Michele G. Sullivan

Osteopenia was present in more than a quarter of both men and women in early middle age, according to findings from a cross-sectional study.

The high prevalence of osteopenia – once viewed as restricted largely to older women – in the study’s younger, cross-sex population should spur physicians to ask all patients about calcium intake and exercise as well as to screen for osteoporosis in all patients, Martha A. Bass, PhD,`wrote in the Journal of the American Osteopathic Association.

“It is important that early detection of the precursors for osteoporosis become part of the annual physical for people in this age range, as well as in older patients,” noted Dr Bass of the University of Mississippi School of Applied Sciences in Oxford, and coauthors. “Primary care physicians should begin educating patients as early as adolescence or young adulthood so the consequences of osteoporosis can be prevented. The result would be the prevention of future bone fractures and the morbidity and mortality associated with bone fractures, thus leading to improved quality of life.”

The researchers set out to examine the likelihood of low bone mineral density (BMD) and related risk factors in 173 adults aged 35-50 years. All of the participants completed a questionnaire assessing calcium intake, weekly exercise, smoking, and body mass index, and all underwent screening for BMD. The study’s primary outcome was BMD at the femoral neck, trochanter, intertrochanteric crest, total femur, and lumbar spine.

Among the 81 men in the sample, 25 (30%) had a normal body mass index, and the remainder were either overweight (47.5%) or obese (22.5%). One of the women was underweight, 48.9% were normal weight, 28.3% were overweight, and 21.7% were obese.

Most of the sample, regardless of gender, reported consuming fewer than three dairy items per day. Exercise frequency was better, with 68% of men and 56.4% of women saying they exercised at least 20 times per month.

There were no total femur osteoporosis findings in either sex. However, osteopenia at the femoral neck was present in 28.4% of the men and 26.1% of the women. Osteopenia at the lumbar spine occurred in 21% of men and 15.2% of women, with 6.2% of men and 2.2% of women showing osteoporosis at this site.

An adjusted analysis determined that exercise correlated significantly and negatively with femoral neck BMD in men. But in women, there was a significant and positive correlation with BMD at the lumbar spine and at all femoral measurements.

Body mass index also played into the risk picture. Among men, almost all BMD measurements (trochanter, intertrochanteric crest, total femur, and lumbar spine) were positively associated with higher BMI. For women, higher BMI was associated with better BMD at the all the femoral sites, but not at the lumbar spine.

The negative correlation between femoral neck BMD and exercise in men seemed to contradict findings from previous studies. The authors said that could be a result of reporting bias, with men overestimating their amount of exercise, and could suggest that higher BMI confers some protection against bone loss in men.

The study found no significant correlations between dairy intake and BMD at any site in either sex. The finding suggests that both sexes need to improve both vitamin D and calcium intake.

None of the authors reported any financial disclosures.

[email protected]

SOURCE: Bass MA et al. J Am Osteopath Assoc. 2019;119(6):357-63.

Osteopenia was present in more than a quarter of both men and women in early middle age, according to findings from a cross-sectional study.

The high prevalence of osteopenia – once viewed as restricted largely to older women – in the study’s younger, cross-sex population should spur physicians to ask all patients about calcium intake and exercise as well as to screen for osteoporosis in all patients, Martha A. Bass, PhD,`wrote in the Journal of the American Osteopathic Association.

“It is important that early detection of the precursors for osteoporosis become part of the annual physical for people in this age range, as well as in older patients,” noted Dr Bass of the University of Mississippi School of Applied Sciences in Oxford, and coauthors. “Primary care physicians should begin educating patients as early as adolescence or young adulthood so the consequences of osteoporosis can be prevented. The result would be the prevention of future bone fractures and the morbidity and mortality associated with bone fractures, thus leading to improved quality of life.”

The researchers set out to examine the likelihood of low bone mineral density (BMD) and related risk factors in 173 adults aged 35-50 years. All of the participants completed a questionnaire assessing calcium intake, weekly exercise, smoking, and body mass index, and all underwent screening for BMD. The study’s primary outcome was BMD at the femoral neck, trochanter, intertrochanteric crest, total femur, and lumbar spine.

Among the 81 men in the sample, 25 (30%) had a normal body mass index, and the remainder were either overweight (47.5%) or obese (22.5%). One of the women was underweight, 48.9% were normal weight, 28.3% were overweight, and 21.7% were obese.

Most of the sample, regardless of gender, reported consuming fewer than three dairy items per day. Exercise frequency was better, with 68% of men and 56.4% of women saying they exercised at least 20 times per month.

There were no total femur osteoporosis findings in either sex. However, osteopenia at the femoral neck was present in 28.4% of the men and 26.1% of the women. Osteopenia at the lumbar spine occurred in 21% of men and 15.2% of women, with 6.2% of men and 2.2% of women showing osteoporosis at this site.

An adjusted analysis determined that exercise correlated significantly and negatively with femoral neck BMD in men. But in women, there was a significant and positive correlation with BMD at the lumbar spine and at all femoral measurements.

Body mass index also played into the risk picture. Among men, almost all BMD measurements (trochanter, intertrochanteric crest, total femur, and lumbar spine) were positively associated with higher BMI. For women, higher BMI was associated with better BMD at the all the femoral sites, but not at the lumbar spine.

The negative correlation between femoral neck BMD and exercise in men seemed to contradict findings from previous studies. The authors said that could be a result of reporting bias, with men overestimating their amount of exercise, and could suggest that higher BMI confers some protection against bone loss in men.

The study found no significant correlations between dairy intake and BMD at any site in either sex. The finding suggests that both sexes need to improve both vitamin D and calcium intake.

None of the authors reported any financial disclosures.

[email protected]

SOURCE: Bass MA et al. J Am Osteopath Assoc. 2019;119(6):357-63.

Osteopenia was present in more than a quarter of both men and women in early middle age, according to findings from a cross-sectional study.

The high prevalence of osteopenia – once viewed as restricted largely to older women – in the study’s younger, cross-sex population should spur physicians to ask all patients about calcium intake and exercise as well as to screen for osteoporosis in all patients, Martha A. Bass, PhD,`wrote in the Journal of the American Osteopathic Association.

“It is important that early detection of the precursors for osteoporosis become part of the annual physical for people in this age range, as well as in older patients,” noted Dr Bass of the University of Mississippi School of Applied Sciences in Oxford, and coauthors. “Primary care physicians should begin educating patients as early as adolescence or young adulthood so the consequences of osteoporosis can be prevented. The result would be the prevention of future bone fractures and the morbidity and mortality associated with bone fractures, thus leading to improved quality of life.”

The researchers set out to examine the likelihood of low bone mineral density (BMD) and related risk factors in 173 adults aged 35-50 years. All of the participants completed a questionnaire assessing calcium intake, weekly exercise, smoking, and body mass index, and all underwent screening for BMD. The study’s primary outcome was BMD at the femoral neck, trochanter, intertrochanteric crest, total femur, and lumbar spine.

Among the 81 men in the sample, 25 (30%) had a normal body mass index, and the remainder were either overweight (47.5%) or obese (22.5%). One of the women was underweight, 48.9% were normal weight, 28.3% were overweight, and 21.7% were obese.

Most of the sample, regardless of gender, reported consuming fewer than three dairy items per day. Exercise frequency was better, with 68% of men and 56.4% of women saying they exercised at least 20 times per month.

There were no total femur osteoporosis findings in either sex. However, osteopenia at the femoral neck was present in 28.4% of the men and 26.1% of the women. Osteopenia at the lumbar spine occurred in 21% of men and 15.2% of women, with 6.2% of men and 2.2% of women showing osteoporosis at this site.

An adjusted analysis determined that exercise correlated significantly and negatively with femoral neck BMD in men. But in women, there was a significant and positive correlation with BMD at the lumbar spine and at all femoral measurements.

Body mass index also played into the risk picture. Among men, almost all BMD measurements (trochanter, intertrochanteric crest, total femur, and lumbar spine) were positively associated with higher BMI. For women, higher BMI was associated with better BMD at the all the femoral sites, but not at the lumbar spine.

The negative correlation between femoral neck BMD and exercise in men seemed to contradict findings from previous studies. The authors said that could be a result of reporting bias, with men overestimating their amount of exercise, and could suggest that higher BMI confers some protection against bone loss in men.

The study found no significant correlations between dairy intake and BMD at any site in either sex. The finding suggests that both sexes need to improve both vitamin D and calcium intake.

None of the authors reported any financial disclosures.

[email protected]

SOURCE: Bass MA et al. J Am Osteopath Assoc. 2019;119(6):357-63.

DALLAS – Warfarin appears to increase the risk of lung transplant or death for patients with fibrotic lung disease who need anticoagulation therapy, Christopher King, MD, said at the American Thoracic Society’s international conference.

Michele G. Sullivan/MDedge News

Compared with direct oral anticoagulation (DOAC), warfarin doubled the risk of those outcomes, even after the researchers controlled for multiple morbidities that accompany the need for anticoagulation, said Dr. King, medical director of the transplant and advanced lung disease critical care program at Inova Fairfax (Va.) Hospital.

“The need for anticoagulation in patients with interstitial lung disease is already associated with an increased risk of death or transplant,” he said. Warfarin – but not oral anticoagulation – seems to increase that risk even more “no matter how you analyze it,” he said.

“We know now that fibrosis and coagulation are entwined, and there’s background epidemiologic data showing an increased incidence of venous thromboembolism and acute coronary syndrome in patients with pulmonary fibrosis. This suggests that a dysregulated coagulation cascade may play a role in the pathogenesis of fibrosis.”

The relationship has been explored for the last decade or so. Two recent meta-analyses came to similar conclusions.

In 2013, a 125-patient retrospective cohort study compared clinical characteristics and survival among patients with idiopathic pulmonary fibrosis (IPF) who received anticoagulant therapy with those who did not (Sarcoidosis Vasc Diffuse Lung Dis. 2013 Aug 1;30[2]:121-7). Those who got the treatment had worse survival outcomes at 1 and 3 years than did those who received no therapy (84% vs. 53% and 89% vs. 64%, respectively).

In 2016, a post hoc analysis of three placebo-controlled studies determined that any anticoagulant use independently increased the risk of death among patients with IPF, compared with nonuse: 15.6% vs 6.3% all-cause mortality (Eur Respir J. 2016. doi: 10.1183/13993003.02087-2015).

But these investigations didn’t parse out the types of anticoagulation. Direct oral anticoagulation (DOAC) is much more common now, however, and Dr. King and colleagues wanted to find out how warfarin and DOAC compared.

They retrospectively analyzed data from the Pulmonary Fibrosis Foundation’s database and compared the risk of lung transplant and death for patients on anticoagulation or no anticoagulation and for those receiving DOACs versus warfarin versus no anticoagulation.

The study comprised 1,918 patients, 91% of whom were not on anticoagulation therapy. The remaining 164 were either taking DOAC (n = 83) or warfarin (n = 81). Both of these groups were significantly older than those not on anticoagulation (70 vs. 67 years). As expected , they were significantly more likely to have cardiac arrhythmias, heart failure, or pulmonary embolism or deep vein thrombosis and significantly more likely to be on immunosuppressant therapy or steroids. Their diffusing capacity of lung for carbon dioxide was also significantly lower.

There were no significant lung disease–related differences in anticoagulation therapy, other than a trend toward more use among those with connective tissue disease–associated interstitial lung disease.

Over 2 years, the entire cohort experienced 110 deaths (5.7%), 52 transplants (2.7%), and 29 withdrawals (1.5%). Among patients with IPF, there were 80 deaths (6.7%), 43 transplants (3.6%) and 20 withdrawals (1.7%).

In an unadjusted analysis, anticoagulation more than doubled the risk of an event, compared with no anticoagulation (hazard ratio, 2.4). This was slightly attenuated, but still significant, in a multivariate model that controlled for age, gender, oxygen use, gastroesophageal reflux disease, obstructive sleep apnea, arrhythmia, cancer, heart failure, obesity, venous thromboembolism, and antifibrotics (HR, 1.88).

A second whole-cohort analysis looked at the survival ratios for both warfarin and DOAC, compared with no treatment. In the fully adjusted model, warfarin was associated with a significantly increased risk HR (2.28) but DOAC was not.

The investigators then examined risk in only patients with lung disease. Among those with IPF, the fully adjusted model showed that warfarin nearly tripled the risk of transplant or death (HR, 2.8), while DOAC had no significant effect.

The reason for this association remains unclear, Dr. King said. “Renal failure may be a big reason patients get warfarin instead of DOAC. It’s difficult to say whether these patients were frail or prone to bleeding. Even something like the care team not being as up to date with treatment could be affecting the numbers. And is it the direct effect of warfarin on fibrotic lung disease? Or maybe DOAC has some beneficial effect on pulmonary fibrosis? We don’t know.

“But what we can take away from this is that warfarin is associated with worse outcomes than DOAC in patients with IPF. It seems reasonable to use DOAC over warfarin if there’s no specific contraindication to DOAC. If you have a patient with pulmonary thrombosis who has indications for anticoagulation I would use DOAC, based on the evidence that we now have available.”

Dr. King had no disclosures.

[email protected]

DALLAS – Warfarin appears to increase the risk of lung transplant or death for patients with fibrotic lung disease who need anticoagulation therapy, Christopher King, MD, said at the American Thoracic Society’s international conference.

Michele G. Sullivan/MDedge News

Compared with direct oral anticoagulation (DOAC), warfarin doubled the risk of those outcomes, even after the researchers controlled for multiple morbidities that accompany the need for anticoagulation, said Dr. King, medical director of the transplant and advanced lung disease critical care program at Inova Fairfax (Va.) Hospital.

“The need for anticoagulation in patients with interstitial lung disease is already associated with an increased risk of death or transplant,” he said. Warfarin – but not oral anticoagulation – seems to increase that risk even more “no matter how you analyze it,” he said.

