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Comorbidities emerge in adulthood for many patients with JIA
MADRID – More than half of young adults with juvenile idiopathic arthritis have comorbid conditions that impact their daily quality of life.
The issues range from directly disease-related – like uveitis – to more tangentially associated problems, like depression, Kirsten Minden, MD, said at the European Congress of Rheumatology.
She discussed the findings of two large German registries, Biologika in der Kinder-Rheumatologie (BiKeR) and Juvenile Arthritis-Methotrexate/Biologics Long-Term Observation (JUMBO).
Children enter BiKeR as soon as they receive a JIA diagnosis; they transfer to JuMBO when they turn 18 years old. Since 2001, 1,022 children have transitioned from the pediatric to young adult databases.
These patients are largely female (68%), with a mean age of 23 years and a mean disease duration of 13 years. Most (77%) had received at least one biologic disease-modifying antirheumatic drug; the mean number of those drugs received was 3. They were diagnosed with a wide variety of JIA subtypes: polyarthritis RF-negative (27%); enthesitis-related (20%); extended oligoarthritis (17%); polyarthritis RF-positive (9%); psoriatic arthritis (9%); persistent oligoarthritis (9%); and systemic arthritis (5%). The remainder had other subtypes.
More than half of the patients had at least one comorbidity; the mean number of issues per patient was two. Eye disorders were most common (17%), with uveitis making up 16% of that. Immune disorders were also common (12%). Psychiatric disorders occurred in 10%, with most of that (9%) being depression. Another 9% had skin or subcutaneous tissue disorders, including psoriasis (3%).
Autoimmune thyroiditis occurred in 2.5%, as did inflammatory bowel disease. General gastrointestinal disorders were present in 5%.
Men and women experienced different comorbidity clusters. Depression was more common among women (12% vs. 3%), as were pain disorders (6% vs. 2%) and autoimmune disorders (3% vs. 1%). Men, however, experienced more inflammatory bowel disease than women (4% vs. 2%).
Comorbidities were also expressed differently among the different JIA subtypes. Those with systemic disease were more likely to have hypertension (21%), osteoporosis (10%), and amyloidosis (4%). Uveitis was most common among those with extended oligoarthritis (35%). Psoriasis was most common among those with psoriatic arthritis (20%).
A progressive enrollment assessment showed some encouraging trends, however. The patients who enrolled in the earliest epoch (2001-2005) were also oldest at initial assessment (26). The majority of those (71%) had at least one comorbidity. But from 2006-2009, patients were younger when assessed, and fewer had comorbidities (55%). In the last epoch of 2010-2016, patients were a mean of 20 when assessed, and about 45% endorsed at least one comorbidity.
Hypertension, uveitis, and depression have all decreased since the first epoch, Dr. Minden noted. Hypertension has gone down from a rate of 21% in 2001-2005 to 13% most recently. Depression declined from 11.5%-6%, and uveitis, from 17%-2%.
This improvement, she said, may reflect newer trends in earlier diagnosis, earlier treatment, and more effective disease-modifying drugs.
“Age and disease duration do play a role in the presence of comorbidities, but whether the lower rates are due to younger age now is questionable,” she said. “It may be that the decreasing rates are due to earlier and better treatment strategies, and we are analyzing this now.”
A key finding supports this hypothesis, she noted.
“When we look at the presence of short stature over time, we can be encouraged about this. In the earliest period, 5% had short stature. That is now seen in less than 1% of our patients enrolled in the last decade.”
Dr. Minden is on the speakers bureau of Pfizer, Roche, and Pharm-Allergan. BiKeR is funded by unconditional grants from AbbVie, Germany, Novartis, Germany, and Roche, Germany, JuMBO by unconditional grants from AbbVie, Pfizer, and Roche.
[email protected]
On Twitter @Alz_gal
MADRID – More than half of young adults with juvenile idiopathic arthritis have comorbid conditions that impact their daily quality of life.
The issues range from directly disease-related – like uveitis – to more tangentially associated problems, like depression, Kirsten Minden, MD, said at the European Congress of Rheumatology.
She discussed the findings of two large German registries, Biologika in der Kinder-Rheumatologie (BiKeR) and Juvenile Arthritis-Methotrexate/Biologics Long-Term Observation (JUMBO).
Children enter BiKeR as soon as they receive a JIA diagnosis; they transfer to JuMBO when they turn 18 years old. Since 2001, 1,022 children have transitioned from the pediatric to young adult databases.
These patients are largely female (68%), with a mean age of 23 years and a mean disease duration of 13 years. Most (77%) had received at least one biologic disease-modifying antirheumatic drug; the mean number of those drugs received was 3. They were diagnosed with a wide variety of JIA subtypes: polyarthritis RF-negative (27%); enthesitis-related (20%); extended oligoarthritis (17%); polyarthritis RF-positive (9%); psoriatic arthritis (9%); persistent oligoarthritis (9%); and systemic arthritis (5%). The remainder had other subtypes.
More than half of the patients had at least one comorbidity; the mean number of issues per patient was two. Eye disorders were most common (17%), with uveitis making up 16% of that. Immune disorders were also common (12%). Psychiatric disorders occurred in 10%, with most of that (9%) being depression. Another 9% had skin or subcutaneous tissue disorders, including psoriasis (3%).
Autoimmune thyroiditis occurred in 2.5%, as did inflammatory bowel disease. General gastrointestinal disorders were present in 5%.
Men and women experienced different comorbidity clusters. Depression was more common among women (12% vs. 3%), as were pain disorders (6% vs. 2%) and autoimmune disorders (3% vs. 1%). Men, however, experienced more inflammatory bowel disease than women (4% vs. 2%).
Comorbidities were also expressed differently among the different JIA subtypes. Those with systemic disease were more likely to have hypertension (21%), osteoporosis (10%), and amyloidosis (4%). Uveitis was most common among those with extended oligoarthritis (35%). Psoriasis was most common among those with psoriatic arthritis (20%).
A progressive enrollment assessment showed some encouraging trends, however. The patients who enrolled in the earliest epoch (2001-2005) were also oldest at initial assessment (26). The majority of those (71%) had at least one comorbidity. But from 2006-2009, patients were younger when assessed, and fewer had comorbidities (55%). In the last epoch of 2010-2016, patients were a mean of 20 when assessed, and about 45% endorsed at least one comorbidity.
Hypertension, uveitis, and depression have all decreased since the first epoch, Dr. Minden noted. Hypertension has gone down from a rate of 21% in 2001-2005 to 13% most recently. Depression declined from 11.5%-6%, and uveitis, from 17%-2%.
This improvement, she said, may reflect newer trends in earlier diagnosis, earlier treatment, and more effective disease-modifying drugs.
“Age and disease duration do play a role in the presence of comorbidities, but whether the lower rates are due to younger age now is questionable,” she said. “It may be that the decreasing rates are due to earlier and better treatment strategies, and we are analyzing this now.”
A key finding supports this hypothesis, she noted.
“When we look at the presence of short stature over time, we can be encouraged about this. In the earliest period, 5% had short stature. That is now seen in less than 1% of our patients enrolled in the last decade.”
Dr. Minden is on the speakers bureau of Pfizer, Roche, and Pharm-Allergan. BiKeR is funded by unconditional grants from AbbVie, Germany, Novartis, Germany, and Roche, Germany, JuMBO by unconditional grants from AbbVie, Pfizer, and Roche.
[email protected]
On Twitter @Alz_gal
MADRID – More than half of young adults with juvenile idiopathic arthritis have comorbid conditions that impact their daily quality of life.
The issues range from directly disease-related – like uveitis – to more tangentially associated problems, like depression, Kirsten Minden, MD, said at the European Congress of Rheumatology.
She discussed the findings of two large German registries, Biologika in der Kinder-Rheumatologie (BiKeR) and Juvenile Arthritis-Methotrexate/Biologics Long-Term Observation (JUMBO).
Children enter BiKeR as soon as they receive a JIA diagnosis; they transfer to JuMBO when they turn 18 years old. Since 2001, 1,022 children have transitioned from the pediatric to young adult databases.
These patients are largely female (68%), with a mean age of 23 years and a mean disease duration of 13 years. Most (77%) had received at least one biologic disease-modifying antirheumatic drug; the mean number of those drugs received was 3. They were diagnosed with a wide variety of JIA subtypes: polyarthritis RF-negative (27%); enthesitis-related (20%); extended oligoarthritis (17%); polyarthritis RF-positive (9%); psoriatic arthritis (9%); persistent oligoarthritis (9%); and systemic arthritis (5%). The remainder had other subtypes.
More than half of the patients had at least one comorbidity; the mean number of issues per patient was two. Eye disorders were most common (17%), with uveitis making up 16% of that. Immune disorders were also common (12%). Psychiatric disorders occurred in 10%, with most of that (9%) being depression. Another 9% had skin or subcutaneous tissue disorders, including psoriasis (3%).
Autoimmune thyroiditis occurred in 2.5%, as did inflammatory bowel disease. General gastrointestinal disorders were present in 5%.
Men and women experienced different comorbidity clusters. Depression was more common among women (12% vs. 3%), as were pain disorders (6% vs. 2%) and autoimmune disorders (3% vs. 1%). Men, however, experienced more inflammatory bowel disease than women (4% vs. 2%).
Comorbidities were also expressed differently among the different JIA subtypes. Those with systemic disease were more likely to have hypertension (21%), osteoporosis (10%), and amyloidosis (4%). Uveitis was most common among those with extended oligoarthritis (35%). Psoriasis was most common among those with psoriatic arthritis (20%).
A progressive enrollment assessment showed some encouraging trends, however. The patients who enrolled in the earliest epoch (2001-2005) were also oldest at initial assessment (26). The majority of those (71%) had at least one comorbidity. But from 2006-2009, patients were younger when assessed, and fewer had comorbidities (55%). In the last epoch of 2010-2016, patients were a mean of 20 when assessed, and about 45% endorsed at least one comorbidity.
Hypertension, uveitis, and depression have all decreased since the first epoch, Dr. Minden noted. Hypertension has gone down from a rate of 21% in 2001-2005 to 13% most recently. Depression declined from 11.5%-6%, and uveitis, from 17%-2%.
This improvement, she said, may reflect newer trends in earlier diagnosis, earlier treatment, and more effective disease-modifying drugs.
“Age and disease duration do play a role in the presence of comorbidities, but whether the lower rates are due to younger age now is questionable,” she said. “It may be that the decreasing rates are due to earlier and better treatment strategies, and we are analyzing this now.”
A key finding supports this hypothesis, she noted.
“When we look at the presence of short stature over time, we can be encouraged about this. In the earliest period, 5% had short stature. That is now seen in less than 1% of our patients enrolled in the last decade.”
Dr. Minden is on the speakers bureau of Pfizer, Roche, and Pharm-Allergan. BiKeR is funded by unconditional grants from AbbVie, Germany, Novartis, Germany, and Roche, Germany, JuMBO by unconditional grants from AbbVie, Pfizer, and Roche.
[email protected]
On Twitter @Alz_gal
AT THE EULAR 2017 CONGRESS
Key clinical point:
Major finding: More than half of these patients (54%) have at least one comorbidity that interferes with their quality of life.
Data source: The JuMBO registry used in the study comprised 1,022 patients.
Disclosures: Dr. Minden is on the speakers bureau of Pfizer, Roche, and Pharm-Allergan. BiKeR is funded by unconditional grants from AbbVie, Germany, Novartis, Germany, and Roche, Germany; JuMBO by unconditional grants from AbbVie, Pfizer, and Roch
Ustekinumab trumps TNF-blockade for enthesitis in patients with psoriatic arthritis
MADRID – The anti-IL-23 antibody ustekinumab cleared enthesitis significantly better than did TNF-blockade in a small, open-label trial of patients with psoriatic arthritis
After 6 months on the drug, 71% of those taking the antibody achieved a score of 0 on the Spondyloarthritis Research Consortium of Canada (SPARCC) scale, representing a complete absence of enthesitis, Elizabeth Araujo, MD, said at the European Congress of Rheumatology. Just 38% of those on TNF-inhibitors achieved that score.
Enthesitis is often more bothersome to arthritis patients than their primary disease, said Dr. Araujo of the Centre of Internal Medicine, Universitätsklinikum Erlangen, Germany.
“Despite being a hallmark of PsA patients, enthesitis still receives rather peripheral attention as an outcome, especially when compared with ‘classical’ arthritis. Nonetheless, in clinical practice, enthesitis is an important factor for PsA-associated pain in many patients,” explained Dr. Araujo.
Yet it’s frequently ignored or under-treated. When it is addressed, enthesitis is often treated using TNF-inhibitors. But recent increases in the treatment options for PsA patients got Dr. Araujo thinking that PsA patients with enthesitis might respond better to a different therapy.
She investigated this with the open-label ECLIPSA trial, which randomized 51 PsA patients (47 with active enthesitis) to a 6-month treatment regimen of ustekinumab or a TNF-inhibitor. The primary endpoint of the observational study was a SPARCC score of 0.
Patients were a mean of 61 years, with a mean disease duration of 2.5 years. The mean baseline SPARCC score was 4. The mean Psoriatic Area and Severity Score (PASI) was 3.
Patients’ arthritis symptoms responded equally well to both drugs, with similar marked decreases in tender and swollen joint counts. But there was a clear, significant between-group separation on the SPARCC score, with 71% of the ustekinumab group reaching a 0 compared to 38% of the TNF-inhibition group.
Ustekinumab also effected better skin clearance than TNF-inhibition, she said. Among the TNF-inhibition group, about 20% achieved a PASI 90 and 20%, a PASI 100. Among those taking ustekinumab, about 80% achieved a PASI 90 and 55% a PASI 100.
The data point the way to more stratified treatment approaches for PsA patients, where PsA that predominantly involves enthesitis is treated by drugs like ustekinumab, Dr. Araujo said. Since both TNF-inhibitors and ustekinumab are approved for treatment of PsA, treatment could be tailored.
“Stratification of PsA patients according to clinical features (enthesitis driven vs. arthritis driven) appears within reach and will allow a more selective use of cytokine-blocking agents in PsA in the future,” said Dr. Araujo.
“More attention on enthesial-driven PsA patients is needed in the future as this patient group is well known to clinicians working in the PsA field but is massively underrepresented in clinical studies. Comparative studies of biological [disease-modifying antirheumatic drugs] in PsA need to take into account the differences in the clinical profile of PsA patients and should not be confined to the traditional polyarticular arthritis–driven disease population,” she added.
Dr. Araujo had no financial disclosures.
[email protected]
On Twitter @Alz_gal
MADRID – The anti-IL-23 antibody ustekinumab cleared enthesitis significantly better than did TNF-blockade in a small, open-label trial of patients with psoriatic arthritis
After 6 months on the drug, 71% of those taking the antibody achieved a score of 0 on the Spondyloarthritis Research Consortium of Canada (SPARCC) scale, representing a complete absence of enthesitis, Elizabeth Araujo, MD, said at the European Congress of Rheumatology. Just 38% of those on TNF-inhibitors achieved that score.
