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How bariatric surgery improves knee osteoarthritis
LAS VEGAS – Most of the improvement in knee pain that occurs following bariatric surgery in obese patients with knee osteoarthritis happens in the first month after surgery, well before the bulk of the weight loss takes place, Jonathan Samuels, MD, reported at the World Congress on Osteoarthritis.
This observation suggests that bariatric surgery’s mechanism of benefit in patients with knee osteoarthritis (OA) isn’t simply a matter of reduced mechanical load on the joints caused by a lessened weight burden, Dr. Samuels observed at the World Congress on Osteoarthritis, sponsored by the Osteoarthritis Research Society International.
Indeed, his prospective study of 150 obese patients with comorbid knee OA points to metabolic factors as likely playing a key role.
His study, featuring 2 years of follow-up to date, showed that bariatric surgery improved knee OA proportionate to the percentage of excess weight loss achieved. The greatest reduction in knee pain as well as the most profound weight loss occurred in the 35 patients who underwent gastric bypass and the 97 who opted for sleeve gastrectomy; patients who underwent laparoscopic adjustable gastric banding had more modest outcomes on both scores.
The disparate timing of the reductions in excess weight and knee pain was particularly eye catching. With all three forms of bariatric surgery, weight loss continued steadily for roughly the first 12 months. It then plateaued and was generally maintained at the new body mass index for the second 12 months.
In contrast, improvement in knee pain according to the validated Knee Injury and Osteoarthritis Outcome Score (KOOS) leveled out after just 1 month post surgery and was then sustained through 23 months. Levels of the inflammatory cytokines and adipokines interleukin-6, interleukin-1 receptor antagonist, and lipopolysaccharides were elevated at baseline but dropped steadily in concert with the reduction in excess body weight during the first 12 months after surgery. In contrast, levels of the anti-inflammatory cytokine sRAGE (soluble receptor for advanced glycation end products) were abnormally low prior to surgery but increased sharply for the first 3 months afterward before leveling off. And levels of serum leptin, which were roughly sevenfold greater than in normal controls at baseline, fell precipitously during the first month after bariatric surgery before plateauing, following the same pattern as the improvement in knee pain.
“This suggests that perhaps leptin is the key mediator in this OA population,” said Dr. Samuels.
Obese patients with knee OA are in a catch-22 situation. Obese individuals are at greatly increased lifetime risk of developing knee OA, and patients with chronic knee pain have a tough time losing weight.
“The treatments that might work with either obesity or knee pain alone often fail when both of these are present,” he observed.
That’s why bariatric surgery is becoming an increasingly popular treatment strategy in these patients. Sleeve gastrectomy, gastric bypass, and laparoscopic adjustable gastric banding are all Food and Drug Administration approved treatments for obesity in the presence of at least one qualifying comorbid condition, and knee OA qualifies.
Dr. Samuels reported having no financial conflicts regarding his study.
LAS VEGAS – Most of the improvement in knee pain that occurs following bariatric surgery in obese patients with knee osteoarthritis happens in the first month after surgery, well before the bulk of the weight loss takes place, Jonathan Samuels, MD, reported at the World Congress on Osteoarthritis.
This observation suggests that bariatric surgery’s mechanism of benefit in patients with knee osteoarthritis (OA) isn’t simply a matter of reduced mechanical load on the joints caused by a lessened weight burden, Dr. Samuels observed at the World Congress on Osteoarthritis, sponsored by the Osteoarthritis Research Society International.
Indeed, his prospective study of 150 obese patients with comorbid knee OA points to metabolic factors as likely playing a key role.
His study, featuring 2 years of follow-up to date, showed that bariatric surgery improved knee OA proportionate to the percentage of excess weight loss achieved. The greatest reduction in knee pain as well as the most profound weight loss occurred in the 35 patients who underwent gastric bypass and the 97 who opted for sleeve gastrectomy; patients who underwent laparoscopic adjustable gastric banding had more modest outcomes on both scores.
The disparate timing of the reductions in excess weight and knee pain was particularly eye catching. With all three forms of bariatric surgery, weight loss continued steadily for roughly the first 12 months. It then plateaued and was generally maintained at the new body mass index for the second 12 months.
In contrast, improvement in knee pain according to the validated Knee Injury and Osteoarthritis Outcome Score (KOOS) leveled out after just 1 month post surgery and was then sustained through 23 months. Levels of the inflammatory cytokines and adipokines interleukin-6, interleukin-1 receptor antagonist, and lipopolysaccharides were elevated at baseline but dropped steadily in concert with the reduction in excess body weight during the first 12 months after surgery. In contrast, levels of the anti-inflammatory cytokine sRAGE (soluble receptor for advanced glycation end products) were abnormally low prior to surgery but increased sharply for the first 3 months afterward before leveling off. And levels of serum leptin, which were roughly sevenfold greater than in normal controls at baseline, fell precipitously during the first month after bariatric surgery before plateauing, following the same pattern as the improvement in knee pain.
“This suggests that perhaps leptin is the key mediator in this OA population,” said Dr. Samuels.
Obese patients with knee OA are in a catch-22 situation. Obese individuals are at greatly increased lifetime risk of developing knee OA, and patients with chronic knee pain have a tough time losing weight.
“The treatments that might work with either obesity or knee pain alone often fail when both of these are present,” he observed.
That’s why bariatric surgery is becoming an increasingly popular treatment strategy in these patients. Sleeve gastrectomy, gastric bypass, and laparoscopic adjustable gastric banding are all Food and Drug Administration approved treatments for obesity in the presence of at least one qualifying comorbid condition, and knee OA qualifies.
Dr. Samuels reported having no financial conflicts regarding his study.
LAS VEGAS – Most of the improvement in knee pain that occurs following bariatric surgery in obese patients with knee osteoarthritis happens in the first month after surgery, well before the bulk of the weight loss takes place, Jonathan Samuels, MD, reported at the World Congress on Osteoarthritis.
This observation suggests that bariatric surgery’s mechanism of benefit in patients with knee osteoarthritis (OA) isn’t simply a matter of reduced mechanical load on the joints caused by a lessened weight burden, Dr. Samuels observed at the World Congress on Osteoarthritis, sponsored by the Osteoarthritis Research Society International.
Indeed, his prospective study of 150 obese patients with comorbid knee OA points to metabolic factors as likely playing a key role.
His study, featuring 2 years of follow-up to date, showed that bariatric surgery improved knee OA proportionate to the percentage of excess weight loss achieved. The greatest reduction in knee pain as well as the most profound weight loss occurred in the 35 patients who underwent gastric bypass and the 97 who opted for sleeve gastrectomy; patients who underwent laparoscopic adjustable gastric banding had more modest outcomes on both scores.
