” apps are available for iPhone and Android. But only one, the Accu-Check Connect app, is cleared by the FDA for use with a prescription, she confirmed in an interview. Some app makers claim that their technology has been cleared in their countries of origin, but that raises questions about whether the technology has gone through proper vetting, she said.

“The idea you’d let someone with no medical experience just design [an app], put it out there for you, and then tell you how to dose seems a bit odd,” but that’s the way things work in the “murky, uncharted territory” of apps, she said.

Why is there a need for diabetes apps in the first place? As Ms. McElwee noted, many diabetes patients make crucial decisions about their insulin injections each day. “There aren’t a lot of other diseases where you’re dosing something that could kill you if you dose it incorrectly.” That is exactly why “people look for things like an app that can help them,” she noted.

The FDA does indeed regulate medical apps but far from all of them. It doesn’t regulate apps such as calorie counters and exercise trackers because they’re considered to be low risk, said Courtney Lias, PhD, director of the FDA’s Division of Chemistry and Toxicology Devices. “They don’t give advice or tell patients what action to take,” she said. Nor does the FDA regulate apps that retrospectively analyze data from insulin pumps, she said.

The FDA regulates apps such as insulin-dosing calculators and those used to calculate the levels of insulin injections via a pump, she said. But Apple’s App Store and Google’s Google Play, both of which sell apps, aren’t required to take down apps that don’t comply with FDA regulations, according to Ms. McElwee. Indeed, the FDA says it doesn’t regulate app stores, nor does it regulate manufacturers of devices such as smartphones, although the stores may set their own policies. Instead, “the onus is on the company, the developer, to take the correct regulatory pathway,” Ms. McElwee said.

What’s next? Dr. Lias noted that the FDA will monitor apps that command and control insulin pumps, especially as automated insulin delivery systems loom on the horizon. But there are a variety of technical challenges. How will operating systems be updated? What will happen to critical functions when a phone call interrupts the operation of a diabetes app? What about warnings when the phone is muted? Dr. Lias wondered.

One thing is clear, she said: “The explosion of apps is directly related to how much they’re needed.”

Ms. McElwee and Dr. Lias reported having no relevant financial disclosures.

The American Headache Society (AHS) has released a new guideline for the treatment of cluster headache. According to the authors, the AHS guideline can be used for understanding which therapies are superior to placebo or sham treatment in the management of cluster headache. “In clinical practice, these recommendations should be considered in concert with other variables, including safety, side effects, patient preferences, clinician experience, cost, and the invasiveness of the intervention,” said lead author Matthew S. Robbins, MD, an Associate Professor of Clinical Neurology at Montefiore Headache Center at Albert Einstein College of Medicine in the Bronx, New York, and his coauthors. The guideline was published in the July/August issue of Headache.

The guideline is based on a systematic review of the literature regarding abortive and preventive treatment of cluster headache, and represents an update of the American Academy of Neurology’s 2010 recommendations. “The interval of time that has elapsed since completion of the 2010 literature review necessitates these updated recommendations,” the authors said.

For the current literature review, the authors searched the Medline, PubMed, and EMBASE databases for double-blind, randomized, controlled trials that investigated treatment of cluster headache in adults.

For acute treatment, sumatriptan subcutaneous, zolmitriptan nasal spray, and high-flow oxygen remain the treatments with a Level A recommendation. A study of sphenopalatine ganglion stimulation conducted after the 2010 review was added to the current guideline with a Level B recommendation.

The previous guideline included no Level A recommendation for prophylactic therapy. For the current guideline, suboccipital steroid injections have emerged as the only treatment to receive a Level A recommendation, due to the publication of a second Class I study in the literature. Other newly evaluated treatments since the 2010 guideline include a negative study of deep brain stimulation (Level B), a positive study of warfarin (Level C), and negative studies of cimetidine/chlorpheniramine (Level C), and a negative study of candesartan (Level C). Frovatriptan received a Level U recommendation.

The authors concluded that “given the lack of Class I evidence and Level A recommendations, particularly for a number of commonly used preventive therapies, further studies are warranted to demonstrate safety and efficacy for established and emerging therapies.”