Enthesitis is often more bothersome to arthritis patients than their primary disease, said Dr. Araujo of the Centre of Internal Medicine, Universitätsklinikum Erlangen, Germany.
“Despite being a hallmark of PsA patients, enthesitis still receives rather peripheral attention as an outcome, especially when compared with ‘classical’ arthritis. Nonetheless, in clinical practice, enthesitis is an important factor for PsA-associated pain in many patients,” explained Dr. Araujo.
Yet it’s frequently ignored or under-treated. When it is addressed, enthesitis is often treated using TNF-inhibitors. But recent increases in the treatment options for PsA patients got Dr. Araujo thinking that PsA patients with enthesitis might respond better to a different therapy.
She investigated this with the open-label ECLIPSA trial, which randomized 51 PsA patients (47 with active enthesitis) to a 6-month treatment regimen of ustekinumab or a TNF-inhibitor. The primary endpoint of the observational study was a SPARCC score of 0.
Patients were a mean of 61 years, with a mean disease duration of 2.5 years. The mean baseline SPARCC score was 4. The mean Psoriatic Area and Severity Score (PASI) was 3.
Patients’ arthritis symptoms responded equally well to both drugs, with similar marked decreases in tender and swollen joint counts. But there was a clear, significant between-group separation on the SPARCC score, with 71% of the ustekinumab group reaching a 0 compared to 38% of the TNF-inhibition group.
Ustekinumab also effected better skin clearance than TNF-inhibition, she said. Among the TNF-inhibition group, about 20% achieved a PASI 90 and 20%, a PASI 100. Among those taking ustekinumab, about 80% achieved a PASI 90 and 55% a PASI 100.
The data point the way to more stratified treatment approaches for PsA patients, where PsA that predominantly involves enthesitis is treated by drugs like ustekinumab, Dr. Araujo said. Since both TNF-inhibitors and ustekinumab are approved for treatment of PsA, treatment could be tailored.
“Stratification of PsA patients according to clinical features (enthesitis driven vs. arthritis driven) appears within reach and will allow a more selective use of cytokine-blocking agents in PsA in the future,” said Dr. Araujo.
“More attention on enthesial-driven PsA patients is needed in the future as this patient group is well known to clinicians working in the PsA field but is massively underrepresented in clinical studies. Comparative studies of biological [disease-modifying antirheumatic drugs] in PsA need to take into account the differences in the clinical profile of PsA patients and should not be confined to the traditional polyarticular arthritis–driven disease population,” she added.
Dr. Araujo had no financial disclosures.
[email protected]
On Twitter @Alz_gal
MADRID – The anti-IL-23 antibody ustekinumab cleared enthesitis significantly better than did TNF-blockade in a small, open-label trial of patients with psoriatic arthritis
After 6 months on the drug, 71% of those taking the antibody achieved a score of 0 on the Spondyloarthritis Research Consortium of Canada (SPARCC) scale, representing a complete absence of enthesitis, Elizabeth Araujo, MD, said at the European Congress of Rheumatology. Just 38% of those on TNF-inhibitors achieved that score.
Enthesitis is often more bothersome to arthritis patients than their primary disease, said Dr. Araujo of the Centre of Internal Medicine, Universitätsklinikum Erlangen, Germany.
“Despite being a hallmark of PsA patients, enthesitis still receives rather peripheral attention as an outcome, especially when compared with ‘classical’ arthritis. Nonetheless, in clinical practice, enthesitis is an important factor for PsA-associated pain in many patients,” explained Dr. Araujo.
Yet it’s frequently ignored or under-treated. When it is addressed, enthesitis is often treated using TNF-inhibitors. But recent increases in the treatment options for PsA patients got Dr. Araujo thinking that PsA patients with enthesitis might respond better to a different therapy.
She investigated this with the open-label ECLIPSA trial, which randomized 51 PsA patients (47 with active enthesitis) to a 6-month treatment regimen of ustekinumab or a TNF-inhibitor. The primary endpoint of the observational study was a SPARCC score of 0.
Patients were a mean of 61 years, with a mean disease duration of 2.5 years. The mean baseline SPARCC score was 4. The mean Psoriatic Area and Severity Score (PASI) was 3.
Patients’ arthritis symptoms responded equally well to both drugs, with similar marked decreases in tender and swollen joint counts. But there was a clear, significant between-group separation on the SPARCC score, with 71% of the ustekinumab group reaching a 0 compared to 38% of the TNF-inhibition group.
Ustekinumab also effected better skin clearance than TNF-inhibition, she said. Among the TNF-inhibition group, about 20% achieved a PASI 90 and 20%, a PASI 100. Among those taking ustekinumab, about 80% achieved a PASI 90 and 55% a PASI 100.
The data point the way to more stratified treatment approaches for PsA patients, where PsA that predominantly involves enthesitis is treated by drugs like ustekinumab, Dr. Araujo said. Since both TNF-inhibitors and ustekinumab are approved for treatment of PsA, treatment could be tailored.
“Stratification of PsA patients according to clinical features (enthesitis driven vs. arthritis driven) appears within reach and will allow a more selective use of cytokine-blocking agents in PsA in the future,” said Dr. Araujo.
“More attention on enthesial-driven PsA patients is needed in the future as this patient group is well known to clinicians working in the PsA field but is massively underrepresented in clinical studies. Comparative studies of biological [disease-modifying antirheumatic drugs] in PsA need to take into account the differences in the clinical profile of PsA patients and should not be confined to the traditional polyarticular arthritis–driven disease population,” she added.
Dr. Araujo had no financial disclosures.
[email protected]
On Twitter @Alz_gal
AT EULAR 2017
Key clinical point:
Major finding: After 6 months, 71% of those taking ustekinumab and 38% of those taking TNF-blockers achieved total enthesitis clearance.
Data source: The open-label trial randomized 51 patients - 47 of whom had active enthesitis.
Disclosures: Dr. Araujo had no financial disclosures.
VIDEO: Guselkumab bests placebo in psoriatic arthritis
MADRID – Guselkumab, an IL-23 blocker that has proved its mettle in psoriasis, also posted excellent results in an early-phase psoriatic arthritis trial.
The fully human monoclonal antibody, which is being developed by Janssen, targets the p19 subunit of interleukin-23, Atul Deodhar, MD, said at the European Congress of Rheumatology. The 52-week phase 2a study randomized 149 patients to 100 mg guselkumab or placebo given subcutaneously at baseline and week 4, then every 8 weeks, for 24 weeks. Patients who didn’t respond adequately in either arm could begin using ustekinumab. After 24 weeks, everyone remaining in the placebo group switched to guselkumab, and patients in both arms continued open-label treatment until 52 weeks.
Dr. Deodhar of the Oregon Health and Science University, Portland, reported 24-week outcomes. A full year of data will be presented at the American College of Rheumatology meeting in San Diego in November.
Guselkumab aced the study’s primary endpoint – ACR 20 response by week 24 (58% vs. 18% with the placebo, P less than .001). Improvement developed rapidly, with a significant separation between the groups by week 4 (21% vs. 0%; P less than .001). It also succeeded on the secondary endpoints of ACR 50 response (34% vs. 10%) and ACR 70 (14% vs. 2%). The antibody also significantly outperformed placebo on the Health Assessment Questionnaire Disability Index (HAQ-DI), 36-Item Short Form Health Survey (SF-36), and Minimal Disease Activity score. Skin clearance was strikingly good, Dr. Deodhar said: 39% achieved complete clearance, with a Psoriasis Area and Severity Index (PASI) score of 100; 66% achieved a PASI of 90; and 79% acheived a PASI of 75.
Guselkumab also significantly improved enthesitis – a symptom that can be terribly troubling for patients with psoriatic arthritis. Enthesitis was present in 106 at baseline. By 24 weeks, it had resolved in 56.6% of those taking the antibody and 29% of those taking the placebo (P = .012.).
A phase III trial in psoriatic arthritis will be forthcoming, Dr. Deodhar said.
Dr. Deodhar has received research funding and is a consultant for Janssen and other pharmaceutical companies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @alz_gal
MADRID – Guselkumab, an IL-23 blocker that has proved its mettle in psoriasis, also posted excellent results in an early-phase psoriatic arthritis trial.
The fully human monoclonal antibody, which is being developed by Janssen, targets the p19 subunit of interleukin-23, Atul Deodhar, MD, said at the European Congress of Rheumatology. The 52-week phase 2a study randomized 149 patients to 100 mg guselkumab or placebo given subcutaneously at baseline and week 4, then every 8 weeks, for 24 weeks. Patients who didn’t respond adequately in either arm could begin using ustekinumab. After 24 weeks, everyone remaining in the placebo group switched to guselkumab, and patients in both arms continued open-label treatment until 52 weeks.
Dr. Deodhar of the Oregon Health and Science University, Portland, reported 24-week outcomes. A full year of data will be presented at the American College of Rheumatology meeting in San Diego in November.
Guselkumab aced the study’s primary endpoint – ACR 20 response by week 24 (58% vs. 18% with the placebo, P less than .001). Improvement developed rapidly, with a significant separation between the groups by week 4 (21% vs. 0%; P less than .001). It also succeeded on the secondary endpoints of ACR 50 response (34% vs. 10%) and ACR 70 (14% vs. 2%). The antibody also significantly outperformed placebo on the Health Assessment Questionnaire Disability Index (HAQ-DI), 36-Item Short Form Health Survey (SF-36), and Minimal Disease Activity score. Skin clearance was strikingly good, Dr. Deodhar said: 39% achieved complete clearance, with a Psoriasis Area and Severity Index (PASI) score of 100; 66% achieved a PASI of 90; and 79% acheived a PASI of 75.
Guselkumab also significantly improved enthesitis – a symptom that can be terribly troubling for patients with psoriatic arthritis. Enthesitis was present in 106 at baseline. By 24 weeks, it had resolved in 56.6% of those taking the antibody and 29% of those taking the placebo (P = .012.).
A phase III trial in psoriatic arthritis will be forthcoming, Dr. Deodhar said.
Dr. Deodhar has received research funding and is a consultant for Janssen and other pharmaceutical companies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @alz_gal
MADRID – Guselkumab, an IL-23 blocker that has proved its mettle in psoriasis, also posted excellent results in an early-phase psoriatic arthritis trial.
The fully human monoclonal antibody, which is being developed by Janssen, targets the p19 subunit of interleukin-23, Atul Deodhar, MD, said at the European Congress of Rheumatology. The 52-week phase 2a study randomized 149 patients to 100 mg guselkumab or placebo given subcutaneously at baseline and week 4, then every 8 weeks, for 24 weeks. Patients who didn’t respond adequately in either arm could begin using ustekinumab. After 24 weeks, everyone remaining in the placebo group switched to guselkumab, and patients in both arms continued open-label treatment until 52 weeks.
Dr. Deodhar of the Oregon Health and Science University, Portland, reported 24-week outcomes. A full year of data will be presented at the American College of Rheumatology meeting in San Diego in November.
Guselkumab aced the study’s primary endpoint – ACR 20 response by week 24 (58% vs. 18% with the placebo, P less than .001). Improvement developed rapidly, with a significant separation between the groups by week 4 (21% vs. 0%; P less than .001). It also succeeded on the secondary endpoints of ACR 50 response (34% vs. 10%) and ACR 70 (14% vs. 2%). The antibody also significantly outperformed placebo on the Health Assessment Questionnaire Disability Index (HAQ-DI), 36-Item Short Form Health Survey (SF-36), and Minimal Disease Activity score. Skin clearance was strikingly good, Dr. Deodhar said: 39% achieved complete clearance, with a Psoriasis Area and Severity Index (PASI) score of 100; 66% achieved a PASI of 90; and 79% acheived a PASI of 75.
Guselkumab also significantly improved enthesitis – a symptom that can be terribly troubling for patients with psoriatic arthritis. Enthesitis was present in 106 at baseline. By 24 weeks, it had resolved in 56.6% of those taking the antibody and 29% of those taking the placebo (P = .012.).
A phase III trial in psoriatic arthritis will be forthcoming, Dr. Deodhar said.
Dr. Deodhar has received research funding and is a consultant for Janssen and other pharmaceutical companies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @alz_gal
AT THE EULAR 2017 CONGRESS
Key clinical point:
Major finding: ACR 20 response at 24 weeks was 58% in the treated group, vs. 18% in the placebo group.
Data source: The 52-week 2a study randomized 149 patients to guselkumab or placebo.
Disclosures: Dr. Deodhar has received research monies and is a consultant for Janssen, which is developing guselkumab.
VIDEO: Adding ultrasound to treat to target doesn’t improve RA remission outcomes
MADRID – Adding ultrasound exams to a treat to target (T2T) protocol did not improve remission outcomes in patients with rheumatoid arthritis.
In fact, seven-joint ultrasound actually reduced the chance that patients would achieve clinical remission in several remission assessment tools, Alexandre Sepriano, MD, said at the European Congress of Rheumatology.
“We saw no advantage in using ultrasound of seven joints in addition to clinical examination, compared to clinical examination alone,” said Dr. Sepriano of Leiden (the Netherlands) University Medical Center. “We can speculate on the reasons why, but, in truth, this is the same message we have now seen in two other studies.”
Subclinical, ultrasound-detected synovitis has been shown to be predictive of disease flare in people with rheumatoid arthritis (RA), suggesting that ultrasound may have a role in defining treatment strategies, but recent trials integrating musculoskeletal ultrasound assessments into a T2T protocol have not shown better outcomes than when standard clinical definitions of remission are used.
Dr. Sepriano presented findings from BIODAM, a 2-year observational cohort of RA patients across 10 countries who are managed under a T2T protocol.
Several studies, including BIODAM, have helped to establish T2T – which intensifies treatment if patients are not in remission and eases treatment intensity when patients are in remission – as an optimal management strategy in RA. Dr. Sepriano and his colleagues set out to learn whether using ultrasound data in T2T would result in better outcomes, by creating a combined new strategy using both ultrasound and clinical measures, than does use of the established T2T strategy that uses only clinical data.
To do this, they looked at a subgroup of 130 patients from six countries who were treated at the BIODAM centers that had expertise in ultrasound. Patients’ clinical and ultrasound data were collected every 3 months through 2 years (for 1,037 visits in total) and were managed by rheumatologists under established T2T protocols. These patients were a mean of 55 years old, with a mean disease duration of 6 years.
As in the broader BIODAM study, the researchers used multiple clinical definitions of remission, including 28-joint and 44-joint Disease Activity Scores and the European League against Rheumatism/American College of Rheumatology–Boolean criteria. For the ultrasound measure, they used the previously validated US-7, which looks at seven joints for signs of synovitis.