The disparate timing of the reductions in excess weight and knee pain was particularly eye catching. With all three forms of bariatric surgery, weight loss continued steadily for roughly the first 12 months. It then plateaued and was generally maintained at the new body mass index for the second 12 months.
In contrast, improvement in knee pain according to the validated Knee Injury and Osteoarthritis Outcome Score (KOOS) leveled out after just 1 month post surgery and was then sustained through 23 months. Levels of the inflammatory cytokines and adipokines interleukin-6, interleukin-1 receptor antagonist, and lipopolysaccharides were elevated at baseline but dropped steadily in concert with the reduction in excess body weight during the first 12 months after surgery. In contrast, levels of the anti-inflammatory cytokine sRAGE (soluble receptor for advanced glycation end products) were abnormally low prior to surgery but increased sharply for the first 3 months afterward before leveling off. And levels of serum leptin, which were roughly sevenfold greater than in normal controls at baseline, fell precipitously during the first month after bariatric surgery before plateauing, following the same pattern as the improvement in knee pain.
“This suggests that perhaps leptin is the key mediator in this OA population,” said Dr. Samuels.
Obese patients with knee OA are in a catch-22 situation. Obese individuals are at greatly increased lifetime risk of developing knee OA, and patients with chronic knee pain have a tough time losing weight.
“The treatments that might work with either obesity or knee pain alone often fail when both of these are present,” he observed.
That’s why bariatric surgery is becoming an increasingly popular treatment strategy in these patients. Sleeve gastrectomy, gastric bypass, and laparoscopic adjustable gastric banding are all Food and Drug Administration approved treatments for obesity in the presence of at least one qualifying comorbid condition, and knee OA qualifies.
Dr. Samuels reported having no financial conflicts regarding his study.
AT OARSI 2017
Key clinical point:
Major finding: Most of the improvement in knee pain – and most of the accompanying drop in serum leptin – happens in the first month following bariatric surgery, well before most weight loss has occurred.
Data source: A prospective observational study of 150 obese patients with knee osteoarthritis who underwent bariatric surgery.
Disclosures: The study presenter reported having no financial conflicts.
OARSI to FDA: Take osteoarthritis seriously
LAS VEGAS – The Osteoarthritis Research Society International has submitted a 103-page white paper to the Food and Drug Administration, the gist of which is captured in its title: “Osteoarthritis: A Serious Disease.”
The purpose of the voluminous white paper is to persuade FDA officials that osteoarthritis (OA) meets the agency’s formal definition of a serious disease for which there are currently no satisfactory treatments. That recognition would result in removal of current regulatory barriers to development of new structure-modifying treatments for OA, instead allowing such efforts to fall within the agency’s accelerated approval program, Marc C. Hochberg, MD, a coauthor of the white paper, explained at the World Congress on Osteoarthritis.
OARSI would like to see novel investigational therapies be allowed to advance through the developmental pipeline on the basis of favorable changes in clinically relevant biomarkers – be they biochemical or imaging – as intermediate endpoints serving as surrogates for structural change endpoints and meaningful clinical outcomes.
There is an enormous unmet need for effective disease-modifying therapies for OA. Establishing a more flexible regulatory environment for drug development by designating OA as a serious disease is expected to rekindle pharmaceutical industry interest in developing such products, which at present is at an ebb, he continued at the congress sponsored by the Osteoarthritis Research Society International.
The FDA has defined a serious disease as “a disease or condition associated with morbidity that has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient, but the morbidity need not be irreversible if it is persistent or recurrent. Whether a disease or condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one.”
The white paper makes the case that OA fits that description to a T. Dr. Hochberg said the big picture regarding OA as described in the white paper is this: It’s the most common form of arthritis, affecting more than 250 million people worldwide. And its costs approach 2% of the gross national product in the United States and other developed countries.
“Osteoarthritis accounts for more functional limitation, work loss, and physical disability than any other chronic disease, including cardiovascular disease and chronic obstructive pulmonary disease,” the rheumatologist said.
The white paper cites published data in support of these and other key points. At OARSI 2017, Dr. Hochberg presented highlights from the white paper, submitted to the FDA in December 2016:
• OA prevalence is relentlessly climbing. The Centers for Disease Control and Prevention put the U.S. prevalence of OA at 46 million in 2004 and has projected that it will reach 63 million in 2020 and 78 million Americans by 2040. The rise is being driven by the aging of the baby boomers, the obesity epidemic, predisposing physical injuries, and sedentary behavior.
• OA is expensive for patients and society. The combined direct medical costs and indirect costs stemming from lost earnings from OA amount to an estimated $461 billion annually in the United States.
• OA exacts a steep toll in years lived with disability (YLD). Estimated YLD from OA jumped by 75% during 1990-2013. This increase in YLD was exceeded only by dementia at 84% and diabetes at 135%. OA accounts for 1.6% of overall YLD in the United States, a rate comparable to ischemic heart disease at 1.63% and more than twice that for rheumatoid arthritis at 0.68%.
• Comorbidities are the rule. Various studies have estimated that 59%-87% of adults with OA have at least one additional significant chronic condition. The median number is two. One-third of OA patients have four or more additional comorbid conditions. The most common are cardiovascular disease, diabetes, obesity, metabolic syndrome, depression, anxiety, and falls and fractures.
• No effective treatments exist. There are no approved drugs that can prevent or even slow progression of OA to the point where total joint replacement is needed. Current medications are focused on pain relief and maintenance of functional independence. But these drugs are associated with significant risks of life-threatening side effects. NSAIDs have been linked to increased risk of cardiovascular events, GI bleeding, chronic kidney disease, and heart failure. And while opioids provide a small benefit in terms of pain relief, this is outweighed by the associated risks of falls, fractures, dependence, overdose, and death. All of these risks are accentuated in the presence of the common comorbid conditions associated with OA.
• OA increases the risk of dying prematurely. In a meta-analysis of individual patient data from the Multicenter Osteoarthritis Study and the Johnston County (N.C.) Osteoarthritis Project conducted specifically for the white paper, investigators determined that OA was associated with a 23% increase in the risk of death independent of age, race, and sex. This excess mortality is attributable in part to the presence of the metabolic syndrome and other commonly comorbid conditions, reduced physical activity because of OA disability, and the use of NSAIDs and opioid analgesics for symptomatic control.
The OARSI initiative is supported by EMD Serono, Fidia Pharma, Flexion Therapeutics, Nordic Biosciences, and Spinifex. Dr. Hochberg reported having numerous financial relationships with industry.
LAS VEGAS – The Osteoarthritis Research Society International has submitted a 103-page white paper to the Food and Drug Administration, the gist of which is captured in its title: “Osteoarthritis: A Serious Disease.”