—Glenn S. Williams

The American Headache Society (AHS) has released a new guideline for the treatment of cluster headache. According to the authors, the AHS guideline can be used for understanding which therapies are superior to placebo or sham treatment in the management of cluster headache. “In clinical practice, these recommendations should be considered in concert with other variables, including safety, side effects, patient preferences, clinician experience, cost, and the invasiveness of the intervention,” said lead author Matthew S. Robbins, MD, an Associate Professor of Clinical Neurology at Montefiore Headache Center at Albert Einstein College of Medicine in the Bronx, New York, and his coauthors. The guideline was published in the July/August issue of Headache.

The guideline is based on a systematic review of the literature regarding abortive and preventive treatment of cluster headache, and represents an update of the American Academy of Neurology’s 2010 recommendations. “The interval of time that has elapsed since completion of the 2010 literature review necessitates these updated recommendations,” the authors said.

For the current literature review, the authors searched the Medline, PubMed, and EMBASE databases for double-blind, randomized, controlled trials that investigated treatment of cluster headache in adults.

For acute treatment, sumatriptan subcutaneous, zolmitriptan nasal spray, and high-flow oxygen remain the treatments with a Level A recommendation. A study of sphenopalatine ganglion stimulation conducted after the 2010 review was added to the current guideline with a Level B recommendation.

The previous guideline included no Level A recommendation for prophylactic therapy. For the current guideline, suboccipital steroid injections have emerged as the only treatment to receive a Level A recommendation, due to the publication of a second Class I study in the literature. Other newly evaluated treatments since the 2010 guideline include a negative study of deep brain stimulation (Level B), a positive study of warfarin (Level C), and negative studies of cimetidine/chlorpheniramine (Level C), and a negative study of candesartan (Level C). Frovatriptan received a Level U recommendation.

The authors concluded that “given the lack of Class I evidence and Level A recommendations, particularly for a number of commonly used preventive therapies, further studies are warranted to demonstrate safety and efficacy for established and emerging therapies.”

—Glenn S. Williams

The American Headache Society (AHS) has released a new guideline for the treatment of cluster headache. According to the authors, the AHS guideline can be used for understanding which therapies are superior to placebo or sham treatment in the management of cluster headache. “In clinical practice, these recommendations should be considered in concert with other variables, including safety, side effects, patient preferences, clinician experience, cost, and the invasiveness of the intervention,” said lead author Matthew S. Robbins, MD, an Associate Professor of Clinical Neurology at Montefiore Headache Center at Albert Einstein College of Medicine in the Bronx, New York, and his coauthors. The guideline was published in the July/August issue of Headache.

The guideline is based on a systematic review of the literature regarding abortive and preventive treatment of cluster headache, and represents an update of the American Academy of Neurology’s 2010 recommendations. “The interval of time that has elapsed since completion of the 2010 literature review necessitates these updated recommendations,” the authors said.

For the current literature review, the authors searched the Medline, PubMed, and EMBASE databases for double-blind, randomized, controlled trials that investigated treatment of cluster headache in adults.

For acute treatment, sumatriptan subcutaneous, zolmitriptan nasal spray, and high-flow oxygen remain the treatments with a Level A recommendation. A study of sphenopalatine ganglion stimulation conducted after the 2010 review was added to the current guideline with a Level B recommendation.

The previous guideline included no Level A recommendation for prophylactic therapy. For the current guideline, suboccipital steroid injections have emerged as the only treatment to receive a Level A recommendation, due to the publication of a second Class I study in the literature. Other newly evaluated treatments since the 2010 guideline include a negative study of deep brain stimulation (Level B), a positive study of warfarin (Level C), and negative studies of cimetidine/chlorpheniramine (Level C), and a negative study of candesartan (Level C). Frovatriptan received a Level U recommendation.

The authors concluded that “given the lack of Class I evidence and Level A recommendations, particularly for a number of commonly used preventive therapies, further studies are warranted to demonstrate safety and efficacy for established and emerging therapies.”

—Glenn S. Williams

TORONTO—Modifiable risk factors predict memory resilience in aging adults with genetic risk for Alzheimer’s disease, according to data presented at the Alzheimer’s Association International Conference. Several factors predict memory resilience in both sexes. A greater number of sex-specific factors apply to females than to males, however. The predictive factors are similar, regardless of whether risk results from APOE or CLU.

Kirstie McDermott, graduate student at the University of Alberta in Edmonton, Canada, and colleagues sought to determine whether longitudinal memory trajectories suggest a distinct phenotype of memory resilience, which they defined as high memory performance despite genetic risk for Alzheimer’s disease. The researchers also looked for predictors of memory resilience.