In general, the proportion of patients in clinical remission rose over the study period, no matter what assessment tool was used. However, Dr. Sepriano and his colleagues found that the combined clinical and ultrasound benchmark for T2T decreased the likelihood of DAS-44 clinical remission after 3 months by 41% when compared with the conventional strategy. The story was similar for other assessments: The reduction was 49% on the DAS-28, 55% on Boolean remission, and 66% on Simple Disease Activity Index remission.
The reasons for this finding are difficult to discern, Dr. Sepriano said, and are complicated by the fact that this study was not a randomized, controlled trial but a longitudinal cohort in real-world practice settings.
Given the many variables involved, Dr. Sepriano said, “it may be not entirely linear to have an explanation as to why, when we used ultrasound, we actually got worse results.”
But, he noted, results from two randomized trials in more restricted populations of RA patients have also shown no benefit from adding ultrasound.
“What the data are telling us is that the clinician should be encouraged to use clinical data in his or her decisions – so we stress the importance of following a T2T strategy according to clinical data,” Dr. Sepriano said. “Adding ultrasound may not be an advantage in this scenario.”
Additional studies may end up changing this outlook on ultrasound, but, for now, the evidence does not exist, he said in a video interview.
Dr. Sepriano and his associates had no conflicts of interest to declare.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
MADRID – Adding ultrasound exams to a treat to target (T2T) protocol did not improve remission outcomes in patients with rheumatoid arthritis.
In fact, seven-joint ultrasound actually reduced the chance that patients would achieve clinical remission in several remission assessment tools, Alexandre Sepriano, MD, said at the European Congress of Rheumatology.
“We saw no advantage in using ultrasound of seven joints in addition to clinical examination, compared to clinical examination alone,” said Dr. Sepriano of Leiden (the Netherlands) University Medical Center. “We can speculate on the reasons why, but, in truth, this is the same message we have now seen in two other studies.”
Subclinical, ultrasound-detected synovitis has been shown to be predictive of disease flare in people with rheumatoid arthritis (RA), suggesting that ultrasound may have a role in defining treatment strategies, but recent trials integrating musculoskeletal ultrasound assessments into a T2T protocol have not shown better outcomes than when standard clinical definitions of remission are used.
Dr. Sepriano presented findings from BIODAM, a 2-year observational cohort of RA patients across 10 countries who are managed under a T2T protocol.
Several studies, including BIODAM, have helped to establish T2T – which intensifies treatment if patients are not in remission and eases treatment intensity when patients are in remission – as an optimal management strategy in RA. Dr. Sepriano and his colleagues set out to learn whether using ultrasound data in T2T would result in better outcomes, by creating a combined new strategy using both ultrasound and clinical measures, than does use of the established T2T strategy that uses only clinical data.
To do this, they looked at a subgroup of 130 patients from six countries who were treated at the BIODAM centers that had expertise in ultrasound. Patients’ clinical and ultrasound data were collected every 3 months through 2 years (for 1,037 visits in total) and were managed by rheumatologists under established T2T protocols. These patients were a mean of 55 years old, with a mean disease duration of 6 years.
As in the broader BIODAM study, the researchers used multiple clinical definitions of remission, including 28-joint and 44-joint Disease Activity Scores and the European League against Rheumatism/American College of Rheumatology–Boolean criteria. For the ultrasound measure, they used the previously validated US-7, which looks at seven joints for signs of synovitis.
In general, the proportion of patients in clinical remission rose over the study period, no matter what assessment tool was used. However, Dr. Sepriano and his colleagues found that the combined clinical and ultrasound benchmark for T2T decreased the likelihood of DAS-44 clinical remission after 3 months by 41% when compared with the conventional strategy. The story was similar for other assessments: The reduction was 49% on the DAS-28, 55% on Boolean remission, and 66% on Simple Disease Activity Index remission.
The reasons for this finding are difficult to discern, Dr. Sepriano said, and are complicated by the fact that this study was not a randomized, controlled trial but a longitudinal cohort in real-world practice settings.
Given the many variables involved, Dr. Sepriano said, “it may be not entirely linear to have an explanation as to why, when we used ultrasound, we actually got worse results.”
But, he noted, results from two randomized trials in more restricted populations of RA patients have also shown no benefit from adding ultrasound.
“What the data are telling us is that the clinician should be encouraged to use clinical data in his or her decisions – so we stress the importance of following a T2T strategy according to clinical data,” Dr. Sepriano said. “Adding ultrasound may not be an advantage in this scenario.”
Additional studies may end up changing this outlook on ultrasound, but, for now, the evidence does not exist, he said in a video interview.
Dr. Sepriano and his associates had no conflicts of interest to declare.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
MADRID – Adding ultrasound exams to a treat to target (T2T) protocol did not improve remission outcomes in patients with rheumatoid arthritis.
In fact, seven-joint ultrasound actually reduced the chance that patients would achieve clinical remission in several remission assessment tools, Alexandre Sepriano, MD, said at the European Congress of Rheumatology.
“We saw no advantage in using ultrasound of seven joints in addition to clinical examination, compared to clinical examination alone,” said Dr. Sepriano of Leiden (the Netherlands) University Medical Center. “We can speculate on the reasons why, but, in truth, this is the same message we have now seen in two other studies.”
Subclinical, ultrasound-detected synovitis has been shown to be predictive of disease flare in people with rheumatoid arthritis (RA), suggesting that ultrasound may have a role in defining treatment strategies, but recent trials integrating musculoskeletal ultrasound assessments into a T2T protocol have not shown better outcomes than when standard clinical definitions of remission are used.
Dr. Sepriano presented findings from BIODAM, a 2-year observational cohort of RA patients across 10 countries who are managed under a T2T protocol.
Several studies, including BIODAM, have helped to establish T2T – which intensifies treatment if patients are not in remission and eases treatment intensity when patients are in remission – as an optimal management strategy in RA. Dr. Sepriano and his colleagues set out to learn whether using ultrasound data in T2T would result in better outcomes, by creating a combined new strategy using both ultrasound and clinical measures, than does use of the established T2T strategy that uses only clinical data.
To do this, they looked at a subgroup of 130 patients from six countries who were treated at the BIODAM centers that had expertise in ultrasound. Patients’ clinical and ultrasound data were collected every 3 months through 2 years (for 1,037 visits in total) and were managed by rheumatologists under established T2T protocols. These patients were a mean of 55 years old, with a mean disease duration of 6 years.
As in the broader BIODAM study, the researchers used multiple clinical definitions of remission, including 28-joint and 44-joint Disease Activity Scores and the European League against Rheumatism/American College of Rheumatology–Boolean criteria. For the ultrasound measure, they used the previously validated US-7, which looks at seven joints for signs of synovitis.
In general, the proportion of patients in clinical remission rose over the study period, no matter what assessment tool was used. However, Dr. Sepriano and his colleagues found that the combined clinical and ultrasound benchmark for T2T decreased the likelihood of DAS-44 clinical remission after 3 months by 41% when compared with the conventional strategy. The story was similar for other assessments: The reduction was 49% on the DAS-28, 55% on Boolean remission, and 66% on Simple Disease Activity Index remission.
The reasons for this finding are difficult to discern, Dr. Sepriano said, and are complicated by the fact that this study was not a randomized, controlled trial but a longitudinal cohort in real-world practice settings.
Given the many variables involved, Dr. Sepriano said, “it may be not entirely linear to have an explanation as to why, when we used ultrasound, we actually got worse results.”
But, he noted, results from two randomized trials in more restricted populations of RA patients have also shown no benefit from adding ultrasound.
“What the data are telling us is that the clinician should be encouraged to use clinical data in his or her decisions – so we stress the importance of following a T2T strategy according to clinical data,” Dr. Sepriano said. “Adding ultrasound may not be an advantage in this scenario.”
Additional studies may end up changing this outlook on ultrasound, but, for now, the evidence does not exist, he said in a video interview.
Dr. Sepriano and his associates had no conflicts of interest to declare.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE EULAR 2017 CONGRESS
Key clinical point:
Major finding: Adding ultrasound to the treatment protocol actually reduced the likelihood of patients achieving remission by up to 66%, depending on the remission assessment used.
Data source: The observational study comprised 130 patients and more than 1,000 clinical visits.
Disclosures: Dr. Sepriano had no financial disclosures.
Romosozumab cuts new vertebral fracture risk by 73%, but safety data are concerning
MADRID – Romosozumab, an investigational bone-building agent, reduced new vertebral fractures by 73% among postmenopausal women with osteoporosis.
Compared with placebo, the monoclonal antibody also reduced the risk of a clinical fracture by 36% after 12 months of treatment, Piet Geusens, MD, said at the European Congress of Rheumatology. The effect was maintained at 24 months, with a 50% reduction in fracture risk, said Dr. Geusens of Maastricht University, the Netherlands.
Romosozumab also significantly reduced clinical and nonvertebral fractures and increased bone mineral density at the total hip, femoral neck, and lumbar spine in the phase III FRAME study, cosponsored by Amgen and UCB Pharma.
But recently, the finding of increased cardiovascular events in another highly anticipated phase III study of romosozumab cast a cloud of doubt over its rising star. During an interview at EULAR, a UCB company spokesman said the company no longer anticipates a 2017 Food and Drug Administration approval.
FRAME randomized 7,180 postmenopausal women with osteoporosis to monthly injections of romosozumab 210 mg or placebo for 12 months; after that, patients who had been taking placebo switched to denosumab. Dr. Geusens presented only the first year’s placebo-controlled portion. The full FRAME study was published in the New England Journal of Medicine last September (doi: 10.1056/NEJMoa1607948).
At baseline, the women had a mean bone mineral density T score of –2.7 at the lumbar spine, –2.4 at the total hip, and –2.7 at the femoral neck. Mean age was 71 years. About 20% of the women had a previous vertebral fracture, and 22% a previous nonvertebral fracture. The mean FRAX (fracture risk assessment tool) score was 13.4 in both groups.
After 12 months, a new vertebral fracture had occurred in 59 women taking placebo and 16 taking romosozumab (1.8% vs. 0.5%). This amounted to a 73% risk reduction, Dr. Geusens said. Although he did not present 24-month data, the published article cited the antibody’s sustained effect, with a 50% risk reduction evident after the 12-month comparison with denosumab.
The drug also exerted its benefit quickly, Dr. Geusens said. Most of the fractures in the active group occurred in the first 6 months of treatment, with only two additional fractures later.
Romosozumab also was associated with a 36% decrease in the risk of clinical fracture by 12 months (1.6% vs. 2.5% placebo). There was also a positive effect on nonvertebral fractures, which constituted more than 85% of the clinical fractures. Nonvertebral fractures occurred in 56 of those taking the antibody and 75 of those taking placebo (1.6% vs. 2.1%; hazard ratio [HR], .75).
By 12 months, bone mineral density had increased in the romosozumab group by 13% more than in the placebo group at the lumbar spine, by 7% more at the total hip, and by 6% more at the femoral neck.
Dr. Geusens did not address the adverse event profile during his talk. However, according to the published study, romosozumab was generally well tolerated. Serious hypersensitivity events occurred in seven romosozumab patients. Injection site reactions were mostly mild and occurred in 5% of the active group and 3% of the placebo group.
Two patients taking romosozumab experienced osteonecrosis of the jaw; both incidences occurred during the second 12 months and in conjunction with dental issues (tooth extraction and poorly fitted dentures). Anti-romosozumab antibodies developed in 18% and neutralizing antibodies in 0.7%.
Serious cardiovascular events occurred in about 1% of each treatment group, with 17 among those taking romosozumab and15 cardiovascular deaths among those taking placebo – not a significant difference.
UCB and Amgen were pleased with FRAME’s results and, last July, submitted a Biologics License Application to the FDA based on the positive data. A 2017 approval was anticipated, UCB spokesman Scott Fleming said in an interview. But in May, the primary safety analysis of another phase III study, ARCH, threw a monkey wrench in the works.
ARCH compared romosozumab to alendronate in 4,100 postmenopausal women with osteoporosis. ARCH met its primary and secondary endpoints, reducing the incidence of new vertebral fractures by 50%, clinical fractures by 27%, and nonvertebral fractures by 19%. But significantly more women taking the antibody experienced an adjudicated serious cardiovascular event (2.5% vs. 1.9% on alendronate).
On May 21, the companies said these new data would delay romosozumab’s progress toward approval, despite the fact that the submission was based on FRAMES’s positive safety and efficacy data.
Mr. Fleming confirmed this in an interview.
“Amgen has agreed with the FDA that the ARCH data should be considered in the regulatory review prior to the initial marketing authorization, and as a result we do not expect approval of romosozumab in the U.S. to occur in 2017,” he said. “Patient safety is of utmost importance and whilst the cardiac imbalance observed in ARCH was not seen in FRAME, it is important and our responsibility to better understand this imbalance. Further analysis of the ARCH study data is ongoing and will be submitted to a future medical conference and for publication.”
Dr. Geusens refused to comment on the cardiovascular adverse events, saying he had not seen the ARCH data; nor did he explain the cardiovascular events that did occur in FRAME.
Romosozumab also is being reviewed in Canada and Japan; those processes are still underway. Mr. Fleming said the companies are preparing a European Medicines Agency application as well. “The preparation for the European regulatory submission will continue as planned – second half of 2017,” he said.
Dr. Geusens has received research support from Amgen and other pharmaceutical companies. He is a consultant for Amgen and a member of its speakers bureau.
[email protected]
On Twitter @Alz_gal
MADRID – Romosozumab, an investigational bone-building agent, reduced new vertebral fractures by 73% among postmenopausal women with osteoporosis.
Compared with placebo, the monoclonal antibody also reduced the risk of a clinical fracture by 36% after 12 months of treatment, Piet Geusens, MD, said at the European Congress of Rheumatology. The effect was maintained at 24 months, with a 50% reduction in fracture risk, said Dr. Geusens of Maastricht University, the Netherlands.
Romosozumab also significantly reduced clinical and nonvertebral fractures and increased bone mineral density at the total hip, femoral neck, and lumbar spine in the phase III FRAME study, cosponsored by Amgen and UCB Pharma.
But recently, the finding of increased cardiovascular events in another highly anticipated phase III study of romosozumab cast a cloud of doubt over its rising star. During an interview at EULAR, a UCB company spokesman said the company no longer anticipates a 2017 Food and Drug Administration approval.
FRAME randomized 7,180 postmenopausal women with osteoporosis to monthly injections of romosozumab 210 mg or placebo for 12 months; after that, patients who had been taking placebo switched to denosumab. Dr. Geusens presented only the first year’s placebo-controlled portion. The full FRAME study was published in the New England Journal of Medicine last September (doi: 10.1056/NEJMoa1607948).
At baseline, the women had a mean bone mineral density T score of –2.7 at the lumbar spine, –2.4 at the total hip, and –2.7 at the femoral neck. Mean age was 71 years. About 20% of the women had a previous vertebral fracture, and 22% a previous nonvertebral fracture. The mean FRAX (fracture risk assessment tool) score was 13.4 in both groups.