The purpose of the voluminous white paper is to persuade FDA officials that osteoarthritis (OA) meets the agency’s formal definition of a serious disease for which there are currently no satisfactory treatments. That recognition would result in removal of current regulatory barriers to development of new structure-modifying treatments for OA, instead allowing such efforts to fall within the agency’s accelerated approval program, Marc C. Hochberg, MD, a coauthor of the white paper, explained at the World Congress on Osteoarthritis.
OARSI would like to see novel investigational therapies be allowed to advance through the developmental pipeline on the basis of favorable changes in clinically relevant biomarkers – be they biochemical or imaging – as intermediate endpoints serving as surrogates for structural change endpoints and meaningful clinical outcomes.
There is an enormous unmet need for effective disease-modifying therapies for OA. Establishing a more flexible regulatory environment for drug development by designating OA as a serious disease is expected to rekindle pharmaceutical industry interest in developing such products, which at present is at an ebb, he continued at the congress sponsored by the Osteoarthritis Research Society International.
The FDA has defined a serious disease as “a disease or condition associated with morbidity that has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient, but the morbidity need not be irreversible if it is persistent or recurrent. Whether a disease or condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one.”
The white paper makes the case that OA fits that description to a T. Dr. Hochberg said the big picture regarding OA as described in the white paper is this: It’s the most common form of arthritis, affecting more than 250 million people worldwide. And its costs approach 2% of the gross national product in the United States and other developed countries.
“Osteoarthritis accounts for more functional limitation, work loss, and physical disability than any other chronic disease, including cardiovascular disease and chronic obstructive pulmonary disease,” the rheumatologist said.
The white paper cites published data in support of these and other key points. At OARSI 2017, Dr. Hochberg presented highlights from the white paper, submitted to the FDA in December 2016:
• OA prevalence is relentlessly climbing. The Centers for Disease Control and Prevention put the U.S. prevalence of OA at 46 million in 2004 and has projected that it will reach 63 million in 2020 and 78 million Americans by 2040. The rise is being driven by the aging of the baby boomers, the obesity epidemic, predisposing physical injuries, and sedentary behavior.
• OA is expensive for patients and society. The combined direct medical costs and indirect costs stemming from lost earnings from OA amount to an estimated $461 billion annually in the United States.
• OA exacts a steep toll in years lived with disability (YLD). Estimated YLD from OA jumped by 75% during 1990-2013. This increase in YLD was exceeded only by dementia at 84% and diabetes at 135%. OA accounts for 1.6% of overall YLD in the United States, a rate comparable to ischemic heart disease at 1.63% and more than twice that for rheumatoid arthritis at 0.68%.
• Comorbidities are the rule. Various studies have estimated that 59%-87% of adults with OA have at least one additional significant chronic condition. The median number is two. One-third of OA patients have four or more additional comorbid conditions. The most common are cardiovascular disease, diabetes, obesity, metabolic syndrome, depression, anxiety, and falls and fractures.
• No effective treatments exist. There are no approved drugs that can prevent or even slow progression of OA to the point where total joint replacement is needed. Current medications are focused on pain relief and maintenance of functional independence. But these drugs are associated with significant risks of life-threatening side effects. NSAIDs have been linked to increased risk of cardiovascular events, GI bleeding, chronic kidney disease, and heart failure. And while opioids provide a small benefit in terms of pain relief, this is outweighed by the associated risks of falls, fractures, dependence, overdose, and death. All of these risks are accentuated in the presence of the common comorbid conditions associated with OA.
• OA increases the risk of dying prematurely. In a meta-analysis of individual patient data from the Multicenter Osteoarthritis Study and the Johnston County (N.C.) Osteoarthritis Project conducted specifically for the white paper, investigators determined that OA was associated with a 23% increase in the risk of death independent of age, race, and sex. This excess mortality is attributable in part to the presence of the metabolic syndrome and other commonly comorbid conditions, reduced physical activity because of OA disability, and the use of NSAIDs and opioid analgesics for symptomatic control.
The OARSI initiative is supported by EMD Serono, Fidia Pharma, Flexion Therapeutics, Nordic Biosciences, and Spinifex. Dr. Hochberg reported having numerous financial relationships with industry.
LAS VEGAS – The Osteoarthritis Research Society International has submitted a 103-page white paper to the Food and Drug Administration, the gist of which is captured in its title: “Osteoarthritis: A Serious Disease.”
The purpose of the voluminous white paper is to persuade FDA officials that osteoarthritis (OA) meets the agency’s formal definition of a serious disease for which there are currently no satisfactory treatments. That recognition would result in removal of current regulatory barriers to development of new structure-modifying treatments for OA, instead allowing such efforts to fall within the agency’s accelerated approval program, Marc C. Hochberg, MD, a coauthor of the white paper, explained at the World Congress on Osteoarthritis.
OARSI would like to see novel investigational therapies be allowed to advance through the developmental pipeline on the basis of favorable changes in clinically relevant biomarkers – be they biochemical or imaging – as intermediate endpoints serving as surrogates for structural change endpoints and meaningful clinical outcomes.
There is an enormous unmet need for effective disease-modifying therapies for OA. Establishing a more flexible regulatory environment for drug development by designating OA as a serious disease is expected to rekindle pharmaceutical industry interest in developing such products, which at present is at an ebb, he continued at the congress sponsored by the Osteoarthritis Research Society International.
The FDA has defined a serious disease as “a disease or condition associated with morbidity that has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient, but the morbidity need not be irreversible if it is persistent or recurrent. Whether a disease or condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one.”
The white paper makes the case that OA fits that description to a T. Dr. Hochberg said the big picture regarding OA as described in the white paper is this: It’s the most common form of arthritis, affecting more than 250 million people worldwide. And its costs approach 2% of the gross national product in the United States and other developed countries.
“Osteoarthritis accounts for more functional limitation, work loss, and physical disability than any other chronic disease, including cardiovascular disease and chronic obstructive pulmonary disease,” the rheumatologist said.
The white paper cites published data in support of these and other key points. At OARSI 2017, Dr. Hochberg presented highlights from the white paper, submitted to the FDA in December 2016:
• OA prevalence is relentlessly climbing. The Centers for Disease Control and Prevention put the U.S. prevalence of OA at 46 million in 2004 and has projected that it will reach 63 million in 2020 and 78 million Americans by 2040. The rise is being driven by the aging of the baby boomers, the obesity epidemic, predisposing physical injuries, and sedentary behavior.
• OA is expensive for patients and society. The combined direct medical costs and indirect costs stemming from lost earnings from OA amount to an estimated $461 billion annually in the United States.