Ms. McDermott and colleagues followed 642 cognitively normal adults between ages 53 and 95 who were participating in the Victoria Longitudinal Study. Maximum follow-up was nine years. Carriers of the APOE ε4 allele or the CLU CC genotype were considered to be at genetic risk for Alzheimer’s disease. The investigators tested 22 predictors of resilience from five nongenetic risk domains (ie, demographic, functional, health, mobility, and lifestyle). They stratified their analyses by sex to compare the effect of these predictors in males and females.

Memory was stable in 67.6% of females and in 52.8% of males. Growth mixture modeling enabled the investigators to identify two similar classes of longitudinal memory trajectories among males and females. Random forest analysis identified younger age, higher education, stronger grip, and more everyday novel cognitive activity (such as playing bridge or filing taxes) as important predictors of memory resilience for both sexes.

For females, living with another person; being married; lower pulse pressure; higher peak expiratory flow; better subjective health rating; faster walking and turning time; more social visits with family, friends, and neighbors; and volunteering more often predicted memory resilience. The only predictor of memory resilience specific to males was a low number of depressive symptoms. The predictors were similar for both genotypes of Alzheimer’s disease risk.

“The more we know about both common and gender-specific factors that may protect against Alzheimer’s risk, the better we can create tailored and appropriate interventions that promote functional maintenance and delay cognitive decline,” said Ms. McDermott.

—Erik Greb

TORONTO—Modifiable risk factors predict memory resilience in aging adults with genetic risk for Alzheimer’s disease, according to data presented at the Alzheimer’s Association International Conference. Several factors predict memory resilience in both sexes. A greater number of sex-specific factors apply to females than to males, however. The predictive factors are similar, regardless of whether risk results from APOE or CLU.

Kirstie McDermott, graduate student at the University of Alberta in Edmonton, Canada, and colleagues sought to determine whether longitudinal memory trajectories suggest a distinct phenotype of memory resilience, which they defined as high memory performance despite genetic risk for Alzheimer’s disease. The researchers also looked for predictors of memory resilience.

Ms. McDermott and colleagues followed 642 cognitively normal adults between ages 53 and 95 who were participating in the Victoria Longitudinal Study. Maximum follow-up was nine years. Carriers of the APOE ε4 allele or the CLU CC genotype were considered to be at genetic risk for Alzheimer’s disease. The investigators tested 22 predictors of resilience from five nongenetic risk domains (ie, demographic, functional, health, mobility, and lifestyle). They stratified their analyses by sex to compare the effect of these predictors in males and females.

Memory was stable in 67.6% of females and in 52.8% of males. Growth mixture modeling enabled the investigators to identify two similar classes of longitudinal memory trajectories among males and females. Random forest analysis identified younger age, higher education, stronger grip, and more everyday novel cognitive activity (such as playing bridge or filing taxes) as important predictors of memory resilience for both sexes.

For females, living with another person; being married; lower pulse pressure; higher peak expiratory flow; better subjective health rating; faster walking and turning time; more social visits with family, friends, and neighbors; and volunteering more often predicted memory resilience. The only predictor of memory resilience specific to males was a low number of depressive symptoms. The predictors were similar for both genotypes of Alzheimer’s disease risk.

“The more we know about both common and gender-specific factors that may protect against Alzheimer’s risk, the better we can create tailored and appropriate interventions that promote functional maintenance and delay cognitive decline,” said Ms. McDermott.

—Erik Greb

TORONTO—Modifiable risk factors predict memory resilience in aging adults with genetic risk for Alzheimer’s disease, according to data presented at the Alzheimer’s Association International Conference. Several factors predict memory resilience in both sexes. A greater number of sex-specific factors apply to females than to males, however. The predictive factors are similar, regardless of whether risk results from APOE or CLU.

Kirstie McDermott, graduate student at the University of Alberta in Edmonton, Canada, and colleagues sought to determine whether longitudinal memory trajectories suggest a distinct phenotype of memory resilience, which they defined as high memory performance despite genetic risk for Alzheimer’s disease. The researchers also looked for predictors of memory resilience.