“We know now that fibrosis and coagulation are entwined, and there’s background epidemiologic data showing an increased incidence of venous thromboembolism and acute coronary syndrome in patients with pulmonary fibrosis. This suggests that a dysregulated coagulation cascade may play a role in the pathogenesis of fibrosis.”

The relationship has been explored for the last decade or so. Two recent meta-analyses came to similar conclusions.

In 2013, a 125-patient retrospective cohort study compared clinical characteristics and survival among patients with idiopathic pulmonary fibrosis (IPF) who received anticoagulant therapy with those who did not (Sarcoidosis Vasc Diffuse Lung Dis. 2013 Aug 1;30[2]:121-7). Those who got the treatment had worse survival outcomes at 1 and 3 years than did those who received no therapy (84% vs. 53% and 89% vs. 64%, respectively).

In 2016, a post hoc analysis of three placebo-controlled studies determined that any anticoagulant use independently increased the risk of death among patients with IPF, compared with nonuse: 15.6% vs 6.3% all-cause mortality (Eur Respir J. 2016. doi: 10.1183/13993003.02087-2015).

But these investigations didn’t parse out the types of anticoagulation. Direct oral anticoagulation (DOAC) is much more common now, however, and Dr. King and colleagues wanted to find out how warfarin and DOAC compared.

They retrospectively analyzed data from the Pulmonary Fibrosis Foundation’s database and compared the risk of lung transplant and death for patients on anticoagulation or no anticoagulation and for those receiving DOACs versus warfarin versus no anticoagulation.

The study comprised 1,918 patients, 91% of whom were not on anticoagulation therapy. The remaining 164 were either taking DOAC (n = 83) or warfarin (n = 81). Both of these groups were significantly older than those not on anticoagulation (70 vs. 67 years). As expected , they were significantly more likely to have cardiac arrhythmias, heart failure, or pulmonary embolism or deep vein thrombosis and significantly more likely to be on immunosuppressant therapy or steroids. Their diffusing capacity of lung for carbon dioxide was also significantly lower.

There were no significant lung disease–related differences in anticoagulation therapy, other than a trend toward more use among those with connective tissue disease–associated interstitial lung disease.

Over 2 years, the entire cohort experienced 110 deaths (5.7%), 52 transplants (2.7%), and 29 withdrawals (1.5%). Among patients with IPF, there were 80 deaths (6.7%), 43 transplants (3.6%) and 20 withdrawals (1.7%).

In an unadjusted analysis, anticoagulation more than doubled the risk of an event, compared with no anticoagulation (hazard ratio, 2.4). This was slightly attenuated, but still significant, in a multivariate model that controlled for age, gender, oxygen use, gastroesophageal reflux disease, obstructive sleep apnea, arrhythmia, cancer, heart failure, obesity, venous thromboembolism, and antifibrotics (HR, 1.88).

A second whole-cohort analysis looked at the survival ratios for both warfarin and DOAC, compared with no treatment. In the fully adjusted model, warfarin was associated with a significantly increased risk HR (2.28) but DOAC was not.

The investigators then examined risk in only patients with lung disease. Among those with IPF, the fully adjusted model showed that warfarin nearly tripled the risk of transplant or death (HR, 2.8), while DOAC had no significant effect.

The reason for this association remains unclear, Dr. King said. “Renal failure may be a big reason patients get warfarin instead of DOAC. It’s difficult to say whether these patients were frail or prone to bleeding. Even something like the care team not being as up to date with treatment could be affecting the numbers. And is it the direct effect of warfarin on fibrotic lung disease? Or maybe DOAC has some beneficial effect on pulmonary fibrosis? We don’t know.

“But what we can take away from this is that warfarin is associated with worse outcomes than DOAC in patients with IPF. It seems reasonable to use DOAC over warfarin if there’s no specific contraindication to DOAC. If you have a patient with pulmonary thrombosis who has indications for anticoagulation I would use DOAC, based on the evidence that we now have available.”

Dr. King had no disclosures.

[email protected]

DALLAS – Warfarin appears to increase the risk of lung transplant or death for patients with fibrotic lung disease who need anticoagulation therapy, Christopher King, MD, said at the American Thoracic Society’s international conference.

Michele G. Sullivan/MDedge News

Compared with direct oral anticoagulation (DOAC), warfarin doubled the risk of those outcomes, even after the researchers controlled for multiple morbidities that accompany the need for anticoagulation, said Dr. King, medical director of the transplant and advanced lung disease critical care program at Inova Fairfax (Va.) Hospital.

“The need for anticoagulation in patients with interstitial lung disease is already associated with an increased risk of death or transplant,” he said. Warfarin – but not oral anticoagulation – seems to increase that risk even more “no matter how you analyze it,” he said.

“We know now that fibrosis and coagulation are entwined, and there’s background epidemiologic data showing an increased incidence of venous thromboembolism and acute coronary syndrome in patients with pulmonary fibrosis. This suggests that a dysregulated coagulation cascade may play a role in the pathogenesis of fibrosis.”

The relationship has been explored for the last decade or so. Two recent meta-analyses came to similar conclusions.

In 2013, a 125-patient retrospective cohort study compared clinical characteristics and survival among patients with idiopathic pulmonary fibrosis (IPF) who received anticoagulant therapy with those who did not (Sarcoidosis Vasc Diffuse Lung Dis. 2013 Aug 1;30[2]:121-7). Those who got the treatment had worse survival outcomes at 1 and 3 years than did those who received no therapy (84% vs. 53% and 89% vs. 64%, respectively).

In 2016, a post hoc analysis of three placebo-controlled studies determined that any anticoagulant use independently increased the risk of death among patients with IPF, compared with nonuse: 15.6% vs 6.3% all-cause mortality (Eur Respir J. 2016. doi: 10.1183/13993003.02087-2015).

But these investigations didn’t parse out the types of anticoagulation. Direct oral anticoagulation (DOAC) is much more common now, however, and Dr. King and colleagues wanted to find out how warfarin and DOAC compared.

They retrospectively analyzed data from the Pulmonary Fibrosis Foundation’s database and compared the risk of lung transplant and death for patients on anticoagulation or no anticoagulation and for those receiving DOACs versus warfarin versus no anticoagulation.

The study comprised 1,918 patients, 91% of whom were not on anticoagulation therapy. The remaining 164 were either taking DOAC (n = 83) or warfarin (n = 81). Both of these groups were significantly older than those not on anticoagulation (70 vs. 67 years). As expected , they were significantly more likely to have cardiac arrhythmias, heart failure, or pulmonary embolism or deep vein thrombosis and significantly more likely to be on immunosuppressant therapy or steroids. Their diffusing capacity of lung for carbon dioxide was also significantly lower.

There were no significant lung disease–related differences in anticoagulation therapy, other than a trend toward more use among those with connective tissue disease–associated interstitial lung disease.

Over 2 years, the entire cohort experienced 110 deaths (5.7%), 52 transplants (2.7%), and 29 withdrawals (1.5%). Among patients with IPF, there were 80 deaths (6.7%), 43 transplants (3.6%) and 20 withdrawals (1.7%).

In an unadjusted analysis, anticoagulation more than doubled the risk of an event, compared with no anticoagulation (hazard ratio, 2.4). This was slightly attenuated, but still significant, in a multivariate model that controlled for age, gender, oxygen use, gastroesophageal reflux disease, obstructive sleep apnea, arrhythmia, cancer, heart failure, obesity, venous thromboembolism, and antifibrotics (HR, 1.88).

A second whole-cohort analysis looked at the survival ratios for both warfarin and DOAC, compared with no treatment. In the fully adjusted model, warfarin was associated with a significantly increased risk HR (2.28) but DOAC was not.

The investigators then examined risk in only patients with lung disease. Among those with IPF, the fully adjusted model showed that warfarin nearly tripled the risk of transplant or death (HR, 2.8), while DOAC had no significant effect.

The reason for this association remains unclear, Dr. King said. “Renal failure may be a big reason patients get warfarin instead of DOAC. It’s difficult to say whether these patients were frail or prone to bleeding. Even something like the care team not being as up to date with treatment could be affecting the numbers. And is it the direct effect of warfarin on fibrotic lung disease? Or maybe DOAC has some beneficial effect on pulmonary fibrosis? We don’t know.

“But what we can take away from this is that warfarin is associated with worse outcomes than DOAC in patients with IPF. It seems reasonable to use DOAC over warfarin if there’s no specific contraindication to DOAC. If you have a patient with pulmonary thrombosis who has indications for anticoagulation I would use DOAC, based on the evidence that we now have available.”

Dr. King had no disclosures.

[email protected]

Variants in the apolipoprotein B gene (APOB), which creates the main protein in low-density and very low-density cholesterol, may be associated with early-onset Alzheimer’s disease, Thomas Wingo, MD, and his colleagues have determined.

Kheng guan Toh/Thinkstock

The finding may help fill out the genetic risk picture for early-onset Alzheimer’s disease (EOAD), said Dr. Wingo of the Atlanta Veterans Affairs Medical Center. The study found that the already-known genetic markers for EOAD – mutations of the presenilin (PSEN) 1 and 2 genes and amyloid precursor protein (APP) – account for just a small fraction of cases.

“To place the genetic association between APOB and EOAD in context, we note that only 3.4% of all EOAD cases in our combined data set showed a known pathogenic mutation, and we found a stronger association between EOAD and rare coding variants in APOB, compared with PSEN1 in our fully adjusted analysis,” the team wrote. However, “approximately 5.0% of patients with EOAD and 1.7% of controls were found to harbor a rare coding polymorphism in APOB that is likely to disrupt the structure, functions, or abundance of ApoB protein.”

The team conducted genetic analysis on plasma samples from 2,125 EOAD and control subjects included in several research cohorts. They first determined the association between cholesterol and EOAD, and then the frequency of variants in apolipoprotein E epsilon 4 (APOE e4), APP, PSEN1, PSEN2, and ApoB. Gene sequencing revealed that 3.4% of samples showed mutations in APP, PSEN1, or PSEN2.

“Given the strong associations between APOE e4 and EOAD and elevated circulating LDL cholesterol levels, we expected individuals with EOAD to have elevated LDL levels,” the team said. But an analysis of 267 of the samples for lipid levels found that, even after the researchers controlled for APOE e4, EOAD cases had higher total cholesterol, low-density cholesterol, and plasma ApoB, compared with controls. However, they found no association between EOAD and high-density lipoprotein or triglycerides.

“Because total cholesterol largely consists of LDL-C, and ApoB is the main lipoprotein of LDL-C, these findings are consistent with one another.

“From these data, we estimated that LDL-C explains 7.6% of the variance in liability to EOAD, independently of APOE e4 ... These results demonstrate that elevated levels of LDL-C [and ApoB] were significantly associated with increased EOAD risk, and this effect was only partially mediated by APOE e4 genotype.”

The results also raised a question: What was driving the association between LDL and EOAD? Because variants of the ApoB gene can either raise or lower LDL, the team examined variants associated with coding changes. These variants were significantly more common in EOAD cases than in controls (5.0% vs. 1.7%).

“Two affected individuals ... were compound heterozygotes, with the remainder being heterozygotes,” the researchers wrote. “Each compound heterozygote case was heterozygous for two different rare coding sites ... Of these four variants, only [one] has been previously described.”

“Our finding of a significant association between rare coding variants in APOB and EOAD independently of APOE is novel, important, and consistent with multiple genome-wide association studies that revealed strong associations between late-onset AD and common intron markers of genes involved in brain cholesterol metabolism [ABCA7, BIN1, CLU, and SORL1]. Furthermore, mice overexpressing ApoB show hyperlipidemia, neurodegeneration, increases in APP, accumulation of amyloid plaques, and cognitive impairment similar to mice overexpressing wild-type human APP. Collectively, these studies and our findings suggest an important role of cholesterol metabolism in AD pathogenesis.”

This research was supported by grants from the Veterans Health Administration, the National Institutes of Health, the To Remember Foundation, the Douglas French Alzheimer’s Foundation, and a contract with the State of California Department of Health Services. Several authors reported financial ties to pharmaceutical companies outside of this work.

[email protected]

SOURCE: Wingo TS et al. JAMA Neurol. 2019 May 28. doi: 10.1001/jamaneurol.2019.0648.

Variants in the apolipoprotein B gene (APOB), which creates the main protein in low-density and very low-density cholesterol, may be associated with early-onset Alzheimer’s disease, Thomas Wingo, MD, and his colleagues have determined.

Kheng guan Toh/Thinkstock

The finding may help fill out the genetic risk picture for early-onset Alzheimer’s disease (EOAD), said Dr. Wingo of the Atlanta Veterans Affairs Medical Center. The study found that the already-known genetic markers for EOAD – mutations of the presenilin (PSEN) 1 and 2 genes and amyloid precursor protein (APP) – account for just a small fraction of cases.

“To place the genetic association between APOB and EOAD in context, we note that only 3.4% of all EOAD cases in our combined data set showed a known pathogenic mutation, and we found a stronger association between EOAD and rare coding variants in APOB, compared with PSEN1 in our fully adjusted analysis,” the team wrote. However, “approximately 5.0% of patients with EOAD and 1.7% of controls were found to harbor a rare coding polymorphism in APOB that is likely to disrupt the structure, functions, or abundance of ApoB protein.”

The team conducted genetic analysis on plasma samples from 2,125 EOAD and control subjects included in several research cohorts. They first determined the association between cholesterol and EOAD, and then the frequency of variants in apolipoprotein E epsilon 4 (APOE e4), APP, PSEN1, PSEN2, and ApoB. Gene sequencing revealed that 3.4% of samples showed mutations in APP, PSEN1, or PSEN2.