• OA exacts a steep toll in years lived with disability (YLD). Estimated YLD from OA jumped by 75% during 1990-2013. This increase in YLD was exceeded only by dementia at 84% and diabetes at 135%. OA accounts for 1.6% of overall YLD in the United States, a rate comparable to ischemic heart disease at 1.63% and more than twice that for rheumatoid arthritis at 0.68%.
• Comorbidities are the rule. Various studies have estimated that 59%-87% of adults with OA have at least one additional significant chronic condition. The median number is two. One-third of OA patients have four or more additional comorbid conditions. The most common are cardiovascular disease, diabetes, obesity, metabolic syndrome, depression, anxiety, and falls and fractures.
• No effective treatments exist. There are no approved drugs that can prevent or even slow progression of OA to the point where total joint replacement is needed. Current medications are focused on pain relief and maintenance of functional independence. But these drugs are associated with significant risks of life-threatening side effects. NSAIDs have been linked to increased risk of cardiovascular events, GI bleeding, chronic kidney disease, and heart failure. And while opioids provide a small benefit in terms of pain relief, this is outweighed by the associated risks of falls, fractures, dependence, overdose, and death. All of these risks are accentuated in the presence of the common comorbid conditions associated with OA.
• OA increases the risk of dying prematurely. In a meta-analysis of individual patient data from the Multicenter Osteoarthritis Study and the Johnston County (N.C.) Osteoarthritis Project conducted specifically for the white paper, investigators determined that OA was associated with a 23% increase in the risk of death independent of age, race, and sex. This excess mortality is attributable in part to the presence of the metabolic syndrome and other commonly comorbid conditions, reduced physical activity because of OA disability, and the use of NSAIDs and opioid analgesics for symptomatic control.
The OARSI initiative is supported by EMD Serono, Fidia Pharma, Flexion Therapeutics, Nordic Biosciences, and Spinifex. Dr. Hochberg reported having numerous financial relationships with industry.
AT OARSI 2017
Elder abuse: Strong social support prevents associated psychopathology
SAN FRANCISCO – Victims of elder abuse who have perceived strong social support from family or friends are “completely inoculated” against the otherwise dramatically increased risk of trauma-related psychopathology that pertains to mistreated seniors who lack such support, according to Ron Acierno, PhD.
Dr. Acierno, professor of nursing at the Medical University of South Carolina in Charleston, presented 8-year follow-up data from the National Elder Mistreatment Study, the largest study of elder abuse ever conducted in the United States.
The National Elder Mistreatment Study involved 5,777 randomly selected community-dwelling older adults who, in 2008, participated in structured interviews assessing whether they had experienced physical, psychological, sexual, or neglectful mistreatment. The study made headlines by documenting an unexpectedly high 11% rate of elder mistreatment within the previous 12 months (Am J Public Health. 2010 Feb;100[2]:292-7).
Eight years later, Dr. Acierno and his coinvestigators were able to recontact 173 of the original 684 abused elders, as well as 602 nonabused controls for structured interviews assessing their current mental health. At that point, the participants averaged 84.9 years of age.
Striking differences in mental health status based on elder abuse history were documented. The prevalences of depression, generalized anxiety disorder, and posttraumatic stress disorder were 13%, 7%, and 8%, respectively, in the elder abuse group, compared with 5%, 1%, and 1% in the nonabused controls. Of the group subjected to abuse 8 years earlier, 40% were categorized at follow-up as “in poor health,” compared with 23% of controls.
More importantly, high social support essentially erased the elder abuse group’s increased risk (see graphic), Dr. Acierno said.
The National Elder Mistreatment Study was funded by the National Institute of Justice, the National Institute on Aging, and the Archstone Foundation. Dr. Acierno reported having no financial conflicts.
SAN FRANCISCO – Victims of elder abuse who have perceived strong social support from family or friends are “completely inoculated” against the otherwise dramatically increased risk of trauma-related psychopathology that pertains to mistreated seniors who lack such support, according to Ron Acierno, PhD.
Dr. Acierno, professor of nursing at the Medical University of South Carolina in Charleston, presented 8-year follow-up data from the National Elder Mistreatment Study, the largest study of elder abuse ever conducted in the United States.
The National Elder Mistreatment Study involved 5,777 randomly selected community-dwelling older adults who, in 2008, participated in structured interviews assessing whether they had experienced physical, psychological, sexual, or neglectful mistreatment. The study made headlines by documenting an unexpectedly high 11% rate of elder mistreatment within the previous 12 months (Am J Public Health. 2010 Feb;100[2]:292-7).
Eight years later, Dr. Acierno and his coinvestigators were able to recontact 173 of the original 684 abused elders, as well as 602 nonabused controls for structured interviews assessing their current mental health. At that point, the participants averaged 84.9 years of age.
Striking differences in mental health status based on elder abuse history were documented. The prevalences of depression, generalized anxiety disorder, and posttraumatic stress disorder were 13%, 7%, and 8%, respectively, in the elder abuse group, compared with 5%, 1%, and 1% in the nonabused controls. Of the group subjected to abuse 8 years earlier, 40% were categorized at follow-up as “in poor health,” compared with 23% of controls.
More importantly, high social support essentially erased the elder abuse group’s increased risk (see graphic), Dr. Acierno said.
The National Elder Mistreatment Study was funded by the National Institute of Justice, the National Institute on Aging, and the Archstone Foundation. Dr. Acierno reported having no financial conflicts.
SAN FRANCISCO – Victims of elder abuse who have perceived strong social support from family or friends are “completely inoculated” against the otherwise dramatically increased risk of trauma-related psychopathology that pertains to mistreated seniors who lack such support, according to Ron Acierno, PhD.
Dr. Acierno, professor of nursing at the Medical University of South Carolina in Charleston, presented 8-year follow-up data from the National Elder Mistreatment Study, the largest study of elder abuse ever conducted in the United States.
The National Elder Mistreatment Study involved 5,777 randomly selected community-dwelling older adults who, in 2008, participated in structured interviews assessing whether they had experienced physical, psychological, sexual, or neglectful mistreatment. The study made headlines by documenting an unexpectedly high 11% rate of elder mistreatment within the previous 12 months (Am J Public Health. 2010 Feb;100[2]:292-7).
Eight years later, Dr. Acierno and his coinvestigators were able to recontact 173 of the original 684 abused elders, as well as 602 nonabused controls for structured interviews assessing their current mental health. At that point, the participants averaged 84.9 years of age.
Striking differences in mental health status based on elder abuse history were documented. The prevalences of depression, generalized anxiety disorder, and posttraumatic stress disorder were 13%, 7%, and 8%, respectively, in the elder abuse group, compared with 5%, 1%, and 1% in the nonabused controls. Of the group subjected to abuse 8 years earlier, 40% were categorized at follow-up as “in poor health,” compared with 23% of controls.