Ms. McDermott and colleagues followed 642 cognitively normal adults between ages 53 and 95 who were participating in the Victoria Longitudinal Study. Maximum follow-up was nine years. Carriers of the APOE ε4 allele or the CLU CC genotype were considered to be at genetic risk for Alzheimer’s disease. The investigators tested 22 predictors of resilience from five nongenetic risk domains (ie, demographic, functional, health, mobility, and lifestyle). They stratified their analyses by sex to compare the effect of these predictors in males and females.

Memory was stable in 67.6% of females and in 52.8% of males. Growth mixture modeling enabled the investigators to identify two similar classes of longitudinal memory trajectories among males and females. Random forest analysis identified younger age, higher education, stronger grip, and more everyday novel cognitive activity (such as playing bridge or filing taxes) as important predictors of memory resilience for both sexes.

For females, living with another person; being married; lower pulse pressure; higher peak expiratory flow; better subjective health rating; faster walking and turning time; more social visits with family, friends, and neighbors; and volunteering more often predicted memory resilience. The only predictor of memory resilience specific to males was a low number of depressive symptoms. The predictors were similar for both genotypes of Alzheimer’s disease risk.

“The more we know about both common and gender-specific factors that may protect against Alzheimer’s risk, the better we can create tailored and appropriate interventions that promote functional maintenance and delay cognitive decline,” said Ms. McDermott.

—Erik Greb

SAN DIEGO—Stress is a fact of life. More than 40 years of data have established the relationship between stress and migraine. Biobehavioral treatments such as relaxation training, biofeedback, and cognitive behavioral therapy may help to modify patients’ response to stress and reduce the likelihood of a migraine attack, according to an overview presented at the 58th Annual Scientific Meeting of the American Headache Society.

“It can be difficut or impossible to change many factors in our life that create stress, but we can modify how we think about and react to them. That is what we help our patients do using biobehavioral treatments such as cognitive behavioral therapy,” said Dawn Buse, PhD, Director of Behavioral Medicine at Montefiore Headache Center and Associate Professor of Neurology at Albert Einstein College of Medicine in New York. For example, neurologists can teach patients better coping strategies, reduce catastrophizing, encourage the use of social support, and create healthy lifestyle behaviors and other potentially protective factors.

Stress can play many roles in migraine. It can exacerbate migraine attack frequency or be a premonitory feature, prognostic factor, or a consequence of an attack. In addition, stress can be a risk factor for the onset of migraine and is a common trigger.

In a study by Kelman of 1,750 patients diagnosed with migraine, 76% of the participants reported having triggers. Nine percent of patients experienced triggers very frequently, 27% experienced triggers frequently, and 40% of patients encountered triggers occasionally. In addition, 80% of respondents reported stress as a trigger for migraine, making it the most common trigger. In a study by Wöber et al published in 2007 in Cephalalgia, “stress in private life” and “psychic tension” were associated with an increased risk of migraine attacks. A study published in the European Journal of Pain in 2014 reported strong associations between migraine and job stress, which researchers defined as low job control, high job demands, and low social support.

Other data suggest that migraine attacks may result from a combination of triggers, rather than from one trigger. A study of the association between stress and menstruation in migraine published in the International Journal of Women’s Health in 2014 included 307 participants with migraine without aura. Participants kept a headache diary for 14 months. The data suggested that women were more susceptible to stress in the premenstrual period. The researchers also found a statistically significant relationship between alcohol and migraine attacks only during stressful periods.

Martin and colleagues conducted three studies comparing people with migraine or tension-type headache and controls without headache. Participants attempted to solve difficult anagrams for 35 minutes while receiving negative feedback. They found that the stress condition was associated with increased head pain, compared with controls.

Sleep duration may have a relationship with stress. Data published in Pain in 2012 suggested that two consecutive days of high stress levels or low sleep were strongly predictive of headache. In contrast, two consecutive days of low stress or adequate sleep were considered protective factors that may help raise the headache attack threshold. Information like this may help give patients a sense of control, said Dr. Buse.

Two Types of Stressors

Investigators generally categorize stressors as daily hassles or major life events. According to research published in 1992 in Pain, people with recurrent headache experience more hassles than controls do. Daily hassles are also associated with an increased frequency of headache attacks.

Adverse childhood experiences such as emotional neglect, emotional abuse, sexual abuse, and other forms of abuse are considered major life events and appear comorbid with migraine incidence and attack frequency. Data published in Neurology showed that people who experienced more types of traumatic events in early childhood were more likely to have a higher frequency of severe headache, including chronic migraine.