After 12 months, a new vertebral fracture had occurred in 59 women taking placebo and 16 taking romosozumab (1.8% vs. 0.5%). This amounted to a 73% risk reduction, Dr. Geusens said. Although he did not present 24-month data, the published article cited the antibody’s sustained effect, with a 50% risk reduction evident after the 12-month comparison with denosumab.
The drug also exerted its benefit quickly, Dr. Geusens said. Most of the fractures in the active group occurred in the first 6 months of treatment, with only two additional fractures later.
Romosozumab also was associated with a 36% decrease in the risk of clinical fracture by 12 months (1.6% vs. 2.5% placebo). There was also a positive effect on nonvertebral fractures, which constituted more than 85% of the clinical fractures. Nonvertebral fractures occurred in 56 of those taking the antibody and 75 of those taking placebo (1.6% vs. 2.1%; hazard ratio [HR], .75).
By 12 months, bone mineral density had increased in the romosozumab group by 13% more than in the placebo group at the lumbar spine, by 7% more at the total hip, and by 6% more at the femoral neck.
Dr. Geusens did not address the adverse event profile during his talk. However, according to the published study, romosozumab was generally well tolerated. Serious hypersensitivity events occurred in seven romosozumab patients. Injection site reactions were mostly mild and occurred in 5% of the active group and 3% of the placebo group.
Two patients taking romosozumab experienced osteonecrosis of the jaw; both incidences occurred during the second 12 months and in conjunction with dental issues (tooth extraction and poorly fitted dentures). Anti-romosozumab antibodies developed in 18% and neutralizing antibodies in 0.7%.
Serious cardiovascular events occurred in about 1% of each treatment group, with 17 among those taking romosozumab and15 cardiovascular deaths among those taking placebo – not a significant difference.
UCB and Amgen were pleased with FRAME’s results and, last July, submitted a Biologics License Application to the FDA based on the positive data. A 2017 approval was anticipated, UCB spokesman Scott Fleming said in an interview. But in May, the primary safety analysis of another phase III study, ARCH, threw a monkey wrench in the works.
ARCH compared romosozumab to alendronate in 4,100 postmenopausal women with osteoporosis. ARCH met its primary and secondary endpoints, reducing the incidence of new vertebral fractures by 50%, clinical fractures by 27%, and nonvertebral fractures by 19%. But significantly more women taking the antibody experienced an adjudicated serious cardiovascular event (2.5% vs. 1.9% on alendronate).
On May 21, the companies said these new data would delay romosozumab’s progress toward approval, despite the fact that the submission was based on FRAMES’s positive safety and efficacy data.
Mr. Fleming confirmed this in an interview.
“Amgen has agreed with the FDA that the ARCH data should be considered in the regulatory review prior to the initial marketing authorization, and as a result we do not expect approval of romosozumab in the U.S. to occur in 2017,” he said. “Patient safety is of utmost importance and whilst the cardiac imbalance observed in ARCH was not seen in FRAME, it is important and our responsibility to better understand this imbalance. Further analysis of the ARCH study data is ongoing and will be submitted to a future medical conference and for publication.”
Dr. Geusens refused to comment on the cardiovascular adverse events, saying he had not seen the ARCH data; nor did he explain the cardiovascular events that did occur in FRAME.
Romosozumab also is being reviewed in Canada and Japan; those processes are still underway. Mr. Fleming said the companies are preparing a European Medicines Agency application as well. “The preparation for the European regulatory submission will continue as planned – second half of 2017,” he said.
Dr. Geusens has received research support from Amgen and other pharmaceutical companies. He is a consultant for Amgen and a member of its speakers bureau.
[email protected]
On Twitter @Alz_gal
MADRID – Romosozumab, an investigational bone-building agent, reduced new vertebral fractures by 73% among postmenopausal women with osteoporosis.
Compared with placebo, the monoclonal antibody also reduced the risk of a clinical fracture by 36% after 12 months of treatment, Piet Geusens, MD, said at the European Congress of Rheumatology. The effect was maintained at 24 months, with a 50% reduction in fracture risk, said Dr. Geusens of Maastricht University, the Netherlands.
Romosozumab also significantly reduced clinical and nonvertebral fractures and increased bone mineral density at the total hip, femoral neck, and lumbar spine in the phase III FRAME study, cosponsored by Amgen and UCB Pharma.
But recently, the finding of increased cardiovascular events in another highly anticipated phase III study of romosozumab cast a cloud of doubt over its rising star. During an interview at EULAR, a UCB company spokesman said the company no longer anticipates a 2017 Food and Drug Administration approval.
FRAME randomized 7,180 postmenopausal women with osteoporosis to monthly injections of romosozumab 210 mg or placebo for 12 months; after that, patients who had been taking placebo switched to denosumab. Dr. Geusens presented only the first year’s placebo-controlled portion. The full FRAME study was published in the New England Journal of Medicine last September (doi: 10.1056/NEJMoa1607948).
At baseline, the women had a mean bone mineral density T score of –2.7 at the lumbar spine, –2.4 at the total hip, and –2.7 at the femoral neck. Mean age was 71 years. About 20% of the women had a previous vertebral fracture, and 22% a previous nonvertebral fracture. The mean FRAX (fracture risk assessment tool) score was 13.4 in both groups.
After 12 months, a new vertebral fracture had occurred in 59 women taking placebo and 16 taking romosozumab (1.8% vs. 0.5%). This amounted to a 73% risk reduction, Dr. Geusens said. Although he did not present 24-month data, the published article cited the antibody’s sustained effect, with a 50% risk reduction evident after the 12-month comparison with denosumab.
The drug also exerted its benefit quickly, Dr. Geusens said. Most of the fractures in the active group occurred in the first 6 months of treatment, with only two additional fractures later.
Romosozumab also was associated with a 36% decrease in the risk of clinical fracture by 12 months (1.6% vs. 2.5% placebo). There was also a positive effect on nonvertebral fractures, which constituted more than 85% of the clinical fractures. Nonvertebral fractures occurred in 56 of those taking the antibody and 75 of those taking placebo (1.6% vs. 2.1%; hazard ratio [HR], .75).
By 12 months, bone mineral density had increased in the romosozumab group by 13% more than in the placebo group at the lumbar spine, by 7% more at the total hip, and by 6% more at the femoral neck.
Dr. Geusens did not address the adverse event profile during his talk. However, according to the published study, romosozumab was generally well tolerated. Serious hypersensitivity events occurred in seven romosozumab patients. Injection site reactions were mostly mild and occurred in 5% of the active group and 3% of the placebo group.
Two patients taking romosozumab experienced osteonecrosis of the jaw; both incidences occurred during the second 12 months and in conjunction with dental issues (tooth extraction and poorly fitted dentures). Anti-romosozumab antibodies developed in 18% and neutralizing antibodies in 0.7%.
Serious cardiovascular events occurred in about 1% of each treatment group, with 17 among those taking romosozumab and15 cardiovascular deaths among those taking placebo – not a significant difference.
UCB and Amgen were pleased with FRAME’s results and, last July, submitted a Biologics License Application to the FDA based on the positive data. A 2017 approval was anticipated, UCB spokesman Scott Fleming said in an interview. But in May, the primary safety analysis of another phase III study, ARCH, threw a monkey wrench in the works.
ARCH compared romosozumab to alendronate in 4,100 postmenopausal women with osteoporosis. ARCH met its primary and secondary endpoints, reducing the incidence of new vertebral fractures by 50%, clinical fractures by 27%, and nonvertebral fractures by 19%. But significantly more women taking the antibody experienced an adjudicated serious cardiovascular event (2.5% vs. 1.9% on alendronate).
On May 21, the companies said these new data would delay romosozumab’s progress toward approval, despite the fact that the submission was based on FRAMES’s positive safety and efficacy data.
Mr. Fleming confirmed this in an interview.
“Amgen has agreed with the FDA that the ARCH data should be considered in the regulatory review prior to the initial marketing authorization, and as a result we do not expect approval of romosozumab in the U.S. to occur in 2017,” he said. “Patient safety is of utmost importance and whilst the cardiac imbalance observed in ARCH was not seen in FRAME, it is important and our responsibility to better understand this imbalance. Further analysis of the ARCH study data is ongoing and will be submitted to a future medical conference and for publication.”
Dr. Geusens refused to comment on the cardiovascular adverse events, saying he had not seen the ARCH data; nor did he explain the cardiovascular events that did occur in FRAME.
Romosozumab also is being reviewed in Canada and Japan; those processes are still underway. Mr. Fleming said the companies are preparing a European Medicines Agency application as well. “The preparation for the European regulatory submission will continue as planned – second half of 2017,” he said.
Dr. Geusens has received research support from Amgen and other pharmaceutical companies. He is a consultant for Amgen and a member of its speakers bureau.
[email protected]
On Twitter @Alz_gal
AT THE EULAR 2017 CONGRESS
Key clinical point:
Major finding: Compared with placebo, the antibody reduced the risk of a new-onset vertebral fracture by 73% over 1 year.
Data source: FRAME, which randomized 7,180 women to monthly injections of 210 mg romosozumab or placebo for 12 months; for an additional 12 months, those taking placebo switched to denosumab.
Disclosures: Amgen and UCB Pharma are codeveloping the drug. Dr. Geusens is a consultant and speaker for Amgen, and has received research from the company.
Brain amyloid may herald decline in cognitively normal seniors
Cognitively normal seniors with brain amyloid experienced accelerated cognitive decline over as few as 3-4 years, compared with those who had no brain amyloid at baseline.
At 4 years’ follow-up, prodromal Alzheimer’s disease (AD) had developed in 32% of amyloid-positive people and 15% of the amyloid-normal people – a 16.9% difference. Extrapolating the limited 10-year data they collected, the authors projected that after a decade, 88% of the amyloid-positive cohort would have progressed, compared with 29% of the amyloid-normal cohort.
“This suggests that elevated brain amyloid may indicate a presymptomatic stage of disease rather than a risk factor for disease,” wrote Dr. Donohue of the University of Southern California, San Diego. “AD is a gradually progressive disorder that can be identified at the asymptomatic phase using biomarkers of amyloid.”
The study is a project of the Alzheimer’s Disease Neuroimaging Initiative, an ongoing natural history study assessing the clinical, imaging, genetics, and biomarkers of aging, from normal aging to early and late mild cognitive impairment, dementia, or AD.
This particular substudy tracked the association of baseline amyloid-beta 42 (AB42) and cognition among 445 patients, 202 of whom had elevated brain amyloid as measured by cerebrospinal fluid or brain imaging with florbetapir. They were followed for a mean of 3 years, although a limited number of patients had up to 10 years’ worth of data.
The primary endpoints were score changes on four cognitive batteries: the Preclinical Alzheimer Cognitive Composite, the Mini-Mental State Examination; the Clinical Dementia Rating Scale Sum of Boxes, and the Logical Memory Delayed Recall.
At baseline, mean patient age was 74 years, although amyloid-positive patients were slightly older (74.7 years vs. 73.4 years). The mean educational attainment was 16.4 years. Slightly more patients in the amyloid-positive group reported subjective memory complaints (25% vs. 22%). Significantly more had at least one APOE-e4 allele of the apolipoprotein E gene (42% vs. 16%). All were cognitively normal as measured by the four tests. A fifth measure, the Alzheimer’s Disease Assessment Scale 13-item cognitive subscale, was also within normal limits for both groups, but that was not included in the follow-up analysis.
In addition to showing AB42 deposits in the brain and/or decreased AB42 in cerebrospinal fluid (indicating increased binding in the brain), amyloid-positive patients also had significantly different levels of tau. CSF total tau was 76.8 pg/mL in the amyloid-positive group, compared with 59.4 pg/mL in the amyloid-normal group. CSF phosphorylated tau also was elevated in the amyloid-positive group (38.1 pg/mL vs. 26.5 pg/mL). Increased CSF tau is an indicator of neuronal injury.
The mean follow-up time was 3.9 years. At last contact, only four patients had died; 36% were lost to follow-up. Significantly more in the amyloid-positive group had progressed to Alzheimer’s dementia (13 vs. 7). Twenty in the positive group and nine in the negative group had started an antidementia medication.
At 4 years, the amyloid-positive group had declined significantly from baseline on all four cognitive measures, performing significantly worse than the amyloid-negative group on each. The amyloid-negative group, conversely, had either stayed steady or experienced nonsignificant change on the tests.
“The [Preclinical Alzheimer Cognitive Composite] assessment captures performance on tasks of episodic memory, orientation, and executive function – the prominent domains of AD-related cognitive decline,” the authors wrote. “This finding strengthens the link between elevated amyloid and the primary manifestations of AD. Individuals with normal amyloid remain free of AD-pattern impairment for many years.
“The longitudinal curves demonstrated that those participants with elevated amyloid were more likely to develop early symptoms consistent with prodromal amyloid within 6 years,” the researchers added.
The study also tracked biomarker changes in AB42, tau, and ventricular and hippocampal volume. These markers changed in both groups – although in each case, the changes associated with amyloid positivity were more pronounced.
Nevertheless, the biomarker data offered a more complex picture. “Measures of CSF tau, phosphorylated tau, and AB42 showed marked differences between groups at baseline,” the investigators noted. “Longitudinal change … was similar across groups, suggesting that they are sensitive to elevated amyloid but do not reflect cognitive and clinical decline once amyloidosis is established. Brain atrophy, as reflected by enlargement of ventricular size, showed change in participants with elevated amyloid. This trend is consistent with brain atrophy with normal aging that is aggravated in the presence of amyloid.”
The finding that AB42 can identify patients on the path to cognitive decline suggests that the protein is more than a risk factor for AD – it is, rather, a marker of presymptomatic disease.
“AD is a gradually progressive disorder that can be identified at the asymptomatic phase using biomarkers of amyloid,” Dr. Donohue and his colleagues said. If that view is accepted, it would change the way potential therapeutics are viewed, from agents that reduce the risk of disease to agents that actively manage disease, even if given presymptomatically.
“This view is important in weighing therapeutic options from a regulatory perspective and for an individual,” the investigators noted. “Accurate characterization of the potential progression of earliest symptoms may inform discussion of the utility of screening people for amyloid abnormalities, with or without effective therapeutic options.”
The Alzheimer’s Disease Neuroimaging Initiative is funded by grants from the Alzheimer’s Association, the National Institutes of Health, and numerous pharmaceutical companies. Dr. Donohue reported financial relationships with Eli Lilly and Neurotrack.
[email protected]
On Twitter @Alz_gal
Despite a large, well-established body of evidence that cognitively normal older people can have brain amyloid without suffering memory loss, the protein does appear to be a harbinger of cognitive decline, Pieter Jelle Visser, MD, PhD, and Betty Tijms, PhD, said in an accompanying editorial (JAMA. 2017 Jun 13;317[22]:2285-7).
The natural history study of 445 elderly people showed consistent steady changes in cognition, as well as brain structure and function, over 4-10 years in those who were amyloid positive at baseline. This finding supports once again the idea that Alzheimer’s dementia is a slowly progressive disease with an extended preclinical phase but that amyloid and progression seem inextricably linked, wrote the two coauthors.