More importantly, high social support essentially erased the elder abuse group’s increased risk (see graphic), Dr. Acierno said.
The National Elder Mistreatment Study was funded by the National Institute of Justice, the National Institute on Aging, and the Archstone Foundation. Dr. Acierno reported having no financial conflicts.
AT THE ANXIETY AND DEPRESSION CONFERENCE 2017
Key clinical point:
Major finding: Having a strong social support network virtually eliminated the otherwise sharply increased risk of trauma-related psychopathology in victims of elder abuse.
Data source: An 8-year follow-up report on the mental health status of participants in the largest study of elder mistreatment in US history.
Disclosures: The National Elder Mistreatment Study was funded by the National Institute of Justice, the National Institute on Aging, and the Archstone Foundation. The presenter reported having no financial conflicts.
No increase in hand osteoarthritis seen in Sjögren’s syndrome
LAS VEGAS – Patients with Sjögren’s syndrome do not have an increased prevalence of hand osteoarthritis, but they are strongly predisposed to have a history of hypothyroidism, Jeremie Sellam, MD, reported at the World Congress on Osteoarthritis.
Both of these findings in his small case-control study were unexpected, he added at the congress sponsored by the Osteoarthritis Research Society International.
The study included 34 women with primary Sjögren’s syndrome according to the 2002 American-European Consensus Group criteria and 54 female controls with sicca syndrome but no autoantibodies and no Sjögren’s syndrome. All subjects were evaluated at a specialized tertiary Sjögren’s syndrome clinic. The controls were referred there to ascertain whether they had Sjögren’s syndrome.
Among the Sjögren’s syndrome patients, 41% had radiographic evidence of hand osteoarthritis, 12% had symptomatic hand osteoarthritis, and 9% had erosive hand osteoarthritis. In the sicca syndrome–only patients, the rates were similar at 52%, 28%, and 9%, respectively.
Looking for commonalities and differences between the Sjögren’s syndrome patients and controls, Dr. Sellam and his coinvestigators noted that the Sjögren’s syndrome patients were significantly older, with an average age of 64 years, compared with 48.5 years in the controls.
Impressively, two-thirds of the 15 Sjögren’s syndrome patients with hand osteoarthritis had a history of hypothyroidism, compared with just 15% of the 27 non-autoimmune sicca syndrome patients with hand osteoarthritis and one-quarter of the Sjögren’s syndrome patients without hand osteoarthritis. This suggests a possible interaction between Sjögren’s syndrome, hand osteoarthritis, and a history of hypothyroidism which merits further study, according to the rheumatologist.
Because of the relatively small patient numbers in the French study, Dr. Sellam and coworkers ran a crosscheck with data from the Framingham Osteoarthritis Study and found hand osteoarthritis prevalence rates comparable to their own findings. For example, the prevalences of radiographic and erosive hand osteoarthritis in the French Sjögren’s syndrome and non-autoimmune sicca syndrome groups were similar to the 44% and 10% figures, respectively, in the general population of age-matched Framingham women (Ann Rheum Dis. 2011 Sep;70[9]:1581-6).
He reported having no financial conflicts regarding his study, which was conducted free of commercial support.
LAS VEGAS – Patients with Sjögren’s syndrome do not have an increased prevalence of hand osteoarthritis, but they are strongly predisposed to have a history of hypothyroidism, Jeremie Sellam, MD, reported at the World Congress on Osteoarthritis.
Both of these findings in his small case-control study were unexpected, he added at the congress sponsored by the Osteoarthritis Research Society International.
The study included 34 women with primary Sjögren’s syndrome according to the 2002 American-European Consensus Group criteria and 54 female controls with sicca syndrome but no autoantibodies and no Sjögren’s syndrome. All subjects were evaluated at a specialized tertiary Sjögren’s syndrome clinic. The controls were referred there to ascertain whether they had Sjögren’s syndrome.
Among the Sjögren’s syndrome patients, 41% had radiographic evidence of hand osteoarthritis, 12% had symptomatic hand osteoarthritis, and 9% had erosive hand osteoarthritis. In the sicca syndrome–only patients, the rates were similar at 52%, 28%, and 9%, respectively.
Looking for commonalities and differences between the Sjögren’s syndrome patients and controls, Dr. Sellam and his coinvestigators noted that the Sjögren’s syndrome patients were significantly older, with an average age of 64 years, compared with 48.5 years in the controls.
Impressively, two-thirds of the 15 Sjögren’s syndrome patients with hand osteoarthritis had a history of hypothyroidism, compared with just 15% of the 27 non-autoimmune sicca syndrome patients with hand osteoarthritis and one-quarter of the Sjögren’s syndrome patients without hand osteoarthritis. This suggests a possible interaction between Sjögren’s syndrome, hand osteoarthritis, and a history of hypothyroidism which merits further study, according to the rheumatologist.
Because of the relatively small patient numbers in the French study, Dr. Sellam and coworkers ran a crosscheck with data from the Framingham Osteoarthritis Study and found hand osteoarthritis prevalence rates comparable to their own findings. For example, the prevalences of radiographic and erosive hand osteoarthritis in the French Sjögren’s syndrome and non-autoimmune sicca syndrome groups were similar to the 44% and 10% figures, respectively, in the general population of age-matched Framingham women (Ann Rheum Dis. 2011 Sep;70[9]:1581-6).
He reported having no financial conflicts regarding his study, which was conducted free of commercial support.
LAS VEGAS – Patients with Sjögren’s syndrome do not have an increased prevalence of hand osteoarthritis, but they are strongly predisposed to have a history of hypothyroidism, Jeremie Sellam, MD, reported at the World Congress on Osteoarthritis.
Both of these findings in his small case-control study were unexpected, he added at the congress sponsored by the Osteoarthritis Research Society International.
The study included 34 women with primary Sjögren’s syndrome according to the 2002 American-European Consensus Group criteria and 54 female controls with sicca syndrome but no autoantibodies and no Sjögren’s syndrome. All subjects were evaluated at a specialized tertiary Sjögren’s syndrome clinic. The controls were referred there to ascertain whether they had Sjögren’s syndrome.
Among the Sjögren’s syndrome patients, 41% had radiographic evidence of hand osteoarthritis, 12% had symptomatic hand osteoarthritis, and 9% had erosive hand osteoarthritis. In the sicca syndrome–only patients, the rates were similar at 52%, 28%, and 9%, respectively.
Looking for commonalities and differences between the Sjögren’s syndrome patients and controls, Dr. Sellam and his coinvestigators noted that the Sjögren’s syndrome patients were significantly older, with an average age of 64 years, compared with 48.5 years in the controls.