Appraisal and Self-Efficacy

Years of research support the thesis that modifiable factors such as appraisal and self-efficacy influence migraine, said Dr. Buse. Studies have found that people with tension-type headache appraise stressful life events more negatively than controls do. This result raises the possibility that appraising stressful events less negatively could reduce headache pain or frequency.

People with tension-type headache also perceive themselves as having less control (ie, low self-efficacy). Self-efficacy helps to moderate the impact of stressful events on headache. According to a 1984 electromyography biofeedback study published in the Journal of Consulting and Clinical Psychology, a greater sense of self-efficacy resulted in a reduction in headache.

Coping and Social Support

Improving their coping skills and seeking greater social support also may benefit patients with headache. Migraineurs may respond to stress with more wishful thinking, self-criticism, social withdrawal, and catastrophizing, compared with controls. A study published in the Journal of Behavioral Sciences reported that patients with tension-type headache practiced less effective coping strategies, were more likely to blame themselves, and made less use of social support than did controls. Researchers also found that people with migraine tend to engage in catastrophizing while thinking about their condition.

A study in the European Journal of Pain found that migraine was associated with low social support. In addition to poor coping skills, lack of social support can be both a stressor and a consequence of severe headache. A patient’s social support may decrease if migraine causes him or her to miss events and avoid making social commitments. Furthermore, data indicate that people with headache are significantly less satisfied with the support available to them. Compared with controls, they scored lower in all types of functional support.

Dr. Buse suggested that physicians can help patients modify their response to stressors through behavioral therapies as well as by assessing and improving self-efficacy, enhancing social support, and improving the sense of control. Physicians can improve patients’ psychologic well-being by modifying dysfunctional coping styles, negative attributions, and catastrophizing.

Future Directions in Stress and Migraine Research

“Future directions in migraine treatment may include disseminating behavioral treatments at low cost to large numbers of people via the Internet, smartphones, apps, and wearable technology,” said Dr. Buse. “Technology can be used to collect data related to migraine attacks and deliver messages, including healthy reminders, coping strategies, and relaxtion exercises, in real time. There is an expanding body of literature testing the efficacy of delivering behavioral treatments using these modalties. The possibilites and potential benefits for our patients are very exciting.”

—Erica Robinson

SAN DIEGO—Stress is a fact of life. More than 40 years of data have established the relationship between stress and migraine. Biobehavioral treatments such as relaxation training, biofeedback, and cognitive behavioral therapy may help to modify patients’ response to stress and reduce the likelihood of a migraine attack, according to an overview presented at the 58th Annual Scientific Meeting of the American Headache Society.

“It can be difficut or impossible to change many factors in our life that create stress, but we can modify how we think about and react to them. That is what we help our patients do using biobehavioral treatments such as cognitive behavioral therapy,” said Dawn Buse, PhD, Director of Behavioral Medicine at Montefiore Headache Center and Associate Professor of Neurology at Albert Einstein College of Medicine in New York. For example, neurologists can teach patients better coping strategies, reduce catastrophizing, encourage the use of social support, and create healthy lifestyle behaviors and other potentially protective factors.

Stress can play many roles in migraine. It can exacerbate migraine attack frequency or be a premonitory feature, prognostic factor, or a consequence of an attack. In addition, stress can be a risk factor for the onset of migraine and is a common trigger.

In a study by Kelman of 1,750 patients diagnosed with migraine, 76% of the participants reported having triggers. Nine percent of patients experienced triggers very frequently, 27% experienced triggers frequently, and 40% of patients encountered triggers occasionally. In addition, 80% of respondents reported stress as a trigger for migraine, making it the most common trigger. In a study by Wöber et al published in 2007 in Cephalalgia, “stress in private life” and “psychic tension” were associated with an increased risk of migraine attacks. A study published in the European Journal of Pain in 2014 reported strong associations between migraine and job stress, which researchers defined as low job control, high job demands, and low social support.

Other data suggest that migraine attacks may result from a combination of triggers, rather than from one trigger. A study of the association between stress and menstruation in migraine published in the International Journal of Women’s Health in 2014 included 307 participants with migraine without aura. Participants kept a headache diary for 14 months. The data suggested that women were more susceptible to stress in the premenstrual period. The researchers also found a statistically significant relationship between alcohol and migraine attacks only during stressful periods.