The study “provides further support for the hypothesis that amyloid pathology in cognitively normal individuals should be considered part of a progressive neurodegenerative disease. The results substantiate that amyloid aggregation in cognitively normal individuals is a harbinger of future cognitive decline,” which becomes evident only after extensive damage has occurred.
The work highlights Alzheimer’s long preclinical phase and may present a regulatory conundrum if any antiamyloid therapeutics are ever approved, Dr. Visser and Dr. Tijms said. Although the study demonstrates that amyloid pathology is most certainly not benign, many amyloid-positive elders never develop dementia, probably because they die of something else before becoming symptomatic. Thus, drugs that slow cognitive decline, effectively preventing dementia, may not be cost effective on a population basis.
“However, the other scenario of postponing treatment until an individual has developed cognitive impairments also has disadvantages, because at that stage, irreversible brain damage is so extensive that treatment becomes less effective,” Dr. Visser and Dr. Tijms noted. “This dilemma will require careful evaluation, because optimal patient management strategies will depend on the effectiveness, mechanism, cost, and adverse effects of treatment, as well as patient characteristics and preferences.”
Dr. Visser and Dr. Tijms are associated with the Alzheimer Center at the VU University Medical Center of Amsterdam. Dr. Visser reported financial relationships with Biogen, Eli Lilly, GE Healthcare, and Janssen.
Despite a large, well-established body of evidence that cognitively normal older people can have brain amyloid without suffering memory loss, the protein does appear to be a harbinger of cognitive decline, Pieter Jelle Visser, MD, PhD, and Betty Tijms, PhD, said in an accompanying editorial (JAMA. 2017 Jun 13;317[22]:2285-7).
The natural history study of 445 elderly people showed consistent steady changes in cognition, as well as brain structure and function, over 4-10 years in those who were amyloid positive at baseline. This finding supports once again the idea that Alzheimer’s dementia is a slowly progressive disease with an extended preclinical phase but that amyloid and progression seem inextricably linked, wrote the two coauthors.
The study “provides further support for the hypothesis that amyloid pathology in cognitively normal individuals should be considered part of a progressive neurodegenerative disease. The results substantiate that amyloid aggregation in cognitively normal individuals is a harbinger of future cognitive decline,” which becomes evident only after extensive damage has occurred.
The work highlights Alzheimer’s long preclinical phase and may present a regulatory conundrum if any antiamyloid therapeutics are ever approved, Dr. Visser and Dr. Tijms said. Although the study demonstrates that amyloid pathology is most certainly not benign, many amyloid-positive elders never develop dementia, probably because they die of something else before becoming symptomatic. Thus, drugs that slow cognitive decline, effectively preventing dementia, may not be cost effective on a population basis.
“However, the other scenario of postponing treatment until an individual has developed cognitive impairments also has disadvantages, because at that stage, irreversible brain damage is so extensive that treatment becomes less effective,” Dr. Visser and Dr. Tijms noted. “This dilemma will require careful evaluation, because optimal patient management strategies will depend on the effectiveness, mechanism, cost, and adverse effects of treatment, as well as patient characteristics and preferences.”
Dr. Visser and Dr. Tijms are associated with the Alzheimer Center at the VU University Medical Center of Amsterdam. Dr. Visser reported financial relationships with Biogen, Eli Lilly, GE Healthcare, and Janssen.
Despite a large, well-established body of evidence that cognitively normal older people can have brain amyloid without suffering memory loss, the protein does appear to be a harbinger of cognitive decline, Pieter Jelle Visser, MD, PhD, and Betty Tijms, PhD, said in an accompanying editorial (JAMA. 2017 Jun 13;317[22]:2285-7).
The natural history study of 445 elderly people showed consistent steady changes in cognition, as well as brain structure and function, over 4-10 years in those who were amyloid positive at baseline. This finding supports once again the idea that Alzheimer’s dementia is a slowly progressive disease with an extended preclinical phase but that amyloid and progression seem inextricably linked, wrote the two coauthors.
The study “provides further support for the hypothesis that amyloid pathology in cognitively normal individuals should be considered part of a progressive neurodegenerative disease. The results substantiate that amyloid aggregation in cognitively normal individuals is a harbinger of future cognitive decline,” which becomes evident only after extensive damage has occurred.
The work highlights Alzheimer’s long preclinical phase and may present a regulatory conundrum if any antiamyloid therapeutics are ever approved, Dr. Visser and Dr. Tijms said. Although the study demonstrates that amyloid pathology is most certainly not benign, many amyloid-positive elders never develop dementia, probably because they die of something else before becoming symptomatic. Thus, drugs that slow cognitive decline, effectively preventing dementia, may not be cost effective on a population basis.
“However, the other scenario of postponing treatment until an individual has developed cognitive impairments also has disadvantages, because at that stage, irreversible brain damage is so extensive that treatment becomes less effective,” Dr. Visser and Dr. Tijms noted. “This dilemma will require careful evaluation, because optimal patient management strategies will depend on the effectiveness, mechanism, cost, and adverse effects of treatment, as well as patient characteristics and preferences.”
Dr. Visser and Dr. Tijms are associated with the Alzheimer Center at the VU University Medical Center of Amsterdam. Dr. Visser reported financial relationships with Biogen, Eli Lilly, GE Healthcare, and Janssen.
Cognitively normal seniors with brain amyloid experienced accelerated cognitive decline over as few as 3-4 years, compared with those who had no brain amyloid at baseline.
At 4 years’ follow-up, prodromal Alzheimer’s disease (AD) had developed in 32% of amyloid-positive people and 15% of the amyloid-normal people – a 16.9% difference. Extrapolating the limited 10-year data they collected, the authors projected that after a decade, 88% of the amyloid-positive cohort would have progressed, compared with 29% of the amyloid-normal cohort.
“This suggests that elevated brain amyloid may indicate a presymptomatic stage of disease rather than a risk factor for disease,” wrote Dr. Donohue of the University of Southern California, San Diego. “AD is a gradually progressive disorder that can be identified at the asymptomatic phase using biomarkers of amyloid.”
The study is a project of the Alzheimer’s Disease Neuroimaging Initiative, an ongoing natural history study assessing the clinical, imaging, genetics, and biomarkers of aging, from normal aging to early and late mild cognitive impairment, dementia, or AD.
This particular substudy tracked the association of baseline amyloid-beta 42 (AB42) and cognition among 445 patients, 202 of whom had elevated brain amyloid as measured by cerebrospinal fluid or brain imaging with florbetapir. They were followed for a mean of 3 years, although a limited number of patients had up to 10 years’ worth of data.
The primary endpoints were score changes on four cognitive batteries: the Preclinical Alzheimer Cognitive Composite, the Mini-Mental State Examination; the Clinical Dementia Rating Scale Sum of Boxes, and the Logical Memory Delayed Recall.
At baseline, mean patient age was 74 years, although amyloid-positive patients were slightly older (74.7 years vs. 73.4 years). The mean educational attainment was 16.4 years. Slightly more patients in the amyloid-positive group reported subjective memory complaints (25% vs. 22%). Significantly more had at least one APOE-e4 allele of the apolipoprotein E gene (42% vs. 16%). All were cognitively normal as measured by the four tests. A fifth measure, the Alzheimer’s Disease Assessment Scale 13-item cognitive subscale, was also within normal limits for both groups, but that was not included in the follow-up analysis.
In addition to showing AB42 deposits in the brain and/or decreased AB42 in cerebrospinal fluid (indicating increased binding in the brain), amyloid-positive patients also had significantly different levels of tau. CSF total tau was 76.8 pg/mL in the amyloid-positive group, compared with 59.4 pg/mL in the amyloid-normal group. CSF phosphorylated tau also was elevated in the amyloid-positive group (38.1 pg/mL vs. 26.5 pg/mL). Increased CSF tau is an indicator of neuronal injury.
The mean follow-up time was 3.9 years. At last contact, only four patients had died; 36% were lost to follow-up. Significantly more in the amyloid-positive group had progressed to Alzheimer’s dementia (13 vs. 7). Twenty in the positive group and nine in the negative group had started an antidementia medication.
At 4 years, the amyloid-positive group had declined significantly from baseline on all four cognitive measures, performing significantly worse than the amyloid-negative group on each. The amyloid-negative group, conversely, had either stayed steady or experienced nonsignificant change on the tests.
“The [Preclinical Alzheimer Cognitive Composite] assessment captures performance on tasks of episodic memory, orientation, and executive function – the prominent domains of AD-related cognitive decline,” the authors wrote. “This finding strengthens the link between elevated amyloid and the primary manifestations of AD. Individuals with normal amyloid remain free of AD-pattern impairment for many years.
“The longitudinal curves demonstrated that those participants with elevated amyloid were more likely to develop early symptoms consistent with prodromal amyloid within 6 years,” the researchers added.
The study also tracked biomarker changes in AB42, tau, and ventricular and hippocampal volume. These markers changed in both groups – although in each case, the changes associated with amyloid positivity were more pronounced.
Nevertheless, the biomarker data offered a more complex picture. “Measures of CSF tau, phosphorylated tau, and AB42 showed marked differences between groups at baseline,” the investigators noted. “Longitudinal change … was similar across groups, suggesting that they are sensitive to elevated amyloid but do not reflect cognitive and clinical decline once amyloidosis is established. Brain atrophy, as reflected by enlargement of ventricular size, showed change in participants with elevated amyloid. This trend is consistent with brain atrophy with normal aging that is aggravated in the presence of amyloid.”
The finding that AB42 can identify patients on the path to cognitive decline suggests that the protein is more than a risk factor for AD – it is, rather, a marker of presymptomatic disease.
“AD is a gradually progressive disorder that can be identified at the asymptomatic phase using biomarkers of amyloid,” Dr. Donohue and his colleagues said. If that view is accepted, it would change the way potential therapeutics are viewed, from agents that reduce the risk of disease to agents that actively manage disease, even if given presymptomatically.
“This view is important in weighing therapeutic options from a regulatory perspective and for an individual,” the investigators noted. “Accurate characterization of the potential progression of earliest symptoms may inform discussion of the utility of screening people for amyloid abnormalities, with or without effective therapeutic options.”
The Alzheimer’s Disease Neuroimaging Initiative is funded by grants from the Alzheimer’s Association, the National Institutes of Health, and numerous pharmaceutical companies. Dr. Donohue reported financial relationships with Eli Lilly and Neurotrack.
[email protected]
On Twitter @Alz_gal
Cognitively normal seniors with brain amyloid experienced accelerated cognitive decline over as few as 3-4 years, compared with those who had no brain amyloid at baseline.
At 4 years’ follow-up, prodromal Alzheimer’s disease (AD) had developed in 32% of amyloid-positive people and 15% of the amyloid-normal people – a 16.9% difference. Extrapolating the limited 10-year data they collected, the authors projected that after a decade, 88% of the amyloid-positive cohort would have progressed, compared with 29% of the amyloid-normal cohort.
“This suggests that elevated brain amyloid may indicate a presymptomatic stage of disease rather than a risk factor for disease,” wrote Dr. Donohue of the University of Southern California, San Diego. “AD is a gradually progressive disorder that can be identified at the asymptomatic phase using biomarkers of amyloid.”
The study is a project of the Alzheimer’s Disease Neuroimaging Initiative, an ongoing natural history study assessing the clinical, imaging, genetics, and biomarkers of aging, from normal aging to early and late mild cognitive impairment, dementia, or AD.
This particular substudy tracked the association of baseline amyloid-beta 42 (AB42) and cognition among 445 patients, 202 of whom had elevated brain amyloid as measured by cerebrospinal fluid or brain imaging with florbetapir. They were followed for a mean of 3 years, although a limited number of patients had up to 10 years’ worth of data.
The primary endpoints were score changes on four cognitive batteries: the Preclinical Alzheimer Cognitive Composite, the Mini-Mental State Examination; the Clinical Dementia Rating Scale Sum of Boxes, and the Logical Memory Delayed Recall.
At baseline, mean patient age was 74 years, although amyloid-positive patients were slightly older (74.7 years vs. 73.4 years). The mean educational attainment was 16.4 years. Slightly more patients in the amyloid-positive group reported subjective memory complaints (25% vs. 22%). Significantly more had at least one APOE-e4 allele of the apolipoprotein E gene (42% vs. 16%). All were cognitively normal as measured by the four tests. A fifth measure, the Alzheimer’s Disease Assessment Scale 13-item cognitive subscale, was also within normal limits for both groups, but that was not included in the follow-up analysis.
In addition to showing AB42 deposits in the brain and/or decreased AB42 in cerebrospinal fluid (indicating increased binding in the brain), amyloid-positive patients also had significantly different levels of tau. CSF total tau was 76.8 pg/mL in the amyloid-positive group, compared with 59.4 pg/mL in the amyloid-normal group. CSF phosphorylated tau also was elevated in the amyloid-positive group (38.1 pg/mL vs. 26.5 pg/mL). Increased CSF tau is an indicator of neuronal injury.
The mean follow-up time was 3.9 years. At last contact, only four patients had died; 36% were lost to follow-up. Significantly more in the amyloid-positive group had progressed to Alzheimer’s dementia (13 vs. 7). Twenty in the positive group and nine in the negative group had started an antidementia medication.
At 4 years, the amyloid-positive group had declined significantly from baseline on all four cognitive measures, performing significantly worse than the amyloid-negative group on each. The amyloid-negative group, conversely, had either stayed steady or experienced nonsignificant change on the tests.
“The [Preclinical Alzheimer Cognitive Composite] assessment captures performance on tasks of episodic memory, orientation, and executive function – the prominent domains of AD-related cognitive decline,” the authors wrote. “This finding strengthens the link between elevated amyloid and the primary manifestations of AD. Individuals with normal amyloid remain free of AD-pattern impairment for many years.
“The longitudinal curves demonstrated that those participants with elevated amyloid were more likely to develop early symptoms consistent with prodromal amyloid within 6 years,” the researchers added.
The study also tracked biomarker changes in AB42, tau, and ventricular and hippocampal volume. These markers changed in both groups – although in each case, the changes associated with amyloid positivity were more pronounced.
Nevertheless, the biomarker data offered a more complex picture. “Measures of CSF tau, phosphorylated tau, and AB42 showed marked differences between groups at baseline,” the investigators noted. “Longitudinal change … was similar across groups, suggesting that they are sensitive to elevated amyloid but do not reflect cognitive and clinical decline once amyloidosis is established. Brain atrophy, as reflected by enlargement of ventricular size, showed change in participants with elevated amyloid. This trend is consistent with brain atrophy with normal aging that is aggravated in the presence of amyloid.”
The finding that AB42 can identify patients on the path to cognitive decline suggests that the protein is more than a risk factor for AD – it is, rather, a marker of presymptomatic disease.