Impressively, two-thirds of the 15 Sjögren’s syndrome patients with hand osteoarthritis had a history of hypothyroidism, compared with just 15% of the 27 non-autoimmune sicca syndrome patients with hand osteoarthritis and one-quarter of the Sjögren’s syndrome patients without hand osteoarthritis. This suggests a possible interaction between Sjögren’s syndrome, hand osteoarthritis, and a history of hypothyroidism which merits further study, according to the rheumatologist.
Because of the relatively small patient numbers in the French study, Dr. Sellam and coworkers ran a crosscheck with data from the Framingham Osteoarthritis Study and found hand osteoarthritis prevalence rates comparable to their own findings. For example, the prevalences of radiographic and erosive hand osteoarthritis in the French Sjögren’s syndrome and non-autoimmune sicca syndrome groups were similar to the 44% and 10% figures, respectively, in the general population of age-matched Framingham women (Ann Rheum Dis. 2011 Sep;70[9]:1581-6).
He reported having no financial conflicts regarding his study, which was conducted free of commercial support.
AT OARSI 2017
Key clinical point:
Major finding: Nine percent of women with Sjögren’s syndrome had erosive hand osteoarthritis, a prevalence identical to that in a group with non-autoimmune sicca syndrome only.
Data source: This case-control study included 34 women with Sjögren’s syndrome and 54 women with non-autoimmune sicca syndrome.
Disclosures: The presenter reported having no financial conflicts regarding the study, which was conducted free of commercial support.
Adalimumab strikes out for hand osteoarthritis
LAS VEGAS – Adalimumab proved no better than placebo for the treatment of erosive hand osteoarthritis in the double-blind, placebo-controlled, randomized HUMOR trial, throwing cold water on hopes that a disease-modifying treatment for osteoarthritis might at long last have been found.
“This randomized controlled trial demonstrated that subcutaneous adalimumab at 40 mg every other week was no different from placebo for alleviation of pain, synovitis, or bone marrow lesions in patients with erosive hand osteoarthritis presenting with MRI-detected synovitis. This suggests that pain and inflammation are not responsive to TNF [tumor necrosis factor] inhibition in this patient population,” Dawn Aitken, PhD, declared at the World Congress on Osteoarthritis.
The primary endpoint was change in the visual analog pain score over the course of 12 weeks of therapy. Scores dropped by an average of 3.0 points from a mean baseline of 63.6 with adalimumab and by 0.7 points with placebo. That between-group difference wasn’t statistically significant, nor were those modest reductions clinically meaningful. By convention, a clinically meaningful treatment result requires at least a 15-point improvement on the self-assessed pain scale, noted Dr. Aitken of the University of Tasmania in Hobart, Australia.
It made no difference which treatment arm came first.
“There was absolutely no placebo effect,” she said.
The study proved negative for all prespecified secondary endpoints, too. These included change in the Australian/Canadian Hand OA Index pain, function, and stiffness subscales, as well as change in bone marrow lesions and synovitis. A mere 12% of patients showed improvement in synovitis scores with adalimumab, as did 10% on placebo. Five percent of the adalimumab group and 7% on placebo showed improvement in bone marrow lesion scores.
The proinflammatory cytokine TNF-alpha has been shown to play a key role in OA development and progression. However, several prior studies failed to show a benefit for anti-TNF therapy in terms of reducing pain in hand OA patients, although in one of those negative studies, a post hoc analysis found that adalimumab halted erosive progression in the subset of interphalangeal joints with palpable soft tissue swelling at baseline (Ann Rheum Dis. 2012 Jun;71[6]:891-8).
However, there was a positive signal: In a subgroup analysis confined to the patients with inflammatory joints, the use of etanercept was associated with less structural damage of those joints over time as assessed using the quantitative Ghent University Scoring System, or GUSS, according to Dr. Kloppenburg, professor of rheumatology at Leiden (the Netherlands) University.
The emphatically negative results of the HUMOR trial were greeted with dismay by several disappointed audience members. They raised questions: Might a study featuring more than 12 weeks of treatment have brought positive results? How about a larger study? Why no placebo effect, given that patients were receiving injections? Is this area of investigation of TNF-inhibitor therapy now a dead end? Or could adalimumab and etanercept have differential efficacy in hand OA, even though they are both TNF inhibitors?
Dr. Aitken had an answer for every question.
“I think our study was big enough based on our power calculations to detect a difference of 15 mm on a visual analog scale, which is a clinically important difference. And that’s what we should be chasing in OA, that big effect. Patients are not going to be interested in a treatment that improves their pain by 5 mm,” she said.
As for the possibility that 12 weeks of adalimumab might have been too short to see a treatment effect, Dr. Aitken noted that anti-TNF therapy in rheumatoid arthritis brings a rapid response.
“Ideally, if you did have a disease-modifying drug for osteoarthritis you would want it to have a relatively quick response for pain; if patients aren’t seeing an effect after 3 months they might be less interested in taking it,” she continued.
Also, studies with a crossover design, like HUMOR, are known to have a much smaller placebo effect because patients know that at some point they’re certain to receive the active agent, Dr. Aitken observed.
As for the possibility that etanercept might be effective for erosive hand OA, while adalimumab is not, one physician commented, “That’s really scraping the bottom of the barrel.”
The HUMOR trial was sponsored by AbbVie. Dr. Aitken reported having no financial conflicts.
LAS VEGAS – Adalimumab proved no better than placebo for the treatment of erosive hand osteoarthritis in the double-blind, placebo-controlled, randomized HUMOR trial, throwing cold water on hopes that a disease-modifying treatment for osteoarthritis might at long last have been found.
“This randomized controlled trial demonstrated that subcutaneous adalimumab at 40 mg every other week was no different from placebo for alleviation of pain, synovitis, or bone marrow lesions in patients with erosive hand osteoarthritis presenting with MRI-detected synovitis. This suggests that pain and inflammation are not responsive to TNF [tumor necrosis factor] inhibition in this patient population,” Dawn Aitken, PhD, declared at the World Congress on Osteoarthritis.
The primary endpoint was change in the visual analog pain score over the course of 12 weeks of therapy. Scores dropped by an average of 3.0 points from a mean baseline of 63.6 with adalimumab and by 0.7 points with placebo. That between-group difference wasn’t statistically significant, nor were those modest reductions clinically meaningful. By convention, a clinically meaningful treatment result requires at least a 15-point improvement on the self-assessed pain scale, noted Dr. Aitken of the University of Tasmania in Hobart, Australia.
It made no difference which treatment arm came first.
“There was absolutely no placebo effect,” she said.