Martin and colleagues conducted three studies comparing people with migraine or tension-type headache and controls without headache. Participants attempted to solve difficult anagrams for 35 minutes while receiving negative feedback. They found that the stress condition was associated with increased head pain, compared with controls.

Sleep duration may have a relationship with stress. Data published in Pain in 2012 suggested that two consecutive days of high stress levels or low sleep were strongly predictive of headache. In contrast, two consecutive days of low stress or adequate sleep were considered protective factors that may help raise the headache attack threshold. Information like this may help give patients a sense of control, said Dr. Buse.

Two Types of Stressors

Investigators generally categorize stressors as daily hassles or major life events. According to research published in 1992 in Pain, people with recurrent headache experience more hassles than controls do. Daily hassles are also associated with an increased frequency of headache attacks.

Adverse childhood experiences such as emotional neglect, emotional abuse, sexual abuse, and other forms of abuse are considered major life events and appear comorbid with migraine incidence and attack frequency. Data published in Neurology showed that people who experienced more types of traumatic events in early childhood were more likely to have a higher frequency of severe headache, including chronic migraine.

Appraisal and Self-Efficacy

Years of research support the thesis that modifiable factors such as appraisal and self-efficacy influence migraine, said Dr. Buse. Studies have found that people with tension-type headache appraise stressful life events more negatively than controls do. This result raises the possibility that appraising stressful events less negatively could reduce headache pain or frequency.

People with tension-type headache also perceive themselves as having less control (ie, low self-efficacy). Self-efficacy helps to moderate the impact of stressful events on headache. According to a 1984 electromyography biofeedback study published in the Journal of Consulting and Clinical Psychology, a greater sense of self-efficacy resulted in a reduction in headache.

Coping and Social Support

Improving their coping skills and seeking greater social support also may benefit patients with headache. Migraineurs may respond to stress with more wishful thinking, self-criticism, social withdrawal, and catastrophizing, compared with controls. A study published in the Journal of Behavioral Sciences reported that patients with tension-type headache practiced less effective coping strategies, were more likely to blame themselves, and made less use of social support than did controls. Researchers also found that people with migraine tend to engage in catastrophizing while thinking about their condition.

A study in the European Journal of Pain found that migraine was associated with low social support. In addition to poor coping skills, lack of social support can be both a stressor and a consequence of severe headache. A patient’s social support may decrease if migraine causes him or her to miss events and avoid making social commitments. Furthermore, data indicate that people with headache are significantly less satisfied with the support available to them. Compared with controls, they scored lower in all types of functional support.

Dr. Buse suggested that physicians can help patients modify their response to stressors through behavioral therapies as well as by assessing and improving self-efficacy, enhancing social support, and improving the sense of control. Physicians can improve patients’ psychologic well-being by modifying dysfunctional coping styles, negative attributions, and catastrophizing.

Future Directions in Stress and Migraine Research

“Future directions in migraine treatment may include disseminating behavioral treatments at low cost to large numbers of people via the Internet, smartphones, apps, and wearable technology,” said Dr. Buse. “Technology can be used to collect data related to migraine attacks and deliver messages, including healthy reminders, coping strategies, and relaxtion exercises, in real time. There is an expanding body of literature testing the efficacy of delivering behavioral treatments using these modalties. The possibilites and potential benefits for our patients are very exciting.”

—Erica Robinson

SAN DIEGO—Stress is a fact of life. More than 40 years of data have established the relationship between stress and migraine. Biobehavioral treatments such as relaxation training, biofeedback, and cognitive behavioral therapy may help to modify patients’ response to stress and reduce the likelihood of a migraine attack, according to an overview presented at the 58th Annual Scientific Meeting of the American Headache Society.

“It can be difficut or impossible to change many factors in our life that create stress, but we can modify how we think about and react to them. That is what we help our patients do using biobehavioral treatments such as cognitive behavioral therapy,” said Dawn Buse, PhD, Director of Behavioral Medicine at Montefiore Headache Center and Associate Professor of Neurology at Albert Einstein College of Medicine in New York. For example, neurologists can teach patients better coping strategies, reduce catastrophizing, encourage the use of social support, and create healthy lifestyle behaviors and other potentially protective factors.

Stress can play many roles in migraine. It can exacerbate migraine attack frequency or be a premonitory feature, prognostic factor, or a consequence of an attack. In addition, stress can be a risk factor for the onset of migraine and is a common trigger.