“Given the strong associations between APOE e4 and EOAD and elevated circulating LDL cholesterol levels, we expected individuals with EOAD to have elevated LDL levels,” the team said. But an analysis of 267 of the samples for lipid levels found that, even after the researchers controlled for APOE e4, EOAD cases had higher total cholesterol, low-density cholesterol, and plasma ApoB, compared with controls. However, they found no association between EOAD and high-density lipoprotein or triglycerides.

“Because total cholesterol largely consists of LDL-C, and ApoB is the main lipoprotein of LDL-C, these findings are consistent with one another.

“From these data, we estimated that LDL-C explains 7.6% of the variance in liability to EOAD, independently of APOE e4 ... These results demonstrate that elevated levels of LDL-C [and ApoB] were significantly associated with increased EOAD risk, and this effect was only partially mediated by APOE e4 genotype.”

The results also raised a question: What was driving the association between LDL and EOAD? Because variants of the ApoB gene can either raise or lower LDL, the team examined variants associated with coding changes. These variants were significantly more common in EOAD cases than in controls (5.0% vs. 1.7%).

“Two affected individuals ... were compound heterozygotes, with the remainder being heterozygotes,” the researchers wrote. “Each compound heterozygote case was heterozygous for two different rare coding sites ... Of these four variants, only [one] has been previously described.”

“Our finding of a significant association between rare coding variants in APOB and EOAD independently of APOE is novel, important, and consistent with multiple genome-wide association studies that revealed strong associations between late-onset AD and common intron markers of genes involved in brain cholesterol metabolism [ABCA7, BIN1, CLU, and SORL1]. Furthermore, mice overexpressing ApoB show hyperlipidemia, neurodegeneration, increases in APP, accumulation of amyloid plaques, and cognitive impairment similar to mice overexpressing wild-type human APP. Collectively, these studies and our findings suggest an important role of cholesterol metabolism in AD pathogenesis.”

This research was supported by grants from the Veterans Health Administration, the National Institutes of Health, the To Remember Foundation, the Douglas French Alzheimer’s Foundation, and a contract with the State of California Department of Health Services. Several authors reported financial ties to pharmaceutical companies outside of this work.

[email protected]

SOURCE: Wingo TS et al. JAMA Neurol. 2019 May 28. doi: 10.1001/jamaneurol.2019.0648.

Variants in the apolipoprotein B gene (APOB), which creates the main protein in low-density and very low-density cholesterol, may be associated with early-onset Alzheimer’s disease, Thomas Wingo, MD, and his colleagues have determined.

Kheng guan Toh/Thinkstock

The finding may help fill out the genetic risk picture for early-onset Alzheimer’s disease (EOAD), said Dr. Wingo of the Atlanta Veterans Affairs Medical Center. The study found that the already-known genetic markers for EOAD – mutations of the presenilin (PSEN) 1 and 2 genes and amyloid precursor protein (APP) – account for just a small fraction of cases.

“To place the genetic association between APOB and EOAD in context, we note that only 3.4% of all EOAD cases in our combined data set showed a known pathogenic mutation, and we found a stronger association between EOAD and rare coding variants in APOB, compared with PSEN1 in our fully adjusted analysis,” the team wrote. However, “approximately 5.0% of patients with EOAD and 1.7% of controls were found to harbor a rare coding polymorphism in APOB that is likely to disrupt the structure, functions, or abundance of ApoB protein.”

The team conducted genetic analysis on plasma samples from 2,125 EOAD and control subjects included in several research cohorts. They first determined the association between cholesterol and EOAD, and then the frequency of variants in apolipoprotein E epsilon 4 (APOE e4), APP, PSEN1, PSEN2, and ApoB. Gene sequencing revealed that 3.4% of samples showed mutations in APP, PSEN1, or PSEN2.

“Given the strong associations between APOE e4 and EOAD and elevated circulating LDL cholesterol levels, we expected individuals with EOAD to have elevated LDL levels,” the team said. But an analysis of 267 of the samples for lipid levels found that, even after the researchers controlled for APOE e4, EOAD cases had higher total cholesterol, low-density cholesterol, and plasma ApoB, compared with controls. However, they found no association between EOAD and high-density lipoprotein or triglycerides.

“Because total cholesterol largely consists of LDL-C, and ApoB is the main lipoprotein of LDL-C, these findings are consistent with one another.

“From these data, we estimated that LDL-C explains 7.6% of the variance in liability to EOAD, independently of APOE e4 ... These results demonstrate that elevated levels of LDL-C [and ApoB] were significantly associated with increased EOAD risk, and this effect was only partially mediated by APOE e4 genotype.”

The results also raised a question: What was driving the association between LDL and EOAD? Because variants of the ApoB gene can either raise or lower LDL, the team examined variants associated with coding changes. These variants were significantly more common in EOAD cases than in controls (5.0% vs. 1.7%).

“Two affected individuals ... were compound heterozygotes, with the remainder being heterozygotes,” the researchers wrote. “Each compound heterozygote case was heterozygous for two different rare coding sites ... Of these four variants, only [one] has been previously described.”

“Our finding of a significant association between rare coding variants in APOB and EOAD independently of APOE is novel, important, and consistent with multiple genome-wide association studies that revealed strong associations between late-onset AD and common intron markers of genes involved in brain cholesterol metabolism [ABCA7, BIN1, CLU, and SORL1]. Furthermore, mice overexpressing ApoB show hyperlipidemia, neurodegeneration, increases in APP, accumulation of amyloid plaques, and cognitive impairment similar to mice overexpressing wild-type human APP. Collectively, these studies and our findings suggest an important role of cholesterol metabolism in AD pathogenesis.”

This research was supported by grants from the Veterans Health Administration, the National Institutes of Health, the To Remember Foundation, the Douglas French Alzheimer’s Foundation, and a contract with the State of California Department of Health Services. Several authors reported financial ties to pharmaceutical companies outside of this work.

[email protected]

SOURCE: Wingo TS et al. JAMA Neurol. 2019 May 28. doi: 10.1001/jamaneurol.2019.0648.

DALLAS – A molecule that boosts innate viral immunity may protect elderly people with asthma from the root cause of most exacerbations – viral respiratory tract infections.

Michele G. Sullivan/MDedge News

Dubbed RTB101, the oral medication is a selective, potent inhibitor of target of rapamycin complex 1 (TORC1). In phase 2b data presented at the American Thoracic Society’s international conference, RTB101 decreased by 52% the number of elderly subjects with severe, lab-confirmed respiratory tract infections (RTI) symptoms.

But the molecule was even more effective in patients with asthma aged 65 years and older, Joan Mannick, MD, said in an interview during the meeting. In this group, it reduced by 69% the percentage of subjects who developed RTIs and reduced the rate of infection by about 79%, compared with placebo.

“The core cause of asthma exacerbations in these patients is viral respiratory tract infection,” said Dr. Mannick, chief medical officer of resTORbio, the Boston company developing RTB101. “About 80% of the viruses detected in these infections are rhinoviruses, and there are 170 rhinovirus serotypes. We have never been able to develop a vaccine against rhinovirus, and we have no treatment other than to treat the inflammation caused by the infection.”

Centers for Disease Control and Prevention mortality records confirm the impact of viral respiratory infections on older people who experience asthma exacerbations: 6 of 10,000 will die, compared with less than 2 per 10,000 for all other age groups. Decreasing the number of these infections in older people with asthma would prevent morbidity and mortality and save considerable health care dollars.

“One of the reasons that asthmatics have such difficulty when they get respiratory infections is that they seem to have deficient antiviral immunity in the airways,” Dr. Mannick said. She pointed to a 2008 study of bronchial epithelial cells from both patients with asthma and healthy controls. When inoculated with rhinovirus, the cells from asthmatic airways were unable to mount a healthy immune response and were particularly deficient in producing interferon-beta.

By inhibiting mammalian TORC1 (mTORC1), RBT101 also inhibits sterol regulatory element binding transcription factor 2, a pathway that influences cholesterol synthesis. Cells perceive cholesterol synthesis attenuation as a threat, Dr. Mannick said, and react by up-regulating a number of immune response genes – including some specifically antiviral genes that up-regulate interferon-alpha and -beta production and immune cytokine signaling pathways.

RTB101 is not a particularly new molecule; Novartis originally investigated it as an anticancer agent. “It failed, because it was too selective for mTORC1,” Dr. Mannick said. After Novartis dropped the molecule, resTORbio, a Novartis spin-off, began to investigate it as an immunotherapy for RTIs, particularly in patients with asthma.

reSTORbio’s phase 2 studies on RTB101 comprised 264 healthy subjects aged 65 years and older, who received placebo or 10 mg RTB101 daily for 6 weeks, during cold and flu season. They were followed for a year, confirming the antiviral gene up-regulation. Treatment was also associated with a 42% reduction in the rate of respiratory tract infections.

Conversations with the Food and Drug Administration and payers collected, Dr. Mannick said. “They said that where this drug could really make a difference was if it could decrease these infections in high-risk elderly, who are expensive to treat. So, we targeted people 65 years and older with asthma, chronic obstructive pulmonary disease, and smokers, and people who are 85 years or older.”

The phase 2b trial comprised 652 of these elderly high-risk subjects randomized to the following treatment arms: RTB101 5 mg once daily (n = 61), RTB101 10 mg once daily (n = 176), RTB101 10 mg b.i.d. (n = 120), RTB101 10 mg plus everolimus 0.1 mg daily (n = 115), or matching placebo (n = 180) over 16 weeks, during the entire cold and flu season. The primary endpoint was laboratory-confirmed RTIs in all groups.

The RTB101 10-mg, once-daily group had the best results with a 30.6% reduction in the percentage of patients with lab-confirmed RTIs, compared with placebo, and a 52% reduction in the percentage with severe symptoms.

A subgroup analysis found even more benefit to those with asthma. Among these patients, RTB101 effected a 58.2% decrease in patients with RTIs, and a 66.4% decrease in the rate of infections, compared with placebo.

RTB101 was most effective against rhinoviruses, but it also prevented RTIs associated with influenza A and coronavirus OC43. It also decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

There were no safety signals, Dr. Mannick noted. Adverse events were similar in both placebo and active groups, and none were deemed related to the study drug. About 5% of each group discontinued the drug because an adverse event.

Plans for a phase 3 trial are underway. A phase 3, placebo-controlled study in the Southern Hemisphere is now ongoing, during the winter cold and flu season. The Northern Hemisphere phase 3 will commence fall and winter of 2019.

Whether RBT101 can help younger people with asthma is an open question. Elderly patients not only have the asthma-related immune deficiency, but also the general age-related immune issues. Younger patients, however, still express the same asthma-related impairment of bronchial immunity.

“We would like to investigate this in younger people and in children, but that will have to wait until our other phase 3 studies are complete,” Dr. Mannick said.

The trial was sponsored by resTORbio.

[email protected]

SOURCE: Mannick J et al. ATS 2019, Abstract A2623.

CORRECTION 5/24/2019 The article was corrected to state a decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

DALLAS – A molecule that boosts innate viral immunity may protect elderly people with asthma from the root cause of most exacerbations – viral respiratory tract infections.

Michele G. Sullivan/MDedge News

Dubbed RTB101, the oral medication is a selective, potent inhibitor of target of rapamycin complex 1 (TORC1). In phase 2b data presented at the American Thoracic Society’s international conference, RTB101 decreased by 52% the number of elderly subjects with severe, lab-confirmed respiratory tract infections (RTI) symptoms.

But the molecule was even more effective in patients with asthma aged 65 years and older, Joan Mannick, MD, said in an interview during the meeting. In this group, it reduced by 69% the percentage of subjects who developed RTIs and reduced the rate of infection by about 79%, compared with placebo.

“The core cause of asthma exacerbations in these patients is viral respiratory tract infection,” said Dr. Mannick, chief medical officer of resTORbio, the Boston company developing RTB101. “About 80% of the viruses detected in these infections are rhinoviruses, and there are 170 rhinovirus serotypes. We have never been able to develop a vaccine against rhinovirus, and we have no treatment other than to treat the inflammation caused by the infection.”

Centers for Disease Control and Prevention mortality records confirm the impact of viral respiratory infections on older people who experience asthma exacerbations: 6 of 10,000 will die, compared with less than 2 per 10,000 for all other age groups. Decreasing the number of these infections in older people with asthma would prevent morbidity and mortality and save considerable health care dollars.

“One of the reasons that asthmatics have such difficulty when they get respiratory infections is that they seem to have deficient antiviral immunity in the airways,” Dr. Mannick said. She pointed to a 2008 study of bronchial epithelial cells from both patients with asthma and healthy controls. When inoculated with rhinovirus, the cells from asthmatic airways were unable to mount a healthy immune response and were particularly deficient in producing interferon-beta.

By inhibiting mammalian TORC1 (mTORC1), RBT101 also inhibits sterol regulatory element binding transcription factor 2, a pathway that influences cholesterol synthesis. Cells perceive cholesterol synthesis attenuation as a threat, Dr. Mannick said, and react by up-regulating a number of immune response genes – including some specifically antiviral genes that up-regulate interferon-alpha and -beta production and immune cytokine signaling pathways.

RTB101 is not a particularly new molecule; Novartis originally investigated it as an anticancer agent. “It failed, because it was too selective for mTORC1,” Dr. Mannick said. After Novartis dropped the molecule, resTORbio, a Novartis spin-off, began to investigate it as an immunotherapy for RTIs, particularly in patients with asthma.

reSTORbio’s phase 2 studies on RTB101 comprised 264 healthy subjects aged 65 years and older, who received placebo or 10 mg RTB101 daily for 6 weeks, during cold and flu season. They were followed for a year, confirming the antiviral gene up-regulation. Treatment was also associated with a 42% reduction in the rate of respiratory tract infections.

Conversations with the Food and Drug Administration and payers collected, Dr. Mannick said. “They said that where this drug could really make a difference was if it could decrease these infections in high-risk elderly, who are expensive to treat. So, we targeted people 65 years and older with asthma, chronic obstructive pulmonary disease, and smokers, and people who are 85 years or older.”