“AD is a gradually progressive disorder that can be identified at the asymptomatic phase using biomarkers of amyloid,” Dr. Donohue and his colleagues said. If that view is accepted, it would change the way potential therapeutics are viewed, from agents that reduce the risk of disease to agents that actively manage disease, even if given presymptomatically.
“This view is important in weighing therapeutic options from a regulatory perspective and for an individual,” the investigators noted. “Accurate characterization of the potential progression of earliest symptoms may inform discussion of the utility of screening people for amyloid abnormalities, with or without effective therapeutic options.”
The Alzheimer’s Disease Neuroimaging Initiative is funded by grants from the Alzheimer’s Association, the National Institutes of Health, and numerous pharmaceutical companies. Dr. Donohue reported financial relationships with Eli Lilly and Neurotrack.
[email protected]
On Twitter @Alz_gal
FROM JAMA
Key clinical point:
Major finding: Over 4 years, when compared with seniors without amyloid, amyloid-positive seniors performed significantly worse on four cognitive tests and experienced larger declines in brain volume.
Data source: The study followed 445 cognitively normal older people, mean age 74 years, for a mean of 4 years.
Disclosures: The Alzheimer’s Disease Neuroimaging Initiative is funded by grants from the Alzheimer’s Association, the National Institutes of Health, and numerous pharmaceutical companies. Dr. Donahue reported financial relationships with Eli Lilly and Neurotrack.
IL-23 antibody risankizumab can effect, maintain remission in Crohn’s
CHICAGO – Subcutaneous risankizumab maintained clinical remission for half a year in 76% of Crohn’s disease patients who responded to it during an induction study.
The interleukin-23 antibody (ABBV-066; AbbVie) also maintained endoscopic remission in 52% of patients who entered the open-label maintenance phase of the 52-week study, Brian Feagan, MD, said at the annual Digestive Disease Week®.
The three-phase study enrolled 121 patients with moderate to severe Crohn’s disease. The first 12 weeks consisted of intravenous induction therapy; patients were randomized to monthly infusions of risankizumab 200 mg or 600 mg or placebo. The endpoint was deep clinical remission. Patients who achieved remission exited the study. Results of this study were published in April (Lancet.2017;389[10080]:1699-09).
Phase II included only the patients who did not achieve deep clinical remission. They all received open label 600 mg risankizumab infusions every 4 weeks from weeks 14-26. The endpoints were clinical and endoscopic remission.
Phase III, on which Dr. Feagan reported, included the patients who achieved remission in phase II. These patients continued with subcutaneous risankizumab 180 mg every 8 weeks, from week 26-52.
Patients were an average of about 38 years old, with mean disease duration of 16 years. Their median Crohn’s Disease Activity Index (CDAI) score was around 300; their mean Crohn’s Disease Endoscopic Index score was 12. About a quarter had already taken at least one tumor necrosis factor–alpha inhibitor; half of those had taken at least two of those drugs.
At the end of the first induction period, 25 taking the study drug and 6 taking placebo achieved clinical remission (31% vs. 15%). Those taking 600 mg did better than those taking 200 mg (37% vs. 9%).
Patients who didn’t achieve deep clinical remission (a CDAI of less than 150 plus endoscopic remission) entered into the open-label reinduction phase; all received monthly 600-mg infusions from weeks 14 to 26. Of these, 62 achieved clinical remission and entered the open-label maintenance phase.
By week 52, the majority of patients were still in clinical remission, although this varied by the original treatment group: 76% of those first randomized to 600 mg, 59% of those randomized to 200 mg, and 79% of those randomized to placebo. Endoscopic remission was maintained in 52% of the 600-mg group, 23% of the 200-mg group, and 32% of the placebo group.
Deep remission occurred in a subset of patients: 43% of the 600-mg group, 13.6% of the 200-mg group, and 31.6% of the placebo group.
Dr. Feagan also said C-reactive protein levels remained suppressed in the maintenance period. Patients who entered that period had experienced a mean drop of about 9 mg/L in CRP. By week 52, this had risen slightly, but the median decrease was still around 8 mg/L from baseline measures.
There were 11 drug-related adverse events; these were severe in five patients, causing two to withdraw. There were 22 infections during the study, one of which was serious, but no cases of tuberculosis, cancer, or fungal or opportunistic infections.
“We did not see any new or unexpected safety signals,” Dr. Feagan said. “The drug was well tolerated and appears safe.”
This study showed a superior response for the 600-mg induction dose, but Dr. Feagan said the company may explore higher doses before making a final determination. Last November, the Food and Drug Administration granted Orphan Drug Designation to risankizumab for the investigational treatment of Crohn’s disease in pediatric patients. The company is also investigating it in psoriasis; it recently outperformed ustekinumab in a small phase II study of patients with moderate to severe psoriasis.
The study was funded by Boehringer Ingelheim. Dr. Feagan reported financial relationships with AbbVie and Boehringer Ingelheim.
[email protected]
On Twitter @alz_gal
CHICAGO – Subcutaneous risankizumab maintained clinical remission for half a year in 76% of Crohn’s disease patients who responded to it during an induction study.
The interleukin-23 antibody (ABBV-066; AbbVie) also maintained endoscopic remission in 52% of patients who entered the open-label maintenance phase of the 52-week study, Brian Feagan, MD, said at the annual Digestive Disease Week®.
The three-phase study enrolled 121 patients with moderate to severe Crohn’s disease. The first 12 weeks consisted of intravenous induction therapy; patients were randomized to monthly infusions of risankizumab 200 mg or 600 mg or placebo. The endpoint was deep clinical remission. Patients who achieved remission exited the study. Results of this study were published in April (Lancet.2017;389[10080]:1699-09).
Phase II included only the patients who did not achieve deep clinical remission. They all received open label 600 mg risankizumab infusions every 4 weeks from weeks 14-26. The endpoints were clinical and endoscopic remission.
Phase III, on which Dr. Feagan reported, included the patients who achieved remission in phase II. These patients continued with subcutaneous risankizumab 180 mg every 8 weeks, from week 26-52.
Patients were an average of about 38 years old, with mean disease duration of 16 years. Their median Crohn’s Disease Activity Index (CDAI) score was around 300; their mean Crohn’s Disease Endoscopic Index score was 12. About a quarter had already taken at least one tumor necrosis factor–alpha inhibitor; half of those had taken at least two of those drugs.
At the end of the first induction period, 25 taking the study drug and 6 taking placebo achieved clinical remission (31% vs. 15%). Those taking 600 mg did better than those taking 200 mg (37% vs. 9%).
Patients who didn’t achieve deep clinical remission (a CDAI of less than 150 plus endoscopic remission) entered into the open-label reinduction phase; all received monthly 600-mg infusions from weeks 14 to 26. Of these, 62 achieved clinical remission and entered the open-label maintenance phase.
By week 52, the majority of patients were still in clinical remission, although this varied by the original treatment group: 76% of those first randomized to 600 mg, 59% of those randomized to 200 mg, and 79% of those randomized to placebo. Endoscopic remission was maintained in 52% of the 600-mg group, 23% of the 200-mg group, and 32% of the placebo group.
Deep remission occurred in a subset of patients: 43% of the 600-mg group, 13.6% of the 200-mg group, and 31.6% of the placebo group.
Dr. Feagan also said C-reactive protein levels remained suppressed in the maintenance period. Patients who entered that period had experienced a mean drop of about 9 mg/L in CRP. By week 52, this had risen slightly, but the median decrease was still around 8 mg/L from baseline measures.
There were 11 drug-related adverse events; these were severe in five patients, causing two to withdraw. There were 22 infections during the study, one of which was serious, but no cases of tuberculosis, cancer, or fungal or opportunistic infections.
“We did not see any new or unexpected safety signals,” Dr. Feagan said. “The drug was well tolerated and appears safe.”
This study showed a superior response for the 600-mg induction dose, but Dr. Feagan said the company may explore higher doses before making a final determination. Last November, the Food and Drug Administration granted Orphan Drug Designation to risankizumab for the investigational treatment of Crohn’s disease in pediatric patients. The company is also investigating it in psoriasis; it recently outperformed ustekinumab in a small phase II study of patients with moderate to severe psoriasis.
The study was funded by Boehringer Ingelheim. Dr. Feagan reported financial relationships with AbbVie and Boehringer Ingelheim.
[email protected]
On Twitter @alz_gal
CHICAGO – Subcutaneous risankizumab maintained clinical remission for half a year in 76% of Crohn’s disease patients who responded to it during an induction study.
The interleukin-23 antibody (ABBV-066; AbbVie) also maintained endoscopic remission in 52% of patients who entered the open-label maintenance phase of the 52-week study, Brian Feagan, MD, said at the annual Digestive Disease Week®.
The three-phase study enrolled 121 patients with moderate to severe Crohn’s disease. The first 12 weeks consisted of intravenous induction therapy; patients were randomized to monthly infusions of risankizumab 200 mg or 600 mg or placebo. The endpoint was deep clinical remission. Patients who achieved remission exited the study. Results of this study were published in April (Lancet.2017;389[10080]:1699-09).
Phase II included only the patients who did not achieve deep clinical remission. They all received open label 600 mg risankizumab infusions every 4 weeks from weeks 14-26. The endpoints were clinical and endoscopic remission.
Phase III, on which Dr. Feagan reported, included the patients who achieved remission in phase II. These patients continued with subcutaneous risankizumab 180 mg every 8 weeks, from week 26-52.
Patients were an average of about 38 years old, with mean disease duration of 16 years. Their median Crohn’s Disease Activity Index (CDAI) score was around 300; their mean Crohn’s Disease Endoscopic Index score was 12. About a quarter had already taken at least one tumor necrosis factor–alpha inhibitor; half of those had taken at least two of those drugs.
At the end of the first induction period, 25 taking the study drug and 6 taking placebo achieved clinical remission (31% vs. 15%). Those taking 600 mg did better than those taking 200 mg (37% vs. 9%).
Patients who didn’t achieve deep clinical remission (a CDAI of less than 150 plus endoscopic remission) entered into the open-label reinduction phase; all received monthly 600-mg infusions from weeks 14 to 26. Of these, 62 achieved clinical remission and entered the open-label maintenance phase.
By week 52, the majority of patients were still in clinical remission, although this varied by the original treatment group: 76% of those first randomized to 600 mg, 59% of those randomized to 200 mg, and 79% of those randomized to placebo. Endoscopic remission was maintained in 52% of the 600-mg group, 23% of the 200-mg group, and 32% of the placebo group.
Deep remission occurred in a subset of patients: 43% of the 600-mg group, 13.6% of the 200-mg group, and 31.6% of the placebo group.
Dr. Feagan also said C-reactive protein levels remained suppressed in the maintenance period. Patients who entered that period had experienced a mean drop of about 9 mg/L in CRP. By week 52, this had risen slightly, but the median decrease was still around 8 mg/L from baseline measures.
There were 11 drug-related adverse events; these were severe in five patients, causing two to withdraw. There were 22 infections during the study, one of which was serious, but no cases of tuberculosis, cancer, or fungal or opportunistic infections.
“We did not see any new or unexpected safety signals,” Dr. Feagan said. “The drug was well tolerated and appears safe.”
This study showed a superior response for the 600-mg induction dose, but Dr. Feagan said the company may explore higher doses before making a final determination. Last November, the Food and Drug Administration granted Orphan Drug Designation to risankizumab for the investigational treatment of Crohn’s disease in pediatric patients. The company is also investigating it in psoriasis; it recently outperformed ustekinumab in a small phase II study of patients with moderate to severe psoriasis.
The study was funded by Boehringer Ingelheim. Dr. Feagan reported financial relationships with AbbVie and Boehringer Ingelheim.
[email protected]
On Twitter @alz_gal
AT DDW
Key clinical point:
Major finding: By week 52, clinical remission was maintained in 76% of those first randomized to 600 mg, 59% of those randomized to 200 mg, and 79% of those randomized to placebo.
Disclosures: Dr. Feagan reported financial relationships with Boehringer Ingelheim and AbbVie.
When fecal transplants for C. diff. fail, try, try again
CHICAGO – The best remedy for a failed fecal microbiota transplant for recurrent Clostridium difficile infection is most likely a second – or even a third or fourth attempt, according to Monika Fischer, MD.
Fecal microbiota transplants (FMTs) cure the large majority of those with recurrent C. difficile. But for those who don’t respond or who have an early recurrence, repeating the procedure will almost always effect cure, she said at the annual Digestive Disease Week.
“My recommendation would be to repeat FMT once you make sure the diagnosis actually is recurrent C. difficile,” said Dr. Fischer of Indiana University, Indianapolis. “There are sufficient data showing that the success rate after two FMTs significantly increases independent of the delivery route. But the effectiveness rate is highest when FMT is delivered via colonoscopy, so I recommend the second FMT be delivered that way.”
Recurrent failures can also be a sign that something else is amiss clinically, she said. So before proceeding with multiple procedures, some detective work may be in order. It’s best to start with confirmatory testing for the organism, she said.
“We have seen that about 25% of patients referred for FMT don’t actually have C. difficile at all,” Dr. Fischer said. “Be thinking about an alternative diagnosis when the stool tests negative, but the patient is still symptomatic, or if, before the FMT, there was less than a 50% improvement with vancomycin or fidaxomicin therapy.”
“When evaluating a patient for FMT failure, it should be confirmed by stool testing, preferably by toxin testing. Recent studies suggest that PCR [polymerase chain reaction]–positive but toxin-negative patients may be colonized with C. difficile but that an alternative pathology is driving the symptoms. Toxin-negative patients’ outcome is similar with or without treatment, and it is very rare that toxin-negative patients develop CDI [C. difficile infection]–related complications.”
For these patients, the problem could be any of the conditions that cause chronic diarrhea: inflammatory bowel disease, irritable bowel syndrome, celiac disease, microscopic colitis, bile salt malabsorption, chronic pancreatitis, or some other kind of infection. If C. difficile is the confirmed etiology, repeated FMTs are the way to go, Dr. Fischer said.
However, it may be worth mixing up the delivery method. The ever-expanding data on FMT continue to show that colonoscopy delivery has the lowest failure rate – about 10%. Enema is the least successful, with a 40% failure rate. In between those are nasoduodenal tube delivery, which is associated with a 20% failure rate, and oral capsules, with a failure rate varying from 12% to 30%. Fresh stool is also more effective than frozen, which, in turn, is more effective than the lyophilized preparation, Dr. Fischer said.
“Options are to repeat FMT via colonoscopy, but for patients who have had several failures, consider using the upper and lower route at the same time, and give fresh stool, especially if the first transplants used frozen.”
Although the efficacy of FMT doesn’t appear to depend on donor characteristics, patient characteristics do seem to play a role. Dr. Fischer and her colleagues have created an assessment tool to predict who may be at risk for failure. The model was developed in a 300-patient FMT cohort at two centers and validated in a third academic center FMT population. Of 24 clinical variables, three were incorporated into the failure risk model: severe disease (odds ratio, 6), inpatient status (OR, 3.8), and the number of prior C. difficile–related hospitalizations (OR, 1.4 for each one). For severe disease, patients got 5 points on the scale; for inpatient status, 4 points; and for each prior hospitalization, 1 point.