The study proved negative for all prespecified secondary endpoints, too. These included change in the Australian/Canadian Hand OA Index pain, function, and stiffness subscales, as well as change in bone marrow lesions and synovitis. A mere 12% of patients showed improvement in synovitis scores with adalimumab, as did 10% on placebo. Five percent of the adalimumab group and 7% on placebo showed improvement in bone marrow lesion scores.
The proinflammatory cytokine TNF-alpha has been shown to play a key role in OA development and progression. However, several prior studies failed to show a benefit for anti-TNF therapy in terms of reducing pain in hand OA patients, although in one of those negative studies, a post hoc analysis found that adalimumab halted erosive progression in the subset of interphalangeal joints with palpable soft tissue swelling at baseline (Ann Rheum Dis. 2012 Jun;71[6]:891-8).
However, there was a positive signal: In a subgroup analysis confined to the patients with inflammatory joints, the use of etanercept was associated with less structural damage of those joints over time as assessed using the quantitative Ghent University Scoring System, or GUSS, according to Dr. Kloppenburg, professor of rheumatology at Leiden (the Netherlands) University.
The emphatically negative results of the HUMOR trial were greeted with dismay by several disappointed audience members. They raised questions: Might a study featuring more than 12 weeks of treatment have brought positive results? How about a larger study? Why no placebo effect, given that patients were receiving injections? Is this area of investigation of TNF-inhibitor therapy now a dead end? Or could adalimumab and etanercept have differential efficacy in hand OA, even though they are both TNF inhibitors?
Dr. Aitken had an answer for every question.
“I think our study was big enough based on our power calculations to detect a difference of 15 mm on a visual analog scale, which is a clinically important difference. And that’s what we should be chasing in OA, that big effect. Patients are not going to be interested in a treatment that improves their pain by 5 mm,” she said.
As for the possibility that 12 weeks of adalimumab might have been too short to see a treatment effect, Dr. Aitken noted that anti-TNF therapy in rheumatoid arthritis brings a rapid response.
“Ideally, if you did have a disease-modifying drug for osteoarthritis you would want it to have a relatively quick response for pain; if patients aren’t seeing an effect after 3 months they might be less interested in taking it,” she continued.
Also, studies with a crossover design, like HUMOR, are known to have a much smaller placebo effect because patients know that at some point they’re certain to receive the active agent, Dr. Aitken observed.
As for the possibility that etanercept might be effective for erosive hand OA, while adalimumab is not, one physician commented, “That’s really scraping the bottom of the barrel.”
The HUMOR trial was sponsored by AbbVie. Dr. Aitken reported having no financial conflicts.
LAS VEGAS – Adalimumab proved no better than placebo for the treatment of erosive hand osteoarthritis in the double-blind, placebo-controlled, randomized HUMOR trial, throwing cold water on hopes that a disease-modifying treatment for osteoarthritis might at long last have been found.
“This randomized controlled trial demonstrated that subcutaneous adalimumab at 40 mg every other week was no different from placebo for alleviation of pain, synovitis, or bone marrow lesions in patients with erosive hand osteoarthritis presenting with MRI-detected synovitis. This suggests that pain and inflammation are not responsive to TNF [tumor necrosis factor] inhibition in this patient population,” Dawn Aitken, PhD, declared at the World Congress on Osteoarthritis.
The primary endpoint was change in the visual analog pain score over the course of 12 weeks of therapy. Scores dropped by an average of 3.0 points from a mean baseline of 63.6 with adalimumab and by 0.7 points with placebo. That between-group difference wasn’t statistically significant, nor were those modest reductions clinically meaningful. By convention, a clinically meaningful treatment result requires at least a 15-point improvement on the self-assessed pain scale, noted Dr. Aitken of the University of Tasmania in Hobart, Australia.
It made no difference which treatment arm came first.
“There was absolutely no placebo effect,” she said.
The study proved negative for all prespecified secondary endpoints, too. These included change in the Australian/Canadian Hand OA Index pain, function, and stiffness subscales, as well as change in bone marrow lesions and synovitis. A mere 12% of patients showed improvement in synovitis scores with adalimumab, as did 10% on placebo. Five percent of the adalimumab group and 7% on placebo showed improvement in bone marrow lesion scores.
The proinflammatory cytokine TNF-alpha has been shown to play a key role in OA development and progression. However, several prior studies failed to show a benefit for anti-TNF therapy in terms of reducing pain in hand OA patients, although in one of those negative studies, a post hoc analysis found that adalimumab halted erosive progression in the subset of interphalangeal joints with palpable soft tissue swelling at baseline (Ann Rheum Dis. 2012 Jun;71[6]:891-8).
However, there was a positive signal: In a subgroup analysis confined to the patients with inflammatory joints, the use of etanercept was associated with less structural damage of those joints over time as assessed using the quantitative Ghent University Scoring System, or GUSS, according to Dr. Kloppenburg, professor of rheumatology at Leiden (the Netherlands) University.
The emphatically negative results of the HUMOR trial were greeted with dismay by several disappointed audience members. They raised questions: Might a study featuring more than 12 weeks of treatment have brought positive results? How about a larger study? Why no placebo effect, given that patients were receiving injections? Is this area of investigation of TNF-inhibitor therapy now a dead end? Or could adalimumab and etanercept have differential efficacy in hand OA, even though they are both TNF inhibitors?
Dr. Aitken had an answer for every question.
“I think our study was big enough based on our power calculations to detect a difference of 15 mm on a visual analog scale, which is a clinically important difference. And that’s what we should be chasing in OA, that big effect. Patients are not going to be interested in a treatment that improves their pain by 5 mm,” she said.
As for the possibility that 12 weeks of adalimumab might have been too short to see a treatment effect, Dr. Aitken noted that anti-TNF therapy in rheumatoid arthritis brings a rapid response.
“Ideally, if you did have a disease-modifying drug for osteoarthritis you would want it to have a relatively quick response for pain; if patients aren’t seeing an effect after 3 months they might be less interested in taking it,” she continued.
Also, studies with a crossover design, like HUMOR, are known to have a much smaller placebo effect because patients know that at some point they’re certain to receive the active agent, Dr. Aitken observed.
As for the possibility that etanercept might be effective for erosive hand OA, while adalimumab is not, one physician commented, “That’s really scraping the bottom of the barrel.”
The HUMOR trial was sponsored by AbbVie. Dr. Aitken reported having no financial conflicts.
FROM OARSI 2017
Key clinical point:
Major finding: Scores dropped by an average of 3.0 points from a mean baseline of 63.6 with adalimumab and by 0.7 points with placebo on the primary endpoint of change in the visual analog pain score over the course of 12 weeks.