In a study by Kelman of 1,750 patients diagnosed with migraine, 76% of the participants reported having triggers. Nine percent of patients experienced triggers very frequently, 27% experienced triggers frequently, and 40% of patients encountered triggers occasionally. In addition, 80% of respondents reported stress as a trigger for migraine, making it the most common trigger. In a study by Wöber et al published in 2007 in Cephalalgia, “stress in private life” and “psychic tension” were associated with an increased risk of migraine attacks. A study published in the European Journal of Pain in 2014 reported strong associations between migraine and job stress, which researchers defined as low job control, high job demands, and low social support.

Other data suggest that migraine attacks may result from a combination of triggers, rather than from one trigger. A study of the association between stress and menstruation in migraine published in the International Journal of Women’s Health in 2014 included 307 participants with migraine without aura. Participants kept a headache diary for 14 months. The data suggested that women were more susceptible to stress in the premenstrual period. The researchers also found a statistically significant relationship between alcohol and migraine attacks only during stressful periods.

Martin and colleagues conducted three studies comparing people with migraine or tension-type headache and controls without headache. Participants attempted to solve difficult anagrams for 35 minutes while receiving negative feedback. They found that the stress condition was associated with increased head pain, compared with controls.

Sleep duration may have a relationship with stress. Data published in Pain in 2012 suggested that two consecutive days of high stress levels or low sleep were strongly predictive of headache. In contrast, two consecutive days of low stress or adequate sleep were considered protective factors that may help raise the headache attack threshold. Information like this may help give patients a sense of control, said Dr. Buse.

Two Types of Stressors

Investigators generally categorize stressors as daily hassles or major life events. According to research published in 1992 in Pain, people with recurrent headache experience more hassles than controls do. Daily hassles are also associated with an increased frequency of headache attacks.

Adverse childhood experiences such as emotional neglect, emotional abuse, sexual abuse, and other forms of abuse are considered major life events and appear comorbid with migraine incidence and attack frequency. Data published in Neurology showed that people who experienced more types of traumatic events in early childhood were more likely to have a higher frequency of severe headache, including chronic migraine.

Appraisal and Self-Efficacy

Years of research support the thesis that modifiable factors such as appraisal and self-efficacy influence migraine, said Dr. Buse. Studies have found that people with tension-type headache appraise stressful life events more negatively than controls do. This result raises the possibility that appraising stressful events less negatively could reduce headache pain or frequency.

People with tension-type headache also perceive themselves as having less control (ie, low self-efficacy). Self-efficacy helps to moderate the impact of stressful events on headache. According to a 1984 electromyography biofeedback study published in the Journal of Consulting and Clinical Psychology, a greater sense of self-efficacy resulted in a reduction in headache.

Coping and Social Support

Improving their coping skills and seeking greater social support also may benefit patients with headache. Migraineurs may respond to stress with more wishful thinking, self-criticism, social withdrawal, and catastrophizing, compared with controls. A study published in the Journal of Behavioral Sciences reported that patients with tension-type headache practiced less effective coping strategies, were more likely to blame themselves, and made less use of social support than did controls. Researchers also found that people with migraine tend to engage in catastrophizing while thinking about their condition.

A study in the European Journal of Pain found that migraine was associated with low social support. In addition to poor coping skills, lack of social support can be both a stressor and a consequence of severe headache. A patient’s social support may decrease if migraine causes him or her to miss events and avoid making social commitments. Furthermore, data indicate that people with headache are significantly less satisfied with the support available to them. Compared with controls, they scored lower in all types of functional support.

Dr. Buse suggested that physicians can help patients modify their response to stressors through behavioral therapies as well as by assessing and improving self-efficacy, enhancing social support, and improving the sense of control. Physicians can improve patients’ psychologic well-being by modifying dysfunctional coping styles, negative attributions, and catastrophizing.

Future Directions in Stress and Migraine Research

“Future directions in migraine treatment may include disseminating behavioral treatments at low cost to large numbers of people via the Internet, smartphones, apps, and wearable technology,” said Dr. Buse. “Technology can be used to collect data related to migraine attacks and deliver messages, including healthy reminders, coping strategies, and relaxtion exercises, in real time. There is an expanding body of literature testing the efficacy of delivering behavioral treatments using these modalties. The possibilites and potential benefits for our patients are very exciting.”

—Erica Robinson