The phase 2b trial comprised 652 of these elderly high-risk subjects randomized to the following treatment arms: RTB101 5 mg once daily (n = 61), RTB101 10 mg once daily (n = 176), RTB101 10 mg b.i.d. (n = 120), RTB101 10 mg plus everolimus 0.1 mg daily (n = 115), or matching placebo (n = 180) over 16 weeks, during the entire cold and flu season. The primary endpoint was laboratory-confirmed RTIs in all groups.

The RTB101 10-mg, once-daily group had the best results with a 30.6% reduction in the percentage of patients with lab-confirmed RTIs, compared with placebo, and a 52% reduction in the percentage with severe symptoms.

A subgroup analysis found even more benefit to those with asthma. Among these patients, RTB101 effected a 58.2% decrease in patients with RTIs, and a 66.4% decrease in the rate of infections, compared with placebo.

RTB101 was most effective against rhinoviruses, but it also prevented RTIs associated with influenza A and coronavirus OC43. It also decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

There were no safety signals, Dr. Mannick noted. Adverse events were similar in both placebo and active groups, and none were deemed related to the study drug. About 5% of each group discontinued the drug because an adverse event.

Plans for a phase 3 trial are underway. A phase 3, placebo-controlled study in the Southern Hemisphere is now ongoing, during the winter cold and flu season. The Northern Hemisphere phase 3 will commence fall and winter of 2019.

Whether RBT101 can help younger people with asthma is an open question. Elderly patients not only have the asthma-related immune deficiency, but also the general age-related immune issues. Younger patients, however, still express the same asthma-related impairment of bronchial immunity.

“We would like to investigate this in younger people and in children, but that will have to wait until our other phase 3 studies are complete,” Dr. Mannick said.

The trial was sponsored by resTORbio.

[email protected]

SOURCE: Mannick J et al. ATS 2019, Abstract A2623.

CORRECTION 5/24/2019 The article was corrected to state a decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

DALLAS – A molecule that boosts innate viral immunity may protect elderly people with asthma from the root cause of most exacerbations – viral respiratory tract infections.

Michele G. Sullivan/MDedge News

Dubbed RTB101, the oral medication is a selective, potent inhibitor of target of rapamycin complex 1 (TORC1). In phase 2b data presented at the American Thoracic Society’s international conference, RTB101 decreased by 52% the number of elderly subjects with severe, lab-confirmed respiratory tract infections (RTI) symptoms.

But the molecule was even more effective in patients with asthma aged 65 years and older, Joan Mannick, MD, said in an interview during the meeting. In this group, it reduced by 69% the percentage of subjects who developed RTIs and reduced the rate of infection by about 79%, compared with placebo.

“The core cause of asthma exacerbations in these patients is viral respiratory tract infection,” said Dr. Mannick, chief medical officer of resTORbio, the Boston company developing RTB101. “About 80% of the viruses detected in these infections are rhinoviruses, and there are 170 rhinovirus serotypes. We have never been able to develop a vaccine against rhinovirus, and we have no treatment other than to treat the inflammation caused by the infection.”

Centers for Disease Control and Prevention mortality records confirm the impact of viral respiratory infections on older people who experience asthma exacerbations: 6 of 10,000 will die, compared with less than 2 per 10,000 for all other age groups. Decreasing the number of these infections in older people with asthma would prevent morbidity and mortality and save considerable health care dollars.

“One of the reasons that asthmatics have such difficulty when they get respiratory infections is that they seem to have deficient antiviral immunity in the airways,” Dr. Mannick said. She pointed to a 2008 study of bronchial epithelial cells from both patients with asthma and healthy controls. When inoculated with rhinovirus, the cells from asthmatic airways were unable to mount a healthy immune response and were particularly deficient in producing interferon-beta.

By inhibiting mammalian TORC1 (mTORC1), RBT101 also inhibits sterol regulatory element binding transcription factor 2, a pathway that influences cholesterol synthesis. Cells perceive cholesterol synthesis attenuation as a threat, Dr. Mannick said, and react by up-regulating a number of immune response genes – including some specifically antiviral genes that up-regulate interferon-alpha and -beta production and immune cytokine signaling pathways.

RTB101 is not a particularly new molecule; Novartis originally investigated it as an anticancer agent. “It failed, because it was too selective for mTORC1,” Dr. Mannick said. After Novartis dropped the molecule, resTORbio, a Novartis spin-off, began to investigate it as an immunotherapy for RTIs, particularly in patients with asthma.

reSTORbio’s phase 2 studies on RTB101 comprised 264 healthy subjects aged 65 years and older, who received placebo or 10 mg RTB101 daily for 6 weeks, during cold and flu season. They were followed for a year, confirming the antiviral gene up-regulation. Treatment was also associated with a 42% reduction in the rate of respiratory tract infections.

Conversations with the Food and Drug Administration and payers collected, Dr. Mannick said. “They said that where this drug could really make a difference was if it could decrease these infections in high-risk elderly, who are expensive to treat. So, we targeted people 65 years and older with asthma, chronic obstructive pulmonary disease, and smokers, and people who are 85 years or older.”

The phase 2b trial comprised 652 of these elderly high-risk subjects randomized to the following treatment arms: RTB101 5 mg once daily (n = 61), RTB101 10 mg once daily (n = 176), RTB101 10 mg b.i.d. (n = 120), RTB101 10 mg plus everolimus 0.1 mg daily (n = 115), or matching placebo (n = 180) over 16 weeks, during the entire cold and flu season. The primary endpoint was laboratory-confirmed RTIs in all groups.

The RTB101 10-mg, once-daily group had the best results with a 30.6% reduction in the percentage of patients with lab-confirmed RTIs, compared with placebo, and a 52% reduction in the percentage with severe symptoms.

A subgroup analysis found even more benefit to those with asthma. Among these patients, RTB101 effected a 58.2% decrease in patients with RTIs, and a 66.4% decrease in the rate of infections, compared with placebo.

RTB101 was most effective against rhinoviruses, but it also prevented RTIs associated with influenza A and coronavirus OC43. It also decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

There were no safety signals, Dr. Mannick noted. Adverse events were similar in both placebo and active groups, and none were deemed related to the study drug. About 5% of each group discontinued the drug because an adverse event.

Plans for a phase 3 trial are underway. A phase 3, placebo-controlled study in the Southern Hemisphere is now ongoing, during the winter cold and flu season. The Northern Hemisphere phase 3 will commence fall and winter of 2019.

Whether RBT101 can help younger people with asthma is an open question. Elderly patients not only have the asthma-related immune deficiency, but also the general age-related immune issues. Younger patients, however, still express the same asthma-related impairment of bronchial immunity.

“We would like to investigate this in younger people and in children, but that will have to wait until our other phase 3 studies are complete,” Dr. Mannick said.

The trial was sponsored by resTORbio.

[email protected]

SOURCE: Mannick J et al. ATS 2019, Abstract A2623.

CORRECTION 5/24/2019 The article was corrected to state a decreased the incidence of RTIs caused by respiratory syncytial virus, parainfluenza 4, influenza B, metapneumovirus, or other coronavirus serotypes.

DALLAS – Nintedanib, a tyrosine kinase inhibitor, decreased by 44% the annual rate of lung function decline among patients with interstitial lung disease associated with systemic sclerosis, a year-long study has found.

Michele G. Sullivan/MDedge News

In a placebo-controlled 52-week trial, forced vital capacity (FVC) in patients who took nintedanib (Ofev) declined by a mean of 52 mL – significantly less than the mean 93 mL decline seen among those who were given placebo, Oliver Distler, MD, said at the annual meeting of the American Thoracic Society.

“These are people in their mid-40s and -50s,” said Dr. Distler of the University of Zürich. “They have a long time to go. If there is an annual preservation of lung function by 40%, if you have that every year, it becomes very surely clinically significant. A decline in FVC is also a good surrogate marker of mortality in interstitial lung disease associated with systemic sclerosis. Assuming the effects are ongoing above the 1 year we looked at, then indeed these results are clinically important.”

The study was simultaneously published in the New England Journal of Medicine. Nintedanib is already approved for idiopathic pulmonary fibrosis. But some data suggest that it also exerts antifibrotic and anti-inflammatory effects in animal models of systemic sclerosis and inflammatory lung disease (ILD). SENSCIS (the Safety and Efficacy of Nintedanib in Systemic Sclerosis trial) investigated the molecule’s use in patients with ILD associated with systemic sclerosis.

Conducted in 32 countries, SENSCIS comprised 576 patients with the disorder, whose sclerosis affected at least 10% of their lungs. They were assigned to 52 weeks of either placebo or 150 mg nintedanib twice weekly. However, patients stayed on their blinded treatment until the last patient enrolled had finished the year of treatment; some patients took the drug for 100 weeks, Dr. Distler said. The primary endpoint was annual rate of decline in the forced vital capacity (FEV). Secondary endpoints included changes of the modified Rodnan skin score and in the total score on the St. George’s Respiratory Questionnaire.

Patients were a mean of 54 years old, with a mean disease duration of about 3 years. About half had diffuse cutaneous systemic sclerosis; the sclerosis was limited in the remainder. The mean extent of lung fibrosis was about 36%. Half were taking mycophenolate at baseline, which was allowed as background treatment, along with up to 10 mg/day of prednisone. Any patient who experienced clinically significant lung function deterioration could receive additional therapy at the investigator’s discretion.

The mean baseline FEV for these patients was 72.5% of predicted value. The mean diffusing capacity of the lungs for carbon monoxide was 53% of expected capacity.

Most patients completed the study (80% of the active group and 89% of the placebo group). The mean drug exposure duration was 10 months in the active group and 11 in the placebo group.

Improvement began early in treatment, with the efficacy curves separating by week 12 and continuing to diverge. After 52 weeks of therapy, the annual rate of change was 41 mL less in the active group than in the placebo group (–54.4 mL vs. –93.3 mL). The mean adjusted absolute change from baseline was –54.6 mL in the active group and –101 mL in the placebo at week 52. Significantly fewer patients taking nintedanib also lost more than 10% of FVC by week 52 (16.7% vs. 18%).

The St. George’s Respiratory Questionnaire score improved about one point in the active group and declined about one point in the placebo group.

Nintedanib was equally effective across a number of subgroups, including those divided by sex, age, and race. Antitopoisomerase antibodies and so-called antitopoisomerase I antibody status did not affect nintedanib’s action. Nintedanib also significantly improved scores on the Health Assessment Questionnaire without Disability Index and dyspnea.

More patients in the active group than in on placebo discontinued treatment because of a serious adverse event (16% vs. 8.7%). The most common of these were diarrhea (75.7% vs. 31%), nausea (31.6% vs. 13.5%), and vomiting (24.7% vs.10.4%). Skin ulcers occurred in about 18% of each group. Patients in the active group were significantly more likely to develop elevated alanine and aspartate aminotransferase of up to three times normal levels (4.9% vs. 0.7%).

Treatment did not significantly affect mortality rates, however. Over the treatment period, 10 patients in the nintedanib group and 9 in the placebo group died (3.5% vs. 3.1%).

The study was sponsored by Boehringer Ingelheim. Dr. Distler was the primary investigator on the trial.

[email protected]

SOURCE: Distler O et al. ATS 2019, Abstract A7360.

DALLAS – Nintedanib, a tyrosine kinase inhibitor, decreased by 44% the annual rate of lung function decline among patients with interstitial lung disease associated with systemic sclerosis, a year-long study has found.

Michele G. Sullivan/MDedge News

In a placebo-controlled 52-week trial, forced vital capacity (FVC) in patients who took nintedanib (Ofev) declined by a mean of 52 mL – significantly less than the mean 93 mL decline seen among those who were given placebo, Oliver Distler, MD, said at the annual meeting of the American Thoracic Society.

“These are people in their mid-40s and -50s,” said Dr. Distler of the University of Zürich. “They have a long time to go. If there is an annual preservation of lung function by 40%, if you have that every year, it becomes very surely clinically significant. A decline in FVC is also a good surrogate marker of mortality in interstitial lung disease associated with systemic sclerosis. Assuming the effects are ongoing above the 1 year we looked at, then indeed these results are clinically important.”

The study was simultaneously published in the New England Journal of Medicine. Nintedanib is already approved for idiopathic pulmonary fibrosis. But some data suggest that it also exerts antifibrotic and anti-inflammatory effects in animal models of systemic sclerosis and inflammatory lung disease (ILD). SENSCIS (the Safety and Efficacy of Nintedanib in Systemic Sclerosis trial) investigated the molecule’s use in patients with ILD associated with systemic sclerosis.

Conducted in 32 countries, SENSCIS comprised 576 patients with the disorder, whose sclerosis affected at least 10% of their lungs. They were assigned to 52 weeks of either placebo or 150 mg nintedanib twice weekly. However, patients stayed on their blinded treatment until the last patient enrolled had finished the year of treatment; some patients took the drug for 100 weeks, Dr. Distler said. The primary endpoint was annual rate of decline in the forced vital capacity (FEV). Secondary endpoints included changes of the modified Rodnan skin score and in the total score on the St. George’s Respiratory Questionnaire.

Patients were a mean of 54 years old, with a mean disease duration of about 3 years. About half had diffuse cutaneous systemic sclerosis; the sclerosis was limited in the remainder. The mean extent of lung fibrosis was about 36%. Half were taking mycophenolate at baseline, which was allowed as background treatment, along with up to 10 mg/day of prednisone. Any patient who experienced clinically significant lung function deterioration could receive additional therapy at the investigator’s discretion.

The mean baseline FEV for these patients was 72.5% of predicted value. The mean diffusing capacity of the lungs for carbon monoxide was 53% of expected capacity.

Most patients completed the study (80% of the active group and 89% of the placebo group). The mean drug exposure duration was 10 months in the active group and 11 in the placebo group.