“Patients in the low-risk category [0] had up to 5% chance of failing. Patients with intermediate risk [1-2] had a 15% chance of failing, and patients in the high-risk category [3 or more points] had higher than 35% chance of not responding to single FMT,” Dr. Fischer said.
She also examined this tool in an extended cohort of nearly 500 patients at four additional sites; about 5% had failed more than two FMTs. “We identified two additional risk factors for failing multiple transplants,” Dr. Fischer said. “These were immunocompromised state, which increased the risk by 4 times, and male gender, which increased the risk by 2.5 times.”
She offered some options for the rare patient who has failed repeat FMTs and doesn’t want to try again. “There are some alternative or adjunctive therapies to repeat FMTs that may be considered, in lieu of repeating FMT for the third or fourth time or even following the first FMT failure, if dictated by patient preference. We sometimes offer these for elderly or frail patients or those with a limited life expectancy. These therapy options are from small, nonrandomized trials in multiply recurrent C. difficile infections but have not been vetted in the FMT nonresponder population.”
These include a vancomycin taper, or a vancomycin taper followed by fidaxomicin. Another option, albeit with limited applicability, is suppressive low-dose vancomycin 125 mg given every day, every other day, or every third day, indefinitely. “This can be especially good for elderly, frail patients with limited life expectancy, needing ongoing antibiotic therapy for urinary tract infections,” she said.
Finally, an 8-week vancomycin taper with daily kefir ingestion has been helpful for some patients. Although probiotics have never been proven helpful in C. difficile infections or FMT success, kefir is a different sort of supplement, she said.
“Kefir is different from yogurt. It contains bacteriocins like nisin, a protein with antibacterial properties produced by Lactococcus lactis.”
[email protected]
On Twitter @alz_gal
CHICAGO – The best remedy for a failed fecal microbiota transplant for recurrent Clostridium difficile infection is most likely a second – or even a third or fourth attempt, according to Monika Fischer, MD.
Fecal microbiota transplants (FMTs) cure the large majority of those with recurrent C. difficile. But for those who don’t respond or who have an early recurrence, repeating the procedure will almost always effect cure, she said at the annual Digestive Disease Week.
“My recommendation would be to repeat FMT once you make sure the diagnosis actually is recurrent C. difficile,” said Dr. Fischer of Indiana University, Indianapolis. “There are sufficient data showing that the success rate after two FMTs significantly increases independent of the delivery route. But the effectiveness rate is highest when FMT is delivered via colonoscopy, so I recommend the second FMT be delivered that way.”
Recurrent failures can also be a sign that something else is amiss clinically, she said. So before proceeding with multiple procedures, some detective work may be in order. It’s best to start with confirmatory testing for the organism, she said.
“We have seen that about 25% of patients referred for FMT don’t actually have C. difficile at all,” Dr. Fischer said. “Be thinking about an alternative diagnosis when the stool tests negative, but the patient is still symptomatic, or if, before the FMT, there was less than a 50% improvement with vancomycin or fidaxomicin therapy.”
“When evaluating a patient for FMT failure, it should be confirmed by stool testing, preferably by toxin testing. Recent studies suggest that PCR [polymerase chain reaction]–positive but toxin-negative patients may be colonized with C. difficile but that an alternative pathology is driving the symptoms. Toxin-negative patients’ outcome is similar with or without treatment, and it is very rare that toxin-negative patients develop CDI [C. difficile infection]–related complications.”
For these patients, the problem could be any of the conditions that cause chronic diarrhea: inflammatory bowel disease, irritable bowel syndrome, celiac disease, microscopic colitis, bile salt malabsorption, chronic pancreatitis, or some other kind of infection. If C. difficile is the confirmed etiology, repeated FMTs are the way to go, Dr. Fischer said.
However, it may be worth mixing up the delivery method. The ever-expanding data on FMT continue to show that colonoscopy delivery has the lowest failure rate – about 10%. Enema is the least successful, with a 40% failure rate. In between those are nasoduodenal tube delivery, which is associated with a 20% failure rate, and oral capsules, with a failure rate varying from 12% to 30%. Fresh stool is also more effective than frozen, which, in turn, is more effective than the lyophilized preparation, Dr. Fischer said.
“Options are to repeat FMT via colonoscopy, but for patients who have had several failures, consider using the upper and lower route at the same time, and give fresh stool, especially if the first transplants used frozen.”
Although the efficacy of FMT doesn’t appear to depend on donor characteristics, patient characteristics do seem to play a role. Dr. Fischer and her colleagues have created an assessment tool to predict who may be at risk for failure. The model was developed in a 300-patient FMT cohort at two centers and validated in a third academic center FMT population. Of 24 clinical variables, three were incorporated into the failure risk model: severe disease (odds ratio, 6), inpatient status (OR, 3.8), and the number of prior C. difficile–related hospitalizations (OR, 1.4 for each one). For severe disease, patients got 5 points on the scale; for inpatient status, 4 points; and for each prior hospitalization, 1 point.
“Patients in the low-risk category [0] had up to 5% chance of failing. Patients with intermediate risk [1-2] had a 15% chance of failing, and patients in the high-risk category [3 or more points] had higher than 35% chance of not responding to single FMT,” Dr. Fischer said.
She also examined this tool in an extended cohort of nearly 500 patients at four additional sites; about 5% had failed more than two FMTs. “We identified two additional risk factors for failing multiple transplants,” Dr. Fischer said. “These were immunocompromised state, which increased the risk by 4 times, and male gender, which increased the risk by 2.5 times.”
She offered some options for the rare patient who has failed repeat FMTs and doesn’t want to try again. “There are some alternative or adjunctive therapies to repeat FMTs that may be considered, in lieu of repeating FMT for the third or fourth time or even following the first FMT failure, if dictated by patient preference. We sometimes offer these for elderly or frail patients or those with a limited life expectancy. These therapy options are from small, nonrandomized trials in multiply recurrent C. difficile infections but have not been vetted in the FMT nonresponder population.”
These include a vancomycin taper, or a vancomycin taper followed by fidaxomicin. Another option, albeit with limited applicability, is suppressive low-dose vancomycin 125 mg given every day, every other day, or every third day, indefinitely. “This can be especially good for elderly, frail patients with limited life expectancy, needing ongoing antibiotic therapy for urinary tract infections,” she said.
Finally, an 8-week vancomycin taper with daily kefir ingestion has been helpful for some patients. Although probiotics have never been proven helpful in C. difficile infections or FMT success, kefir is a different sort of supplement, she said.
“Kefir is different from yogurt. It contains bacteriocins like nisin, a protein with antibacterial properties produced by Lactococcus lactis.”
[email protected]
On Twitter @alz_gal
CHICAGO – The best remedy for a failed fecal microbiota transplant for recurrent Clostridium difficile infection is most likely a second – or even a third or fourth attempt, according to Monika Fischer, MD.
Fecal microbiota transplants (FMTs) cure the large majority of those with recurrent C. difficile. But for those who don’t respond or who have an early recurrence, repeating the procedure will almost always effect cure, she said at the annual Digestive Disease Week.
“My recommendation would be to repeat FMT once you make sure the diagnosis actually is recurrent C. difficile,” said Dr. Fischer of Indiana University, Indianapolis. “There are sufficient data showing that the success rate after two FMTs significantly increases independent of the delivery route. But the effectiveness rate is highest when FMT is delivered via colonoscopy, so I recommend the second FMT be delivered that way.”
Recurrent failures can also be a sign that something else is amiss clinically, she said. So before proceeding with multiple procedures, some detective work may be in order. It’s best to start with confirmatory testing for the organism, she said.
“We have seen that about 25% of patients referred for FMT don’t actually have C. difficile at all,” Dr. Fischer said. “Be thinking about an alternative diagnosis when the stool tests negative, but the patient is still symptomatic, or if, before the FMT, there was less than a 50% improvement with vancomycin or fidaxomicin therapy.”
“When evaluating a patient for FMT failure, it should be confirmed by stool testing, preferably by toxin testing. Recent studies suggest that PCR [polymerase chain reaction]–positive but toxin-negative patients may be colonized with C. difficile but that an alternative pathology is driving the symptoms. Toxin-negative patients’ outcome is similar with or without treatment, and it is very rare that toxin-negative patients develop CDI [C. difficile infection]–related complications.”
For these patients, the problem could be any of the conditions that cause chronic diarrhea: inflammatory bowel disease, irritable bowel syndrome, celiac disease, microscopic colitis, bile salt malabsorption, chronic pancreatitis, or some other kind of infection. If C. difficile is the confirmed etiology, repeated FMTs are the way to go, Dr. Fischer said.
However, it may be worth mixing up the delivery method. The ever-expanding data on FMT continue to show that colonoscopy delivery has the lowest failure rate – about 10%. Enema is the least successful, with a 40% failure rate. In between those are nasoduodenal tube delivery, which is associated with a 20% failure rate, and oral capsules, with a failure rate varying from 12% to 30%. Fresh stool is also more effective than frozen, which, in turn, is more effective than the lyophilized preparation, Dr. Fischer said.
“Options are to repeat FMT via colonoscopy, but for patients who have had several failures, consider using the upper and lower route at the same time, and give fresh stool, especially if the first transplants used frozen.”
Although the efficacy of FMT doesn’t appear to depend on donor characteristics, patient characteristics do seem to play a role. Dr. Fischer and her colleagues have created an assessment tool to predict who may be at risk for failure. The model was developed in a 300-patient FMT cohort at two centers and validated in a third academic center FMT population. Of 24 clinical variables, three were incorporated into the failure risk model: severe disease (odds ratio, 6), inpatient status (OR, 3.8), and the number of prior C. difficile–related hospitalizations (OR, 1.4 for each one). For severe disease, patients got 5 points on the scale; for inpatient status, 4 points; and for each prior hospitalization, 1 point.
“Patients in the low-risk category [0] had up to 5% chance of failing. Patients with intermediate risk [1-2] had a 15% chance of failing, and patients in the high-risk category [3 or more points] had higher than 35% chance of not responding to single FMT,” Dr. Fischer said.
She also examined this tool in an extended cohort of nearly 500 patients at four additional sites; about 5% had failed more than two FMTs. “We identified two additional risk factors for failing multiple transplants,” Dr. Fischer said. “These were immunocompromised state, which increased the risk by 4 times, and male gender, which increased the risk by 2.5 times.”
She offered some options for the rare patient who has failed repeat FMTs and doesn’t want to try again. “There are some alternative or adjunctive therapies to repeat FMTs that may be considered, in lieu of repeating FMT for the third or fourth time or even following the first FMT failure, if dictated by patient preference. We sometimes offer these for elderly or frail patients or those with a limited life expectancy. These therapy options are from small, nonrandomized trials in multiply recurrent C. difficile infections but have not been vetted in the FMT nonresponder population.”
These include a vancomycin taper, or a vancomycin taper followed by fidaxomicin. Another option, albeit with limited applicability, is suppressive low-dose vancomycin 125 mg given every day, every other day, or every third day, indefinitely. “This can be especially good for elderly, frail patients with limited life expectancy, needing ongoing antibiotic therapy for urinary tract infections,” she said.
Finally, an 8-week vancomycin taper with daily kefir ingestion has been helpful for some patients. Although probiotics have never been proven helpful in C. difficile infections or FMT success, kefir is a different sort of supplement, she said.
“Kefir is different from yogurt. It contains bacteriocins like nisin, a protein with antibacterial properties produced by Lactococcus lactis.”
[email protected]
On Twitter @alz_gal
AT DDW 2017
First trimester lithium exposure ups risk of cardiac malformations
Cardiac malformations are three times more likely to occur in infants exposed to lithium during the first trimester of gestation than in unexposed infants.
The increased risk could account for one additional cardiac malformation per 100 live births, Elisabetta Patorno, MD, and her colleagues wrote in the June 8 issue of the New England Journal of Medicine (2017;376:2245-54).
Dr. Patorno’s study is the largest conducted since then. It comprised more than 1.3 million pregnancies included in the U.S. Medicaid Analytic eXtract database during 2000-2010. Of these, 663 had first trimester lithium exposure. These were compared with 1,945 pregnancies with first trimester exposure to lamotrigine, another mood stabilizer, and to the remaining 1.3 million pregnancies unexposed to either drug.
There were 16 cardiac malformations in the lithium group (2.41%); 27 in the lamotrigine group (1.39%); and 15,251 in the unexposed group (1.15%). Lithium conferred a 65% increased risk of cardiac defect, compared with unexposed pregnancies. It more than doubled the risk when compared with lamotrigine-exposed pregnancies (risk ratio, 2.25).
The risk was dose dependent, however, with an 11% increase associated with 600 mg/day or less and a 60% increase associated with 601-900 mg/day. Infants exposed to more than 900 mg per day in the first trimester, however, were more than 300% more likely to have a cardiac malformation (RR, 3.22).
The investigators also examined the association of lithium with cardiac defects consistent with Ebstein’s anomaly. Lithium more than doubled the risk, compared with unexposed infants (RR, 2.66). This risk was also dose dependent; all of the right ventricular outflow defects occurred in infants exposed to more than 600 mg/day.
Dr. Patorno reported grant support from National Institute of Mental Health during the study and grant support from Boehringer Ingelheim and GlaxoSmithKline outside of the study. Other authors reported receiving grants or personal fees from various pharmaceutical companies.
[email protected]
On Twitter @Alz_gal
Cardiac malformations are three times more likely to occur in infants exposed to lithium during the first trimester of gestation than in unexposed infants.
The increased risk could account for one additional cardiac malformation per 100 live births, Elisabetta Patorno, MD, and her colleagues wrote in the June 8 issue of the New England Journal of Medicine (2017;376:2245-54).
Dr. Patorno’s study is the largest conducted since then. It comprised more than 1.3 million pregnancies included in the U.S. Medicaid Analytic eXtract database during 2000-2010. Of these, 663 had first trimester lithium exposure. These were compared with 1,945 pregnancies with first trimester exposure to lamotrigine, another mood stabilizer, and to the remaining 1.3 million pregnancies unexposed to either drug.
There were 16 cardiac malformations in the lithium group (2.41%); 27 in the lamotrigine group (1.39%); and 15,251 in the unexposed group (1.15%). Lithium conferred a 65% increased risk of cardiac defect, compared with unexposed pregnancies. It more than doubled the risk when compared with lamotrigine-exposed pregnancies (risk ratio, 2.25).
The risk was dose dependent, however, with an 11% increase associated with 600 mg/day or less and a 60% increase associated with 601-900 mg/day. Infants exposed to more than 900 mg per day in the first trimester, however, were more than 300% more likely to have a cardiac malformation (RR, 3.22).