Improvement began early in treatment, with the efficacy curves separating by week 12 and continuing to diverge. After 52 weeks of therapy, the annual rate of change was 41 mL less in the active group than in the placebo group (–54.4 mL vs. –93.3 mL). The mean adjusted absolute change from baseline was –54.6 mL in the active group and –101 mL in the placebo at week 52. Significantly fewer patients taking nintedanib also lost more than 10% of FVC by week 52 (16.7% vs. 18%).

The St. George’s Respiratory Questionnaire score improved about one point in the active group and declined about one point in the placebo group.

Nintedanib was equally effective across a number of subgroups, including those divided by sex, age, and race. Antitopoisomerase antibodies and so-called antitopoisomerase I antibody status did not affect nintedanib’s action. Nintedanib also significantly improved scores on the Health Assessment Questionnaire without Disability Index and dyspnea.

More patients in the active group than in on placebo discontinued treatment because of a serious adverse event (16% vs. 8.7%). The most common of these were diarrhea (75.7% vs. 31%), nausea (31.6% vs. 13.5%), and vomiting (24.7% vs.10.4%). Skin ulcers occurred in about 18% of each group. Patients in the active group were significantly more likely to develop elevated alanine and aspartate aminotransferase of up to three times normal levels (4.9% vs. 0.7%).

Treatment did not significantly affect mortality rates, however. Over the treatment period, 10 patients in the nintedanib group and 9 in the placebo group died (3.5% vs. 3.1%).

The study was sponsored by Boehringer Ingelheim. Dr. Distler was the primary investigator on the trial.

[email protected]

SOURCE: Distler O et al. ATS 2019, Abstract A7360.

DALLAS – Nintedanib, a tyrosine kinase inhibitor, decreased by 44% the annual rate of lung function decline among patients with interstitial lung disease associated with systemic sclerosis, a year-long study has found.

Michele G. Sullivan/MDedge News

In a placebo-controlled 52-week trial, forced vital capacity (FVC) in patients who took nintedanib (Ofev) declined by a mean of 52 mL – significantly less than the mean 93 mL decline seen among those who were given placebo, Oliver Distler, MD, said at the annual meeting of the American Thoracic Society.

“These are people in their mid-40s and -50s,” said Dr. Distler of the University of Zürich. “They have a long time to go. If there is an annual preservation of lung function by 40%, if you have that every year, it becomes very surely clinically significant. A decline in FVC is also a good surrogate marker of mortality in interstitial lung disease associated with systemic sclerosis. Assuming the effects are ongoing above the 1 year we looked at, then indeed these results are clinically important.”

The study was simultaneously published in the New England Journal of Medicine. Nintedanib is already approved for idiopathic pulmonary fibrosis. But some data suggest that it also exerts antifibrotic and anti-inflammatory effects in animal models of systemic sclerosis and inflammatory lung disease (ILD). SENSCIS (the Safety and Efficacy of Nintedanib in Systemic Sclerosis trial) investigated the molecule’s use in patients with ILD associated with systemic sclerosis.

Conducted in 32 countries, SENSCIS comprised 576 patients with the disorder, whose sclerosis affected at least 10% of their lungs. They were assigned to 52 weeks of either placebo or 150 mg nintedanib twice weekly. However, patients stayed on their blinded treatment until the last patient enrolled had finished the year of treatment; some patients took the drug for 100 weeks, Dr. Distler said. The primary endpoint was annual rate of decline in the forced vital capacity (FEV). Secondary endpoints included changes of the modified Rodnan skin score and in the total score on the St. George’s Respiratory Questionnaire.

Patients were a mean of 54 years old, with a mean disease duration of about 3 years. About half had diffuse cutaneous systemic sclerosis; the sclerosis was limited in the remainder. The mean extent of lung fibrosis was about 36%. Half were taking mycophenolate at baseline, which was allowed as background treatment, along with up to 10 mg/day of prednisone. Any patient who experienced clinically significant lung function deterioration could receive additional therapy at the investigator’s discretion.

The mean baseline FEV for these patients was 72.5% of predicted value. The mean diffusing capacity of the lungs for carbon monoxide was 53% of expected capacity.

Most patients completed the study (80% of the active group and 89% of the placebo group). The mean drug exposure duration was 10 months in the active group and 11 in the placebo group.

Improvement began early in treatment, with the efficacy curves separating by week 12 and continuing to diverge. After 52 weeks of therapy, the annual rate of change was 41 mL less in the active group than in the placebo group (–54.4 mL vs. –93.3 mL). The mean adjusted absolute change from baseline was –54.6 mL in the active group and –101 mL in the placebo at week 52. Significantly fewer patients taking nintedanib also lost more than 10% of FVC by week 52 (16.7% vs. 18%).

The St. George’s Respiratory Questionnaire score improved about one point in the active group and declined about one point in the placebo group.

Nintedanib was equally effective across a number of subgroups, including those divided by sex, age, and race. Antitopoisomerase antibodies and so-called antitopoisomerase I antibody status did not affect nintedanib’s action. Nintedanib also significantly improved scores on the Health Assessment Questionnaire without Disability Index and dyspnea.

More patients in the active group than in on placebo discontinued treatment because of a serious adverse event (16% vs. 8.7%). The most common of these were diarrhea (75.7% vs. 31%), nausea (31.6% vs. 13.5%), and vomiting (24.7% vs.10.4%). Skin ulcers occurred in about 18% of each group. Patients in the active group were significantly more likely to develop elevated alanine and aspartate aminotransferase of up to three times normal levels (4.9% vs. 0.7%).

Treatment did not significantly affect mortality rates, however. Over the treatment period, 10 patients in the nintedanib group and 9 in the placebo group died (3.5% vs. 3.1%).

The study was sponsored by Boehringer Ingelheim. Dr. Distler was the primary investigator on the trial.

[email protected]

SOURCE: Distler O et al. ATS 2019, Abstract A7360.

BALTIMORE – Ultrasound can be a very effective way to track early nodal metastasis in patients with high-stage cutaneous squamous cell carcinomas, and at a fraction of the cost of other imaging modalities.

Bogdanhoda/Thinkstock

The technique shows not only abnormal variations in the shape of nodes, but changes in the core and outer density, and vascular patterns, Emily Ruiz, MD, said at the annual meeting of the American College of Mohs Surgery. And over a 2-year surveillance period, this costs thousands less than radiation-based imaging.

Dr. Ruiz, director of the High-Risk Skin Cancer Clinic at Dana-Farber/Brigham and Women’s Cancer Center, Boston, said the standard imaging technique at that center used to be serial CT scans performed at diagnosis and every 6 months thereafter, for 2 years. But recently, the protocol changed: Ultrasound is now the preferred technique.

“The big problem with CT in this earlier disease, is that it can only identify the nodes that are enlarged, and doesn’t tell us anything about the etiology. Ultrasound, on the other hand, looks at a number of different features of the node.”

Tracking high-risk squamous cell carcinoma patients is a must, she said. “About 4% of people diagnosed with high-risk SCC will develop nodal metastases, and 1.5% of those will die from disease-specific death,” most often from locoregional disease. “So it’s critical to identify nodal diseases early as possible. Earlier identification leads to better outcomes.” Ultrasound simply provides more information about nodal metastasis, Dr. Ruiz added.

Michele G. Sullivan/MDedge News

Cost is another consideration, Dr. Ruiz said. Five CT scans conducted over the recommended 2 years of follow-up will run about $5,000. Five scans with magnetic resonance imaging come in at about $6,500. PET CT is, of course, the most expensive, racking up a national average cost of $28,500 for five scans.

Ultrasound is amazingly inexpensive, Dr. Ruiz said. The national average cost of one scan is around $180, bringing the 2-year cost of five surveillance scans to $900.

Finally, clinicians and patients should consider the potential impact of repeated radiation exposure. “This can really add up over the follow-up period. Because there’s a 10-year latency period for these cancers, this might not be an issue for our older patients, but it really is something to consider in younger ones. “

However, she acknowledged that it’s not a completely rosy picture.

“Ultrasound is very user dependent, but we do think that by putting this in the hands of dermatologists with special training, we can solve this issue. In Europe, ultrasound’s very high sensitivity and specificity, combined with clinical exams, really improves disease detection.”

Unfortunately, at this point, anyone who wants to learn the technique has to go to Europe. “I trained in Germany, where I took a standard 3-day course, did 250 supervised scans, and completed an exam. I realize that’s unrealistic for most people,” she said. But a training protocol is being developed at Brigham and Women’s, under the auspices of the institution’s imaging experts, who felt that 3 days and 250 supervised scans was excessive. The Brigham and Women’s program comprises 8 hours of didactic training and at least 30 supervised scans with at least three abnormalities correctly identified, and will be put into place soon, Dr. Ruiz said.

The biggest obstacle to large-scale adoption of this protocol is data – there are not a lot, at least now.

“We are working on that, too. In conjunction with the Skin Cancer Foundation, we’re launching a prospective study. We want to recruit 80 patients with T2B/T3 cutaneous SCCs. They get both and ultrasound and a CT scan at diagnosis and every 6 months for 2 years,” she said.

[email protected]

BALTIMORE – Ultrasound can be a very effective way to track early nodal metastasis in patients with high-stage cutaneous squamous cell carcinomas, and at a fraction of the cost of other imaging modalities.

Bogdanhoda/Thinkstock

The technique shows not only abnormal variations in the shape of nodes, but changes in the core and outer density, and vascular patterns, Emily Ruiz, MD, said at the annual meeting of the American College of Mohs Surgery. And over a 2-year surveillance period, this costs thousands less than radiation-based imaging.

Dr. Ruiz, director of the High-Risk Skin Cancer Clinic at Dana-Farber/Brigham and Women’s Cancer Center, Boston, said the standard imaging technique at that center used to be serial CT scans performed at diagnosis and every 6 months thereafter, for 2 years. But recently, the protocol changed: Ultrasound is now the preferred technique.

“The big problem with CT in this earlier disease, is that it can only identify the nodes that are enlarged, and doesn’t tell us anything about the etiology. Ultrasound, on the other hand, looks at a number of different features of the node.”

Tracking high-risk squamous cell carcinoma patients is a must, she said. “About 4% of people diagnosed with high-risk SCC will develop nodal metastases, and 1.5% of those will die from disease-specific death,” most often from locoregional disease. “So it’s critical to identify nodal diseases early as possible. Earlier identification leads to better outcomes.” Ultrasound simply provides more information about nodal metastasis, Dr. Ruiz added.

Michele G. Sullivan/MDedge News

Cost is another consideration, Dr. Ruiz said. Five CT scans conducted over the recommended 2 years of follow-up will run about $5,000. Five scans with magnetic resonance imaging come in at about $6,500. PET CT is, of course, the most expensive, racking up a national average cost of $28,500 for five scans.

Ultrasound is amazingly inexpensive, Dr. Ruiz said. The national average cost of one scan is around $180, bringing the 2-year cost of five surveillance scans to $900.

Finally, clinicians and patients should consider the potential impact of repeated radiation exposure. “This can really add up over the follow-up period. Because there’s a 10-year latency period for these cancers, this might not be an issue for our older patients, but it really is something to consider in younger ones. “

However, she acknowledged that it’s not a completely rosy picture.

“Ultrasound is very user dependent, but we do think that by putting this in the hands of dermatologists with special training, we can solve this issue. In Europe, ultrasound’s very high sensitivity and specificity, combined with clinical exams, really improves disease detection.”

Unfortunately, at this point, anyone who wants to learn the technique has to go to Europe. “I trained in Germany, where I took a standard 3-day course, did 250 supervised scans, and completed an exam. I realize that’s unrealistic for most people,” she said. But a training protocol is being developed at Brigham and Women’s, under the auspices of the institution’s imaging experts, who felt that 3 days and 250 supervised scans was excessive. The Brigham and Women’s program comprises 8 hours of didactic training and at least 30 supervised scans with at least three abnormalities correctly identified, and will be put into place soon, Dr. Ruiz said.

The biggest obstacle to large-scale adoption of this protocol is data – there are not a lot, at least now.

“We are working on that, too. In conjunction with the Skin Cancer Foundation, we’re launching a prospective study. We want to recruit 80 patients with T2B/T3 cutaneous SCCs. They get both and ultrasound and a CT scan at diagnosis and every 6 months for 2 years,” she said.

[email protected]

BALTIMORE – Ultrasound can be a very effective way to track early nodal metastasis in patients with high-stage cutaneous squamous cell carcinomas, and at a fraction of the cost of other imaging modalities.

Bogdanhoda/Thinkstock

The technique shows not only abnormal variations in the shape of nodes, but changes in the core and outer density, and vascular patterns, Emily Ruiz, MD, said at the annual meeting of the American College of Mohs Surgery. And over a 2-year surveillance period, this costs thousands less than radiation-based imaging.

Dr. Ruiz, director of the High-Risk Skin Cancer Clinic at Dana-Farber/Brigham and Women’s Cancer Center, Boston, said the standard imaging technique at that center used to be serial CT scans performed at diagnosis and every 6 months thereafter, for 2 years. But recently, the protocol changed: Ultrasound is now the preferred technique.

“The big problem with CT in this earlier disease, is that it can only identify the nodes that are enlarged, and doesn’t tell us anything about the etiology. Ultrasound, on the other hand, looks at a number of different features of the node.”

Tracking high-risk squamous cell carcinoma patients is a must, she said. “About 4% of people diagnosed with high-risk SCC will develop nodal metastases, and 1.5% of those will die from disease-specific death,” most often from locoregional disease. “So it’s critical to identify nodal diseases early as possible. Earlier identification leads to better outcomes.” Ultrasound simply provides more information about nodal metastasis, Dr. Ruiz added.

Michele G. Sullivan/MDedge News

Cost is another consideration, Dr. Ruiz said. Five CT scans conducted over the recommended 2 years of follow-up will run about $5,000. Five scans with magnetic resonance imaging come in at about $6,500. PET CT is, of course, the most expensive, racking up a national average cost of $28,500 for five scans.

Ultrasound is amazingly inexpensive, Dr. Ruiz said. The national average cost of one scan is around $180, bringing the 2-year cost of five surveillance scans to $900.

Finally, clinicians and patients should consider the potential impact of repeated radiation exposure. “This can really add up over the follow-up period. Because there’s a 10-year latency period for these cancers, this might not be an issue for our older patients, but it really is something to consider in younger ones. “

However, she acknowledged that it’s not a completely rosy picture.

“Ultrasound is very user dependent, but we do think that by putting this in the hands of dermatologists with special training, we can solve this issue. In Europe, ultrasound’s very high sensitivity and specificity, combined with clinical exams, really improves disease detection.”

Unfortunately, at this point, anyone who wants to learn the technique has to go to Europe. “I trained in Germany, where I took a standard 3-day course, did 250 supervised scans, and completed an exam. I realize that’s unrealistic for most people,” she said. But a training protocol is being developed at Brigham and Women’s, under the auspices of the institution’s imaging experts, who felt that 3 days and 250 supervised scans was excessive. The Brigham and Women’s program comprises 8 hours of didactic training and at least 30 supervised scans with at least three abnormalities correctly identified, and will be put into place soon, Dr. Ruiz said.

The biggest obstacle to large-scale adoption of this protocol is data – there are not a lot, at least now.

“We are working on that, too. In conjunction with the Skin Cancer Foundation, we’re launching a prospective study. We want to recruit 80 patients with T2B/T3 cutaneous SCCs. They get both and ultrasound and a CT scan at diagnosis and every 6 months for 2 years,” she said.

[email protected]

Neurofilament light (NfL) levels in plasma appear to track cognitive decline in dementia, as well as cortical thinning and hippocampal atrophy that accompany progression from normal cognition to mild cognitive impairment (MCI) to Alzheimer’s disease.

Plasma levels of the axonal protein also correlated with its presence in cerebrospinal fluid, and mirrored the changes in amyloid beta (Abeta) 42, Niklas Mattsson, MD, and colleagues wrote in JAMA Neurology.

“Taken together, these findings suggest that the neurofilament light level is a dynamic biomarker that changes throughout the course of Alzheimer’s disease and is sensitive to progressive neurodegeneration,” wrote Dr. Mattsson of Lund (Sweden) University and his coauthors. “This has important implications, given the unmet need for noninvasive blood-based methods to objectively track longitudinal neurodegeneration in Alzheimer’s disease.”

A blood-based biomarker of Alzheimer’s disease progression could open a new door for drug trials, the authors noted. Previously, NfL levels have only been available by lumbar puncture – a invasive and expensive test that many patients resist. If NfL plasma levels do reliably track dementia progression, the test could become a standard part of clinical trials, providing regular drug response data as the study progresses.

Neurofilaments are polypeptides that give structure to the neuronal cytoskeleton and regulate microtubule function. Injured cells release the protein very quickly. Neurofilaments are elevated in traumatic brain injury, multiple sclerosis, and some psychiatric illnesses. Neurofilament levels have even been used to predict neurologic recovery after cardiac arrest.

Dr. Mattsson and his team used data obtained over 11 years from 1,583 subjects enrolled in the Alzheimer’s Disease Neuroimaging Initiative study. The sample comprised three groups: cognitively unimpaired controls (401), patients with MCI (855), and patients with Alzheimer’s dementia (327). The investigators analyzed 4,326 samples.

In addition to the NfL measurements, they tracked Abeta and tau in cerebrospinal fluid (CSF), structural brain changes by 18fluorodeoxyglucose (FDG)–PET and MRI, and cognitive and functional performance. The primary outcome was NfL’s association with these changes. The team set the lower limit of NfL as 6.7 ng/L and the upper, 1,620 ng/L.

At baseline, only advancing age correlated with NfL levels. But it was significantly higher in patients with MCI (37.9 ng/L) and Alzheimer’s dementia (45.9 ng/L) than it was in the control subjects (32.1 ng/L). Over the years of follow-up, levels increased in all groups, but NfL increased more rapidly among patients with MCI and Alzheimer’s dementia than controls (2.7 vs. 2.4 ng/L per year). The difference was most pronounced when comparing levels in patients with Alzheimer’s dementia and MCI with controls. However, control subjects who were Abeta positive by CSF had greater NfL changes than Abeta-negative controls.

Baseline measures of CSF Abeta and tau, as well as hippocampal and ventricular volume and cortical thickness, also correlated with NfL levels, as did cognition and functional scores.

During follow-up, the diagnostic groups showed different NfL trajectories, which correlated strongly with the other measures.

In the control group, NfL increases correlated with lower FDG-PET measures, lower CSF Abeta, reduced hippocampal volume, and higher ventricular volume. Among patients with MCI, NfL increases correlated most strongly with hippocampal volume, temporal region, and cognition. Among patients with Alzheimer’s dementia, the NfL increase most strongly tracked cognitive decline,

When the investigators applied these findings to the A/T/N (amyloid, tau, neurodegeneration) classification system, NfL most often correlated with neurodegeneration, but not always. This might suggest that the neuronal damage occurred separately from Abeta changes. In all three groups, rapid NfL increases mirrored the rate of change in most other measures.

“In controls and patients with MCI and Alzheimer’s dementia, greater rates of NfL were associated with accelerated reduction in FDG-PET measures … expansion of ventricular volume,” and a reduction in cognitive and functional performance, Dr. Mattsson and his colleagues wrote.“ In addition, greater increases in NfL levels were associated with accelerated loss of hippocampal volume and entorhinal cortical thickness in controls and patients with MCI and with accelerated increases in total tau level, phosphorylated tau level, and white matter lesions in patients with MCI. In general, the concentrations of blood-based NfL appears to reflect the intensity of the neuronal injury.”

Dr Mattsson reported being a consultant for the Alzheimer’s Disease Neuroimaging Initiative.

[email protected]

SOURCE: Mattsson N et al. JAMA Neurol. 2019 Apr 22. doi: 10.1001/jamaneurol.2019.0765.

Neurofilament light (NfL) levels in plasma appear to track cognitive decline in dementia, as well as cortical thinning and hippocampal atrophy that accompany progression from normal cognition to mild cognitive impairment (MCI) to Alzheimer’s disease.

Plasma levels of the axonal protein also correlated with its presence in cerebrospinal fluid, and mirrored the changes in amyloid beta (Abeta) 42, Niklas Mattsson, MD, and colleagues wrote in JAMA Neurology.

“Taken together, these findings suggest that the neurofilament light level is a dynamic biomarker that changes throughout the course of Alzheimer’s disease and is sensitive to progressive neurodegeneration,” wrote Dr. Mattsson of Lund (Sweden) University and his coauthors. “This has important implications, given the unmet need for noninvasive blood-based methods to objectively track longitudinal neurodegeneration in Alzheimer’s disease.”

A blood-based biomarker of Alzheimer’s disease progression could open a new door for drug trials, the authors noted. Previously, NfL levels have only been available by lumbar puncture – a invasive and expensive test that many patients resist. If NfL plasma levels do reliably track dementia progression, the test could become a standard part of clinical trials, providing regular drug response data as the study progresses.

Neurofilaments are polypeptides that give structure to the neuronal cytoskeleton and regulate microtubule function. Injured cells release the protein very quickly. Neurofilaments are elevated in traumatic brain injury, multiple sclerosis, and some psychiatric illnesses. Neurofilament levels have even been used to predict neurologic recovery after cardiac arrest.

Dr. Mattsson and his team used data obtained over 11 years from 1,583 subjects enrolled in the Alzheimer’s Disease Neuroimaging Initiative study. The sample comprised three groups: cognitively unimpaired controls (401), patients with MCI (855), and patients with Alzheimer’s dementia (327). The investigators analyzed 4,326 samples.

In addition to the NfL measurements, they tracked Abeta and tau in cerebrospinal fluid (CSF), structural brain changes by 18fluorodeoxyglucose (FDG)–PET and MRI, and cognitive and functional performance. The primary outcome was NfL’s association with these changes. The team set the lower limit of NfL as 6.7 ng/L and the upper, 1,620 ng/L.

At baseline, only advancing age correlated with NfL levels. But it was significantly higher in patients with MCI (37.9 ng/L) and Alzheimer’s dementia (45.9 ng/L) than it was in the control subjects (32.1 ng/L). Over the years of follow-up, levels increased in all groups, but NfL increased more rapidly among patients with MCI and Alzheimer’s dementia than controls (2.7 vs. 2.4 ng/L per year). The difference was most pronounced when comparing levels in patients with Alzheimer’s dementia and MCI with controls. However, control subjects who were Abeta positive by CSF had greater NfL changes than Abeta-negative controls.

Baseline measures of CSF Abeta and tau, as well as hippocampal and ventricular volume and cortical thickness, also correlated with NfL levels, as did cognition and functional scores.

During follow-up, the diagnostic groups showed different NfL trajectories, which correlated strongly with the other measures.

In the control group, NfL increases correlated with lower FDG-PET measures, lower CSF Abeta, reduced hippocampal volume, and higher ventricular volume. Among patients with MCI, NfL increases correlated most strongly with hippocampal volume, temporal region, and cognition. Among patients with Alzheimer’s dementia, the NfL increase most strongly tracked cognitive decline,

When the investigators applied these findings to the A/T/N (amyloid, tau, neurodegeneration) classification system, NfL most often correlated with neurodegeneration, but not always. This might suggest that the neuronal damage occurred separately from Abeta changes. In all three groups, rapid NfL increases mirrored the rate of change in most other measures.

“In controls and patients with MCI and Alzheimer’s dementia, greater rates of NfL were associated with accelerated reduction in FDG-PET measures … expansion of ventricular volume,” and a reduction in cognitive and functional performance, Dr. Mattsson and his colleagues wrote.“ In addition, greater increases in NfL levels were associated with accelerated loss of hippocampal volume and entorhinal cortical thickness in controls and patients with MCI and with accelerated increases in total tau level, phosphorylated tau level, and white matter lesions in patients with MCI. In general, the concentrations of blood-based NfL appears to reflect the intensity of the neuronal injury.”

Dr Mattsson reported being a consultant for the Alzheimer’s Disease Neuroimaging Initiative.

[email protected]

SOURCE: Mattsson N et al. JAMA Neurol. 2019 Apr 22. doi: 10.1001/jamaneurol.2019.0765.

Neurofilament light (NfL) levels in plasma appear to track cognitive decline in dementia, as well as cortical thinning and hippocampal atrophy that accompany progression from normal cognition to mild cognitive impairment (MCI) to Alzheimer’s disease.

Plasma levels of the axonal protein also correlated with its presence in cerebrospinal fluid, and mirrored the changes in amyloid beta (Abeta) 42, Niklas Mattsson, MD, and colleagues wrote in JAMA Neurology.

“Taken together, these findings suggest that the neurofilament light level is a dynamic biomarker that changes throughout the course of Alzheimer’s disease and is sensitive to progressive neurodegeneration,” wrote Dr. Mattsson of Lund (Sweden) University and his coauthors. “This has important implications, given the unmet need for noninvasive blood-based methods to objectively track longitudinal neurodegeneration in Alzheimer’s disease.”

A blood-based biomarker of Alzheimer’s disease progression could open a new door for drug trials, the authors noted. Previously, NfL levels have only been available by lumbar puncture – a invasive and expensive test that many patients resist. If NfL plasma levels do reliably track dementia progression, the test could become a standard part of clinical trials, providing regular drug response data as the study progresses.

Neurofilaments are polypeptides that give structure to the neuronal cytoskeleton and regulate microtubule function. Injured cells release the protein very quickly. Neurofilaments are elevated in traumatic brain injury, multiple sclerosis, and some psychiatric illnesses. Neurofilament levels have even been used to predict neurologic recovery after cardiac arrest.

Dr. Mattsson and his team used data obtained over 11 years from 1,583 subjects enrolled in the Alzheimer’s Disease Neuroimaging Initiative study. The sample comprised three groups: cognitively unimpaired controls (401), patients with MCI (855), and patients with Alzheimer’s dementia (327). The investigators analyzed 4,326 samples.

In addition to the NfL measurements, they tracked Abeta and tau in cerebrospinal fluid (CSF), structural brain changes by 18fluorodeoxyglucose (FDG)–PET and MRI, and cognitive and functional performance. The primary outcome was NfL’s association with these changes. The team set the lower limit of NfL as 6.7 ng/L and the upper, 1,620 ng/L.

At baseline, only advancing age correlated with NfL levels. But it was significantly higher in patients with MCI (37.9 ng/L) and Alzheimer’s dementia (45.9 ng/L) than it was in the control subjects (32.1 ng/L). Over the years of follow-up, levels increased in all groups, but NfL increased more rapidly among patients with MCI and Alzheimer’s dementia than controls (2.7 vs. 2.4 ng/L per year). The difference was most pronounced when comparing levels in patients with Alzheimer’s dementia and MCI with controls. However, control subjects who were Abeta positive by CSF had greater NfL changes than Abeta-negative controls.

Baseline measures of CSF Abeta and tau, as well as hippocampal and ventricular volume and cortical thickness, also correlated with NfL levels, as did cognition and functional scores.

During follow-up, the diagnostic groups showed different NfL trajectories, which correlated strongly with the other measures.

In the control group, NfL increases correlated with lower FDG-PET measures, lower CSF Abeta, reduced hippocampal volume, and higher ventricular volume. Among patients with MCI, NfL increases correlated most strongly with hippocampal volume, temporal region, and cognition. Among patients with Alzheimer’s dementia, the NfL increase most strongly tracked cognitive decline,

When the investigators applied these findings to the A/T/N (amyloid, tau, neurodegeneration) classification system, NfL most often correlated with neurodegeneration, but not always. This might suggest that the neuronal damage occurred separately from Abeta changes. In all three groups, rapid NfL increases mirrored the rate of change in most other measures.