The investigators also examined the association of lithium with cardiac defects consistent with Ebstein’s anomaly. Lithium more than doubled the risk, compared with unexposed infants (RR, 2.66). This risk was also dose dependent; all of the right ventricular outflow defects occurred in infants exposed to more than 600 mg/day.
Dr. Patorno reported grant support from National Institute of Mental Health during the study and grant support from Boehringer Ingelheim and GlaxoSmithKline outside of the study. Other authors reported receiving grants or personal fees from various pharmaceutical companies.
[email protected]
On Twitter @Alz_gal
Cardiac malformations are three times more likely to occur in infants exposed to lithium during the first trimester of gestation than in unexposed infants.
The increased risk could account for one additional cardiac malformation per 100 live births, Elisabetta Patorno, MD, and her colleagues wrote in the June 8 issue of the New England Journal of Medicine (2017;376:2245-54).
Dr. Patorno’s study is the largest conducted since then. It comprised more than 1.3 million pregnancies included in the U.S. Medicaid Analytic eXtract database during 2000-2010. Of these, 663 had first trimester lithium exposure. These were compared with 1,945 pregnancies with first trimester exposure to lamotrigine, another mood stabilizer, and to the remaining 1.3 million pregnancies unexposed to either drug.
There were 16 cardiac malformations in the lithium group (2.41%); 27 in the lamotrigine group (1.39%); and 15,251 in the unexposed group (1.15%). Lithium conferred a 65% increased risk of cardiac defect, compared with unexposed pregnancies. It more than doubled the risk when compared with lamotrigine-exposed pregnancies (risk ratio, 2.25).
The risk was dose dependent, however, with an 11% increase associated with 600 mg/day or less and a 60% increase associated with 601-900 mg/day. Infants exposed to more than 900 mg per day in the first trimester, however, were more than 300% more likely to have a cardiac malformation (RR, 3.22).
The investigators also examined the association of lithium with cardiac defects consistent with Ebstein’s anomaly. Lithium more than doubled the risk, compared with unexposed infants (RR, 2.66). This risk was also dose dependent; all of the right ventricular outflow defects occurred in infants exposed to more than 600 mg/day.
Dr. Patorno reported grant support from National Institute of Mental Health during the study and grant support from Boehringer Ingelheim and GlaxoSmithKline outside of the study. Other authors reported receiving grants or personal fees from various pharmaceutical companies.
[email protected]
On Twitter @Alz_gal
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: The dose-dependent increased risks ranged from 11% to more than 300%, compared with unexposed pregnancies.
Data source: The Medicaid database review comprised more than 1.3 million pregnancies.
Disclosures: Dr. Patorno reported grant support from National Institute of Mental Health during the study and grant support from Boehringer Ingelheim and GlaxoSmithKline outside of the study. Other authors reported receiving grants or personal fees from various pharmaceutical companies.
Primary care involvement improves chance of meeting recommended surveillance intervals
CHICAGO – Only a small portion of patients with nondysplastic Barrett’s esophagus received appropriately timed endoscopic surveillance, a large database study showed.
But rather than being neglected, patients were more likely to be overassessed, with follow-up endoscopy performed more frequently than the recommended 3- to 5-year intervals, Anna Tavakkoli, MD, reported at the annual Digestive Disease Week.
“Very few patients entered our surveillance program with appropriate surveillance intervals,” said Dr. Tavakkoli, a gastroenterology fellow at the University of Michigan, Ann Arbor.
“We don’t have a formal program at the University of Michigan that drives coordination of care, but we do have great communication here between our primary care providers and our specialists. Our electronic medical records system makes quick messaging between providers easy, and primary care is very good about incorporating diagnoses into patients’ problem lists.”
Malignant transformation of nondysplastic Barrett’s is uncommon, with rates of no more than 4% per year. This understanding led three major societies – the American Gastroenterology Association, the American Society of Gastrointestinal Endoscopy, and the American College of Gastroenterology – to amend their surveillance recommendations in 2011 and 2012. All three societies now recommend a surveillance endoscopy every 3-5 years after the initial diagnosis of nondysplastic Barrett’s esophagus. In fact, the AGA has incorporated this suggestion into its five “Choosing Wisely” recommendations aimed at decreasing overutilization of testing and procedures.
Dr. Tavakkoli’s study examined surveillance timing in a cohort of 1,602 patients with nondysplastic Barrett’s who entered the University of Michigan Barrett’s Esophagus Registry from 1994 to 2016. All of these patents had at least three endoscopies or at least 5 years of follow-up data since their last endoscopy. The primary outcome was identification of trends in the appropriateness of surveillance of patients with nondysplastic Barrett’s esophagus at the University of Michigan. In her analysis, oversurveillance was defined as less than 3 years between the second and third endoscopy; undersurveillance was defined as more than 5 years between them. Dr. Tavakkoli and her colleagues also looked at patients who were lost to follow-up, defined as never receiving a second endoscopy after their initial diagnosis of nondysplastic Barrett’s esophagus and patients who were never surveilled, defined as never receiving their third endoscopy. All patients were compared with those who underwent appropriate surveillance, defined as 3-5 years between their second and third procedure.
The majority of patients were male, and the mean age was 59 years; 30% had long-segment Barrett’s, and 41% had a primary care provider in the university health care system. Most (90%) had their second endoscopy before 2012, when two of the three major societies issued their updated surveillance recommendations.
Of the entire cohort, 40% were lost to follow-up; 17% were never surveilled, and 3% were undersurveilled. Almost a third (31%) were oversurveilled, while just 8% had the appropriate surveillance, Dr. Tavakkoli said.
She then looked at several demographic and clinical factors associated with surveillance in each group, including sex, age, race, and income, comorbidities, length of Barrett’s, family history of esophageal cancer, and whether the patient had a University of Michigan primary care provider.
Having long-segment Barrett’s was associated with a 2.5-times increased risk of receiving a third endoscopy earlier than 3 years, which may be driven by studies that have shown that the risk of malignant transformation increases with Barrett’s length, she said.
The presence of a primary care physician significantly reduced the risk of inappropriate follow-up in every group, except patients who were undersurveilled, she said. The presence of a primary care physician at the University of Michigan decreased the risk of oversurveillance by 56%.
The positive influence of an in-system primary care physician was an important finding in this study, Dr Tavakkoli said. “The oncology data have shown us that poor coordination of care between oncologists and primary care providers contributes to avoidable patient morbidity and mortality, fragmented care, and increased costs. In 2005, the Institute of Medicine published a report emphasizing that coordination between specialists and primary care providers is one of the four key components to cancer survivorship care. There have been a number of GI studies looking at how primary care’s involvement in colorectal screening improves the rates of patients who undergo screening, but among Barrett’s patients, there have not been data showing that having a primary care physician at the center where endoscopic surveillance is done improves utilization patterns.”
Dr. Tavakkoli had no financial disclosures.
[email protected]
On Twitter @alz_gal
CHICAGO – Only a small portion of patients with nondysplastic Barrett’s esophagus received appropriately timed endoscopic surveillance, a large database study showed.
But rather than being neglected, patients were more likely to be overassessed, with follow-up endoscopy performed more frequently than the recommended 3- to 5-year intervals, Anna Tavakkoli, MD, reported at the annual Digestive Disease Week.
“Very few patients entered our surveillance program with appropriate surveillance intervals,” said Dr. Tavakkoli, a gastroenterology fellow at the University of Michigan, Ann Arbor.
“We don’t have a formal program at the University of Michigan that drives coordination of care, but we do have great communication here between our primary care providers and our specialists. Our electronic medical records system makes quick messaging between providers easy, and primary care is very good about incorporating diagnoses into patients’ problem lists.”
Malignant transformation of nondysplastic Barrett’s is uncommon, with rates of no more than 4% per year. This understanding led three major societies – the American Gastroenterology Association, the American Society of Gastrointestinal Endoscopy, and the American College of Gastroenterology – to amend their surveillance recommendations in 2011 and 2012. All three societies now recommend a surveillance endoscopy every 3-5 years after the initial diagnosis of nondysplastic Barrett’s esophagus. In fact, the AGA has incorporated this suggestion into its five “Choosing Wisely” recommendations aimed at decreasing overutilization of testing and procedures.
Dr. Tavakkoli’s study examined surveillance timing in a cohort of 1,602 patients with nondysplastic Barrett’s who entered the University of Michigan Barrett’s Esophagus Registry from 1994 to 2016. All of these patents had at least three endoscopies or at least 5 years of follow-up data since their last endoscopy. The primary outcome was identification of trends in the appropriateness of surveillance of patients with nondysplastic Barrett’s esophagus at the University of Michigan. In her analysis, oversurveillance was defined as less than 3 years between the second and third endoscopy; undersurveillance was defined as more than 5 years between them. Dr. Tavakkoli and her colleagues also looked at patients who were lost to follow-up, defined as never receiving a second endoscopy after their initial diagnosis of nondysplastic Barrett’s esophagus and patients who were never surveilled, defined as never receiving their third endoscopy. All patients were compared with those who underwent appropriate surveillance, defined as 3-5 years between their second and third procedure.
The majority of patients were male, and the mean age was 59 years; 30% had long-segment Barrett’s, and 41% had a primary care provider in the university health care system. Most (90%) had their second endoscopy before 2012, when two of the three major societies issued their updated surveillance recommendations.
Of the entire cohort, 40% were lost to follow-up; 17% were never surveilled, and 3% were undersurveilled. Almost a third (31%) were oversurveilled, while just 8% had the appropriate surveillance, Dr. Tavakkoli said.
She then looked at several demographic and clinical factors associated with surveillance in each group, including sex, age, race, and income, comorbidities, length of Barrett’s, family history of esophageal cancer, and whether the patient had a University of Michigan primary care provider.
Having long-segment Barrett’s was associated with a 2.5-times increased risk of receiving a third endoscopy earlier than 3 years, which may be driven by studies that have shown that the risk of malignant transformation increases with Barrett’s length, she said.
The presence of a primary care physician significantly reduced the risk of inappropriate follow-up in every group, except patients who were undersurveilled, she said. The presence of a primary care physician at the University of Michigan decreased the risk of oversurveillance by 56%.
The positive influence of an in-system primary care physician was an important finding in this study, Dr Tavakkoli said. “The oncology data have shown us that poor coordination of care between oncologists and primary care providers contributes to avoidable patient morbidity and mortality, fragmented care, and increased costs. In 2005, the Institute of Medicine published a report emphasizing that coordination between specialists and primary care providers is one of the four key components to cancer survivorship care. There have been a number of GI studies looking at how primary care’s involvement in colorectal screening improves the rates of patients who undergo screening, but among Barrett’s patients, there have not been data showing that having a primary care physician at the center where endoscopic surveillance is done improves utilization patterns.”
Dr. Tavakkoli had no financial disclosures.
[email protected]
On Twitter @alz_gal
CHICAGO – Only a small portion of patients with nondysplastic Barrett’s esophagus received appropriately timed endoscopic surveillance, a large database study showed.
But rather than being neglected, patients were more likely to be overassessed, with follow-up endoscopy performed more frequently than the recommended 3- to 5-year intervals, Anna Tavakkoli, MD, reported at the annual Digestive Disease Week.
“Very few patients entered our surveillance program with appropriate surveillance intervals,” said Dr. Tavakkoli, a gastroenterology fellow at the University of Michigan, Ann Arbor.
“We don’t have a formal program at the University of Michigan that drives coordination of care, but we do have great communication here between our primary care providers and our specialists. Our electronic medical records system makes quick messaging between providers easy, and primary care is very good about incorporating diagnoses into patients’ problem lists.”
Malignant transformation of nondysplastic Barrett’s is uncommon, with rates of no more than 4% per year. This understanding led three major societies – the American Gastroenterology Association, the American Society of Gastrointestinal Endoscopy, and the American College of Gastroenterology – to amend their surveillance recommendations in 2011 and 2012. All three societies now recommend a surveillance endoscopy every 3-5 years after the initial diagnosis of nondysplastic Barrett’s esophagus. In fact, the AGA has incorporated this suggestion into its five “Choosing Wisely” recommendations aimed at decreasing overutilization of testing and procedures.
Dr. Tavakkoli’s study examined surveillance timing in a cohort of 1,602 patients with nondysplastic Barrett’s who entered the University of Michigan Barrett’s Esophagus Registry from 1994 to 2016. All of these patents had at least three endoscopies or at least 5 years of follow-up data since their last endoscopy. The primary outcome was identification of trends in the appropriateness of surveillance of patients with nondysplastic Barrett’s esophagus at the University of Michigan. In her analysis, oversurveillance was defined as less than 3 years between the second and third endoscopy; undersurveillance was defined as more than 5 years between them. Dr. Tavakkoli and her colleagues also looked at patients who were lost to follow-up, defined as never receiving a second endoscopy after their initial diagnosis of nondysplastic Barrett’s esophagus and patients who were never surveilled, defined as never receiving their third endoscopy. All patients were compared with those who underwent appropriate surveillance, defined as 3-5 years between their second and third procedure.
The majority of patients were male, and the mean age was 59 years; 30% had long-segment Barrett’s, and 41% had a primary care provider in the university health care system. Most (90%) had their second endoscopy before 2012, when two of the three major societies issued their updated surveillance recommendations.
Of the entire cohort, 40% were lost to follow-up; 17% were never surveilled, and 3% were undersurveilled. Almost a third (31%) were oversurveilled, while just 8% had the appropriate surveillance, Dr. Tavakkoli said.
She then looked at several demographic and clinical factors associated with surveillance in each group, including sex, age, race, and income, comorbidities, length of Barrett’s, family history of esophageal cancer, and whether the patient had a University of Michigan primary care provider.
Having long-segment Barrett’s was associated with a 2.5-times increased risk of receiving a third endoscopy earlier than 3 years, which may be driven by studies that have shown that the risk of malignant transformation increases with Barrett’s length, she said.
The presence of a primary care physician significantly reduced the risk of inappropriate follow-up in every group, except patients who were undersurveilled, she said. The presence of a primary care physician at the University of Michigan decreased the risk of oversurveillance by 56%.
The positive influence of an in-system primary care physician was an important finding in this study, Dr Tavakkoli said. “The oncology data have shown us that poor coordination of care between oncologists and primary care providers contributes to avoidable patient morbidity and mortality, fragmented care, and increased costs. In 2005, the Institute of Medicine published a report emphasizing that coordination between specialists and primary care providers is one of the four key components to cancer survivorship care. There have been a number of GI studies looking at how primary care’s involvement in colorectal screening improves the rates of patients who undergo screening, but among Barrett’s patients, there have not been data showing that having a primary care physician at the center where endoscopic surveillance is done improves utilization patterns.”
Dr. Tavakkoli had no financial disclosures.
[email protected]
On Twitter @alz_gal
AT DDW
Key clinical point:
Major finding: Only 8% of patients had the recommended interval of 3-5 years between surveillance endoscopies.
Data source: A retrospective database cohort of 1,602 patients.
Disclosures: Dr. Tavakkoli had no relevant financial disclosures.