“In controls and patients with MCI and Alzheimer’s dementia, greater rates of NfL were associated with accelerated reduction in FDG-PET measures … expansion of ventricular volume,” and a reduction in cognitive and functional performance, Dr. Mattsson and his colleagues wrote.“ In addition, greater increases in NfL levels were associated with accelerated loss of hippocampal volume and entorhinal cortical thickness in controls and patients with MCI and with accelerated increases in total tau level, phosphorylated tau level, and white matter lesions in patients with MCI. In general, the concentrations of blood-based NfL appears to reflect the intensity of the neuronal injury.”

Dr Mattsson reported being a consultant for the Alzheimer’s Disease Neuroimaging Initiative.

[email protected]

SOURCE: Mattsson N et al. JAMA Neurol. 2019 Apr 22. doi: 10.1001/jamaneurol.2019.0765.

More than a fifth of patients with hemophilia may now be using extended half-life (EHL) clotting factors, although the economic impact of these new treatments remains unclear.

Use of EHL factor VIII (FVIII) and IX (FIX) products surged from 10% of patients to 22% over an 18-month period ending in late 2017, Dr. Stacy E. Croteau and her colleagues reported in Haemophilia.

The increase appears to be mostly driven by prescribed prophylaxis rather than on-demand use of the products, wrote Dr. Croteau of Boston Children’s Hospital, and her coauthors. EHL dosages were similar to standard half-life (SHL) dosages and extended the time between infusions. But in the end, the higher cost of the EHL products actually drove up the price of prophylaxis, with a year of EHL FIX topping $1 million.

“Careful assessment of factor consumption and patient outcomes is needed to ensure general cost neutrality of this expensive therapy,” the researchers wrote. “Unless demonstrably offset by reduction in bleed doses, the net effect could be further increases in annual cost of care for this patient population.”

The study examined the use of SHL and EHL clotting factors in 7,893 adults and children with hemophilia A or B, who were being followed in the American Thrombosis and Hemostasis Network (ATHN) database. The authors sought to characterize changes in usage patterns for SHL and EHL factors, and to identify demographic and economic influences on them.

During the study, the number of patients using EHL products for both on-demand and prophylactic factor replacement increased. EHL FVIII use rose from 9% to 21%, and EHL FIX from 14% to 21%, especially among those with hemophilia B.

There were 6,437 patients with full data at both initial and final sampling. Among these, there was a 9.6% increase in the use of an EHL clotting factor by the end of the study (P less than .001). Patients with hemophilia A were less likely than hemophilia B patients to use an EHL product for prophylaxis.

While the EHL products did reduce the number of prophylactic infusions, they also cost much more, the investigators found.

The standard dose of SHL FVIII is 40 IU/g infused three times a week. The projected cost of 156 annual infusions is $690,144. EHL FVII, dosed at 50 IU/kg, cuts infusions to twice a week. The annual projected cost of the 104 infusions is $753,480.

The standard dose of SHL FIX is 67 IU/kg, infused twice a week. The annual projected cost of 104 infusions is $697,497. EHL FIX, dosed at 75 IU/Kg, halves the number of infusions. But the price for those 52 treatments exceeds $1 million ($1,015,560). Despite the cost, however, just 43 patients switched from an EHL product to a SHL factor product during the study period.

Insurance type appeared to have little influence on the choice of SHL or EHL clotting factors. Across payer types, a similar proportion of patients started using them, and 71% were covered by private insurance or Medicaid.

The study was funded HTRS/ATHN Dataset Research Engagement and a DREAM Award from the Hemostasis and Thrombosis Research Society. Dr. Croteau reported consulting for Bayer, Bioverativ, Biomarin, CSL-Behring, and other companies.

[email protected]

SOURCE: Croteau SE et al. Haemophilia. 2019 Apr 17. doi: 10.1111/hae.13758.

More than a fifth of patients with hemophilia may now be using extended half-life (EHL) clotting factors, although the economic impact of these new treatments remains unclear.

Use of EHL factor VIII (FVIII) and IX (FIX) products surged from 10% of patients to 22% over an 18-month period ending in late 2017, Dr. Stacy E. Croteau and her colleagues reported in Haemophilia.

The increase appears to be mostly driven by prescribed prophylaxis rather than on-demand use of the products, wrote Dr. Croteau of Boston Children’s Hospital, and her coauthors. EHL dosages were similar to standard half-life (SHL) dosages and extended the time between infusions. But in the end, the higher cost of the EHL products actually drove up the price of prophylaxis, with a year of EHL FIX topping $1 million.

“Careful assessment of factor consumption and patient outcomes is needed to ensure general cost neutrality of this expensive therapy,” the researchers wrote. “Unless demonstrably offset by reduction in bleed doses, the net effect could be further increases in annual cost of care for this patient population.”

The study examined the use of SHL and EHL clotting factors in 7,893 adults and children with hemophilia A or B, who were being followed in the American Thrombosis and Hemostasis Network (ATHN) database. The authors sought to characterize changes in usage patterns for SHL and EHL factors, and to identify demographic and economic influences on them.

During the study, the number of patients using EHL products for both on-demand and prophylactic factor replacement increased. EHL FVIII use rose from 9% to 21%, and EHL FIX from 14% to 21%, especially among those with hemophilia B.

There were 6,437 patients with full data at both initial and final sampling. Among these, there was a 9.6% increase in the use of an EHL clotting factor by the end of the study (P less than .001). Patients with hemophilia A were less likely than hemophilia B patients to use an EHL product for prophylaxis.

While the EHL products did reduce the number of prophylactic infusions, they also cost much more, the investigators found.

The standard dose of SHL FVIII is 40 IU/g infused three times a week. The projected cost of 156 annual infusions is $690,144. EHL FVII, dosed at 50 IU/kg, cuts infusions to twice a week. The annual projected cost of the 104 infusions is $753,480.

The standard dose of SHL FIX is 67 IU/kg, infused twice a week. The annual projected cost of 104 infusions is $697,497. EHL FIX, dosed at 75 IU/Kg, halves the number of infusions. But the price for those 52 treatments exceeds $1 million ($1,015,560). Despite the cost, however, just 43 patients switched from an EHL product to a SHL factor product during the study period.

Insurance type appeared to have little influence on the choice of SHL or EHL clotting factors. Across payer types, a similar proportion of patients started using them, and 71% were covered by private insurance or Medicaid.

The study was funded HTRS/ATHN Dataset Research Engagement and a DREAM Award from the Hemostasis and Thrombosis Research Society. Dr. Croteau reported consulting for Bayer, Bioverativ, Biomarin, CSL-Behring, and other companies.

[email protected]

SOURCE: Croteau SE et al. Haemophilia. 2019 Apr 17. doi: 10.1111/hae.13758.

More than a fifth of patients with hemophilia may now be using extended half-life (EHL) clotting factors, although the economic impact of these new treatments remains unclear.

Use of EHL factor VIII (FVIII) and IX (FIX) products surged from 10% of patients to 22% over an 18-month period ending in late 2017, Dr. Stacy E. Croteau and her colleagues reported in Haemophilia.

The increase appears to be mostly driven by prescribed prophylaxis rather than on-demand use of the products, wrote Dr. Croteau of Boston Children’s Hospital, and her coauthors. EHL dosages were similar to standard half-life (SHL) dosages and extended the time between infusions. But in the end, the higher cost of the EHL products actually drove up the price of prophylaxis, with a year of EHL FIX topping $1 million.

“Careful assessment of factor consumption and patient outcomes is needed to ensure general cost neutrality of this expensive therapy,” the researchers wrote. “Unless demonstrably offset by reduction in bleed doses, the net effect could be further increases in annual cost of care for this patient population.”

The study examined the use of SHL and EHL clotting factors in 7,893 adults and children with hemophilia A or B, who were being followed in the American Thrombosis and Hemostasis Network (ATHN) database. The authors sought to characterize changes in usage patterns for SHL and EHL factors, and to identify demographic and economic influences on them.

During the study, the number of patients using EHL products for both on-demand and prophylactic factor replacement increased. EHL FVIII use rose from 9% to 21%, and EHL FIX from 14% to 21%, especially among those with hemophilia B.

There were 6,437 patients with full data at both initial and final sampling. Among these, there was a 9.6% increase in the use of an EHL clotting factor by the end of the study (P less than .001). Patients with hemophilia A were less likely than hemophilia B patients to use an EHL product for prophylaxis.

While the EHL products did reduce the number of prophylactic infusions, they also cost much more, the investigators found.

The standard dose of SHL FVIII is 40 IU/g infused three times a week. The projected cost of 156 annual infusions is $690,144. EHL FVII, dosed at 50 IU/kg, cuts infusions to twice a week. The annual projected cost of the 104 infusions is $753,480.

The standard dose of SHL FIX is 67 IU/kg, infused twice a week. The annual projected cost of 104 infusions is $697,497. EHL FIX, dosed at 75 IU/Kg, halves the number of infusions. But the price for those 52 treatments exceeds $1 million ($1,015,560). Despite the cost, however, just 43 patients switched from an EHL product to a SHL factor product during the study period.

Insurance type appeared to have little influence on the choice of SHL or EHL clotting factors. Across payer types, a similar proportion of patients started using them, and 71% were covered by private insurance or Medicaid.

The study was funded HTRS/ATHN Dataset Research Engagement and a DREAM Award from the Hemostasis and Thrombosis Research Society. Dr. Croteau reported consulting for Bayer, Bioverativ, Biomarin, CSL-Behring, and other companies.

[email protected]

SOURCE: Croteau SE et al. Haemophilia. 2019 Apr 17. doi: 10.1111/hae.13758.

A treat-to-target approach using total hip T scores could help guide decisions about how long women with osteoporosis should stay on bone-building therapy, according to Serge Ferrari, MD, and his colleagues.

Using 10 years of follow-up data from 1,343 women who took denosumab in the FREEDOM trial, Dr. Ferrari and his colleagues determined that a T score of at least –2.5 would be an appropriate target for this decision.

“A T-score unit increase of 1.0 was associated with a significant reduction in fracture risk for T scores up to, but no greater than, –2.0, suggesting that a T-score threshold of at least –2.0 would be an appropriate target for therapy to maximize treatment,” said Dr. Ferrari of the University of Geneva and his colleagues. “Further improvements in bone mineral density were not associated with major additional changes in 1-year nonvertebral fracture incidence.”

The findings “highlight the importance of the relationship between hip T score and fracture risk, which is maintained during long-term therapy with denosumab. Regular monitoring of bone mineral density during therapy may be useful to determine when fracture risk has reached a minimal threshold; treatment could therefore be suspended and/or consolidated, as in the case of a reversible therapy such as denosumab.”

[email protected]

SOURCE: Ferrari S et al. J Bone Miner Res. 2019 Mar 28. doi: 10.1002/jbmr.3722.

A treat-to-target approach using total hip T scores could help guide decisions about how long women with osteoporosis should stay on bone-building therapy, according to Serge Ferrari, MD, and his colleagues.

Using 10 years of follow-up data from 1,343 women who took denosumab in the FREEDOM trial, Dr. Ferrari and his colleagues determined that a T score of at least –2.5 would be an appropriate target for this decision.

“A T-score unit increase of 1.0 was associated with a significant reduction in fracture risk for T scores up to, but no greater than, –2.0, suggesting that a T-score threshold of at least –2.0 would be an appropriate target for therapy to maximize treatment,” said Dr. Ferrari of the University of Geneva and his colleagues. “Further improvements in bone mineral density were not associated with major additional changes in 1-year nonvertebral fracture incidence.”

The findings “highlight the importance of the relationship between hip T score and fracture risk, which is maintained during long-term therapy with denosumab. Regular monitoring of bone mineral density during therapy may be useful to determine when fracture risk has reached a minimal threshold; treatment could therefore be suspended and/or consolidated, as in the case of a reversible therapy such as denosumab.”

[email protected]

SOURCE: Ferrari S et al. J Bone Miner Res. 2019 Mar 28. doi: 10.1002/jbmr.3722.

A treat-to-target approach using total hip T scores could help guide decisions about how long women with osteoporosis should stay on bone-building therapy, according to Serge Ferrari, MD, and his colleagues.

Using 10 years of follow-up data from 1,343 women who took denosumab in the FREEDOM trial, Dr. Ferrari and his colleagues determined that a T score of at least –2.5 would be an appropriate target for this decision.

“A T-score unit increase of 1.0 was associated with a significant reduction in fracture risk for T scores up to, but no greater than, –2.0, suggesting that a T-score threshold of at least –2.0 would be an appropriate target for therapy to maximize treatment,” said Dr. Ferrari of the University of Geneva and his colleagues. “Further improvements in bone mineral density were not associated with major additional changes in 1-year nonvertebral fracture incidence.”

The findings “highlight the importance of the relationship between hip T score and fracture risk, which is maintained during long-term therapy with denosumab. Regular monitoring of bone mineral density during therapy may be useful to determine when fracture risk has reached a minimal threshold; treatment could therefore be suspended and/or consolidated, as in the case of a reversible therapy such as denosumab.”

[email protected]

SOURCE: Ferrari S et al. J Bone Miner Res. 2019 Mar 28. doi: 10.1002/jbmr.3722.

Low back pain. A bane of human existence.

Almost everyone – 90% of us in fact – will have at least one bout of it. Snow shoveling, too much weight on the barbell, a strange twist while carrying in the groceries. A quick visit to a primary care doc, a prescription NSAID, a few days or weeks of rest, and a gradual resolution of symptoms is the usual course.

Courtesy Krembil Research Institute

Community back pain clinics

Raja Rampersaud, MD, a spine surgeon at UHN, developed the first model – a community clinic that triages and treats people with low back pain. Primary care providers refer into the clinics, and advanced practice clinicians work with patients to create care plans. These might include low-level medical therapy, exercise, and other self-management techniques.

Ms. Passalent and her team partnered with these clinics in a pilot project to identify axSpA patients. The team provided clinician education and referral criteria for patients. These include back pain of more than 3 months’ duration in patients younger than 50 years who have other signs of inflammatory back pain. Primary care providers can refer such patients to a secondary screening program, run by an advanced care clinician, that further refines the diagnosis.

The clinic work-up includes the following:

• History, involving a description of back pain, peripheral joint involvement, and extra-articular manifestations.
• Physical exam looking at spinal mobility and vital signs, as well as tender/swollen joints, enthesitis, and dactylitis.
• Investigations that include pelvis and lateral lumbar and cervical spine radiographs, HLA-B27 testing, and measurements of C-­reactive protein and erythrocyte sedimentation rate.

For those who don’t tick the axSpA boxes, the practitioner provides education on self-management, basic nonpharmacologic interventions, exercise guidance, and referrals back into primary care for their therapy.

But those who screen positive receive a direct rheumatology referral. This is an especially important component of the program because, like the United States, Canada has a chronic shortage of rheumatologists. However, in Canada there can be even greater distances than in the United States between a patient’s town and the closest rheumatology office. The back pain screening clinic reduced waiting time from up to 2 years to around 3 weeks – a notable accomplishment in a country with only about 500 rheumatologists – less than 1 per 75,000 residents.
 

First data

Ms. Passalent and the team presented their initial data from this model at recent annual meetings of the Canadian Rheumatology Association and the American College of Rheumatology (Arthritis Rheumatol. 2018;70[suppl 10]:Abstract 661).

During the first 3 years of the project, 410 patients were seen. Time from primary care referral to the secondary clinic appointment was roughly 22 days. These patients were young, with a mean age of about 37 years, and had experienced back pain for an average of 7 years. About 14% were positive for HLA-B27, but that characteristic signal actually performed poorly as an independent axSpA screen. It was highly specific (94%) but not very sensitive (28%), with a 71% positive and negative predictive value.

Assessment by the advanced care provider, on the other hand, had 90% specificity and 68% sensitivity. The negative and positive predictive values were 80% and 84%, respectively.

Among those who had a rheumatology consult, 18% received an axSpA diagnosis.

“We were very pleased to be able to decrease the time to diagnosis, from 9 years to 6 or 7,” Ms. Passalent said. “It’s still a long time, but you have to keep in mind this program is just getting started.”
 

Other benefits

It’s proven that early treatment prevents bone damage and improves spine-related function and quality of life for these patients. But if biologics help bone inflammation, could they also benefit the extra-articular manifestations that often accompany axSpA?

“The main comorbidities are anterior uveitis, inflammatory bowel diseases, and psoriasis,” Dr. Inman said. “In our cohort, 35% have uveitis, 12% have IBD, and 10% have psoriasis. Those are significant numbers, and the damage accrues over time. They are all inflammatory and maybe autoimmune.”

These extra-articular manifestations influence individual treatment plans, he said. “The presence of skin, eye, or joint inflammation does inform our selection. Generally, though, blocking TNF-alpha with a monoclonal antibody should also effectively treat these other issues in addition to SpA.”

A 2018 review touched on the uveitis/SpA treatment connection (Perm J. 2018;22:17-041. doi: 10.7812/TPP/17-041). Biologics – especially TNF blockers – are excellent choices for refractory uveitis and may confer a double benefit in patients with both diseases. Biologic choices for IBD and psoriasis also typically overlap those used in axSpA.

The literature is still evolving on this concept of cotreatment, Dr. Inman said, but it could represent an exciting option to prevent damage in multiple systems with one approach.

The future

Ms. Passalent, Dr. Inman, and Dr. Haroon see good things ahead for everyone involved in axSpA if the secondary screening clinic protocol expands throughout Canada.

“The thing that impresses me as a frontline worker, you can be an agent of change. If you’re surrounded by the right people and a supportive organization, you really can help to influence transformative change. It doesn’t happen overnight, but if you stick to it and work with the right champions, it’s amazing what influence on patient care you can have,” Ms. Passalent said.

Dr. Inman, Dr. Haroon, and Ms. Passalent have been consultants and received research funds from several pharmaceutical companies.

[email protected]

Low back pain. A bane of human existence.

Almost everyone – 90% of us in fact – will have at least one bout of it. Snow shoveling, too much weight on the barbell, a strange twist while carrying in the groceries. A quick visit to a primary care doc, a prescription NSAID, a few days or weeks of rest, and a gradual resolution of symptoms is the usual course.

Courtesy Krembil Research Institute

Community back pain clinics

Raja Rampersaud, MD, a spine surgeon at UHN, developed the first model – a community clinic that triages and treats people with low back pain. Primary care providers refer into the clinics, and advanced practice clinicians work with patients to create care plans. These might include low-level medical therapy, exercise, and other self-management techniques.

Ms. Passalent and her team partnered with these clinics in a pilot project to identify axSpA patients. The team provided clinician education and referral criteria for patients. These include back pain of more than 3 months’ duration in patients younger than 50 years who have other signs of inflammatory back pain. Primary care providers can refer such patients to a secondary screening program, run by an advanced care clinician, that further refines the diagnosis.

The clinic work-up includes the following:

• History, involving a description of back pain, peripheral joint involvement, and extra-articular manifestations.
• Physical exam looking at spinal mobility and vital signs, as well as tender/swollen joints, enthesitis, and dactylitis.
• Investigations that include pelvis and lateral lumbar and cervical spine radiographs, HLA-B27 testing, and measurements of C-­reactive protein and erythrocyte sedimentation rate.

For those who don’t tick the axSpA boxes, the practitioner provides education on self-management, basic nonpharmacologic interventions, exercise guidance, and referrals back into primary care for their therapy.

But those who screen positive receive a direct rheumatology referral. This is an especially important component of the program because, like the United States, Canada has a chronic shortage of rheumatologists. However, in Canada there can be even greater distances than in the United States between a patient’s town and the closest rheumatology office. The back pain screening clinic reduced waiting time from up to 2 years to around 3 weeks – a notable accomplishment in a country with only about 500 rheumatologists – less than 1 per 75,000 residents.
 

First data

Ms. Passalent and the team presented their initial data from this model at recent annual meetings of the Canadian Rheumatology Association and the American College of Rheumatology (Arthritis Rheumatol. 2018;70[suppl 10]:Abstract 661).

During the first 3 years of the project, 410 patients were seen. Time from primary care referral to the secondary clinic appointment was roughly 22 days. These patients were young, with a mean age of about 37 years, and had experienced back pain for an average of 7 years. About 14% were positive for HLA-B27, but that characteristic signal actually performed poorly as an independent axSpA screen. It was highly specific (94%) but not very sensitive (28%), with a 71% positive and negative predictive value.

Assessment by the advanced care provider, on the other hand, had 90% specificity and 68% sensitivity. The negative and positive predictive values were 80% and 84%, respectively.

Among those who had a rheumatology consult, 18% received an axSpA diagnosis.

“We were very pleased to be able to decrease the time to diagnosis, from 9 years to 6 or 7,” Ms. Passalent said. “It’s still a long time, but you have to keep in mind this program is just getting started.”
 

Other benefits

It’s proven that early treatment prevents bone damage and improves spine-related function and quality of life for these patients. But if biologics help bone inflammation, could they also benefit the extra-articular manifestations that often accompany axSpA?

“The main comorbidities are anterior uveitis, inflammatory bowel diseases, and psoriasis,” Dr. Inman said. “In our cohort, 35% have uveitis, 12% have IBD, and 10% have psoriasis. Those are significant numbers, and the damage accrues over time. They are all inflammatory and maybe autoimmune.”

These extra-articular manifestations influence individual treatment plans, he said. “The presence of skin, eye, or joint inflammation does inform our selection. Generally, though, blocking TNF-alpha with a monoclonal antibody should also effectively treat these other issues in addition to SpA.”

A 2018 review touched on the uveitis/SpA treatment connection (Perm J. 2018;22:17-041. doi: 10.7812/TPP/17-041). Biologics – especially TNF blockers – are excellent choices for refractory uveitis and may confer a double benefit in patients with both diseases. Biologic choices for IBD and psoriasis also typically overlap those used in axSpA.

The literature is still evolving on this concept of cotreatment, Dr. Inman said, but it could represent an exciting option to prevent damage in multiple systems with one approach.

The future

Ms. Passalent, Dr. Inman, and Dr. Haroon see good things ahead for everyone involved in axSpA if the secondary screening clinic protocol expands throughout Canada.

“The thing that impresses me as a frontline worker, you can be an agent of change. If you’re surrounded by the right people and a supportive organization, you really can help to influence transformative change. It doesn’t happen overnight, but if you stick to it and work with the right champions, it’s amazing what influence on patient care you can have,” Ms. Passalent said.

Dr. Inman, Dr. Haroon, and Ms. Passalent have been consultants and received research funds from several pharmaceutical companies.

[email protected]

Low back pain. A bane of human existence.

Almost everyone – 90% of us in fact – will have at least one bout of it. Snow shoveling, too much weight on the barbell, a strange twist while carrying in the groceries. A quick visit to a primary care doc, a prescription NSAID, a few days or weeks of rest, and a gradual resolution of symptoms is the usual course.

Courtesy Krembil Research Institute

Community back pain clinics

Raja Rampersaud, MD, a spine surgeon at UHN, developed the first model – a community clinic that triages and treats people with low back pain. Primary care providers refer into the clinics, and advanced practice clinicians work with patients to create care plans. These might include low-level medical therapy, exercise, and other self-management techniques.

Ms. Passalent and her team partnered with these clinics in a pilot project to identify axSpA patients. The team provided clinician education and referral criteria for patients. These include back pain of more than 3 months’ duration in patients younger than 50 years who have other signs of inflammatory back pain. Primary care providers can refer such patients to a secondary screening program, run by an advanced care clinician, that further refines the diagnosis.

The clinic work-up includes the following:

• History, involving a description of back pain, peripheral joint involvement, and extra-articular manifestations.
• Physical exam looking at spinal mobility and vital signs, as well as tender/swollen joints, enthesitis, and dactylitis.
• Investigations that include pelvis and lateral lumbar and cervical spine radiographs, HLA-B27 testing, and measurements of C-­reactive protein and erythrocyte sedimentation rate.

For those who don’t tick the axSpA boxes, the practitioner provides education on self-management, basic nonpharmacologic interventions, exercise guidance, and referrals back into primary care for their therapy.

But those who screen positive receive a direct rheumatology referral. This is an especially important component of the program because, like the United States, Canada has a chronic shortage of rheumatologists. However, in Canada there can be even greater distances than in the United States between a patient’s town and the closest rheumatology office. The back pain screening clinic reduced waiting time from up to 2 years to around 3 weeks – a notable accomplishment in a country with only about 500 rheumatologists – less than 1 per 75,000 residents.
 

First data

Ms. Passalent and the team presented their initial data from this model at recent annual meetings of the Canadian Rheumatology Association and the American College of Rheumatology (Arthritis Rheumatol. 2018;70[suppl 10]:Abstract 661).

During the first 3 years of the project, 410 patients were seen. Time from primary care referral to the secondary clinic appointment was roughly 22 days. These patients were young, with a mean age of about 37 years, and had experienced back pain for an average of 7 years. About 14% were positive for HLA-B27, but that characteristic signal actually performed poorly as an independent axSpA screen. It was highly specific (94%) but not very sensitive (28%), with a 71% positive and negative predictive value.

Assessment by the advanced care provider, on the other hand, had 90% specificity and 68% sensitivity. The negative and positive predictive values were 80% and 84%, respectively.

Among those who had a rheumatology consult, 18% received an axSpA diagnosis.

“We were very pleased to be able to decrease the time to diagnosis, from 9 years to 6 or 7,” Ms. Passalent said. “It’s still a long time, but you have to keep in mind this program is just getting started.”
 

Other benefits

It’s proven that early treatment prevents bone damage and improves spine-related function and quality of life for these patients. But if biologics help bone inflammation, could they also benefit the extra-articular manifestations that often accompany axSpA?

“The main comorbidities are anterior uveitis, inflammatory bowel diseases, and psoriasis,” Dr. Inman said. “In our cohort, 35% have uveitis, 12% have IBD, and 10% have psoriasis. Those are significant numbers, and the damage accrues over time. They are all inflammatory and maybe autoimmune.”

These extra-articular manifestations influence individual treatment plans, he said. “The presence of skin, eye, or joint inflammation does inform our selection. Generally, though, blocking TNF-alpha with a monoclonal antibody should also effectively treat these other issues in addition to SpA.”

A 2018 review touched on the uveitis/SpA treatment connection (Perm J. 2018;22:17-041. doi: 10.7812/TPP/17-041). Biologics – especially TNF blockers – are excellent choices for refractory uveitis and may confer a double benefit in patients with both diseases. Biologic choices for IBD and psoriasis also typically overlap those used in axSpA.

The literature is still evolving on this concept of cotreatment, Dr. Inman said, but it could represent an exciting option to prevent damage in multiple systems with one approach.

The future

Ms. Passalent, Dr. Inman, and Dr. Haroon see good things ahead for everyone involved in axSpA if the secondary screening clinic protocol expands throughout Canada.

“The thing that impresses me as a frontline worker, you can be an agent of change. If you’re surrounded by the right people and a supportive organization, you really can help to influence transformative change. It doesn’t happen overnight, but if you stick to it and work with the right champions, it’s amazing what influence on patient care you can have,” Ms. Passalent said.

Dr. Inman, Dr. Haroon, and Ms. Passalent have been consultants and received research funds from several pharmaceutical companies.

[email protected]