Data source: The HUMOR trial was a double-blind, placebo-controlled, randomized, crossover trial in which 43 participants with erosive hand osteoarthritis received 12 weeks of treatment with adalimumab and 12 weeks of placebo.
Disclosures: The study was sponsored by AbbVie. The presenter reported having no financial conflicts.
Novel agent brings clinically meaningful improvements in knee osteoarthritis
LAS VEGAS – The investigational agent FX006 brought improvements in pain and function in patients with knee osteoarthritis that were not only statistically significant but also clinically meaningful by three different yardsticks, according to Scott Kelley, MD.
FX006 (Zilretta) is an extended-release, microsphere-based formulation of triamcinolone acetonide for intra-articular injection now under review for marketing approval by the Food and Drug Administration, which has said it will render a decision in October, Dr. Kelley reported at the World Congress on Osteoarthritis.
He presented a post hoc pooled analysis of the 798 patients with knee OA who participated in two phase II randomized, double-blind clinical trials and in an identically designed pivotal phase III trial of a single 40-mg intra-articular injection of FX006. The three studies included 324 patients who got FX006, 212 who received a single 40-mg intra-articular injection of standard triamcinolone acetonide crystalline suspension, and 262 who got a placebo injection of 5 mL of saline.
All participants had radiographically documented symptomatic knee OA with baseline daily pain scores of 6-9 on a 0-10 scale, corresponding to pain in the moderate-to-severe range. Patients telephoned in their average daily pain scores every day during the studies, one of which lasted 12 weeks while the other two ran for 24 weeks. Patients also visited their clinician every 4 weeks for Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) assessments of pain, stiffness, and physical function.
This secondary analysis was undertaken to demonstrate that FX006 distinguishes itself from current nonsurgical treatments for knee OA, which typically achieve clinical effects that are small, transient, and not clinically relevant, Dr. Kelley said at the congress sponsored by the Osteoarthritis Research Society International.
“What’s different about this product formulation is it maintains a prolonged release of triamcinolone acetonide inside the synovial fluid. The pharmacology has demonstrated prolonged residence time in synovial fluid out to at least 12 weeks after intra-articular administration. In addition, it mitigates the peak plasma level after intra-articular administration, so it blunts the level of corticosteroid in plasma and has a lower systemic exposure over time,” he said.
The clinical relevance of the outcomes achieved in the pooled studies was assessed using three different metrics: the American Academy of Orthopaedic Surgeons (AAOS) criteria for determining whether a result represents a minimal clinically important improvement; the Outcomes Measures in Rheumatology–Osteoarthritis Research Society International (OMERACT-OARSI) “strict responder” definition; and the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT)–defined proportion of patients achieving substantial improvement in pain.
At the 4- and 8-week follow-up visits post injection, only the FX006 group achieved the AAOS threshold of improvement that’s deemed both statistically and clinically significant. Standard triamcinolone couldn’t reach that bar, even at week 4. This makes FX006 the first intra-articular treatment for knee OA to achieve this stringent standard for a clinically meaningful effect. By week 12, the improvement in pain in the FX006 group had slipped to the level of ‘‘statistically and possibly clinically significant.” At weeks 16-24 following a single injection, the FX006 results were no longer statistically or clinically significant.
A significantly greater percentage of the FX006 group met the OMERACT-OARSI strict responder definition of substantial pain improvement at weeks 4, 8, and 12, compared with the standard triamcinolone and placebo groups. The degree of pain improvement in the FX006 group remained superior to placebo through week 16. The OMERACT-OARSI definition of substantial improvement requires at least a 50% improvement in the WOMAC-A pain score plus an absolute improvement of 20 points or more on the WOMAC-A pain score or WOMAC-C physical function 100-point normalized scale.
Substantial clinical improvement as defined by the IMMPACT criteria requires at least a 50% improvement from baseline in the WOMAC-A pain score. Roughly 60% and 50% of the FX006 group met that standard at weeks 4 and 8, respectively, rates that were significantly higher than for standard triamcinolone. The FX006 group’s IMMPACT substantial improvement rate significantly exceeded that of placebo-treated controls throughout all 24 weeks.
These studies as well as the pooled analysis were funded by Flexion Therapeutics.
FX006 is a type of steroid for joint injection that is formulated to stay in the joint longer than typical steroids through the use of microsphere technology. Typical intra-articular steroid injections tend to provide benefit over the short term, and as described by the Cochrane review, the greatest effect is only moderate at 1-2 weeks and decreases from there, with small effects at 13 weeks and none at 26 weeks (Cochrane Database Syst Rev. 2015;10:CD005328).
As we have previously reported (Semin Arthritis Rheum. 2014;43:701-12), intra-articular corticosteroids are widely recommended by professional societies for the management of knee OA, although a specific formulation is not generally given. This compound may fill an important treatment gap by extending the efficacy of a treatment that is generally accepted as useful and safe for this common painful condition. Also, given the controversy surrounding other intra-articular therapies, it may provide a safe and effective alternative for patients who have not benefited from, or not tolerated, one or more traditional intra-articular steroid injection(s).
Amanda E. Nelson, MD, is with the division of rheumatology, allergy, and immunology and the Thurston Arthritis Research Center at the University of North Carolina, Chapel Hill. She is a consultant to GlaxoSmithKline and has received honoraria for online presentations for MedScape and QuantiaMD regarding OA treatment guidelines.
FX006 is a type of steroid for joint injection that is formulated to stay in the joint longer than typical steroids through the use of microsphere technology. Typical intra-articular steroid injections tend to provide benefit over the short term, and as described by the Cochrane review, the greatest effect is only moderate at 1-2 weeks and decreases from there, with small effects at 13 weeks and none at 26 weeks (Cochrane Database Syst Rev. 2015;10:CD005328).
As we have previously reported (Semin Arthritis Rheum. 2014;43:701-12), intra-articular corticosteroids are widely recommended by professional societies for the management of knee OA, although a specific formulation is not generally given. This compound may fill an important treatment gap by extending the efficacy of a treatment that is generally accepted as useful and safe for this common painful condition. Also, given the controversy surrounding other intra-articular therapies, it may provide a safe and effective alternative for patients who have not benefited from, or not tolerated, one or more traditional intra-articular steroid injection(s).
Amanda E. Nelson, MD, is with the division of rheumatology, allergy, and immunology and the Thurston Arthritis Research Center at the University of North Carolina, Chapel Hill. She is a consultant to GlaxoSmithKline and has received honoraria for online presentations for MedScape and QuantiaMD regarding OA treatment guidelines.
FX006 is a type of steroid for joint injection that is formulated to stay in the joint longer than typical steroids through the use of microsphere technology. Typical intra-articular steroid injections tend to provide benefit over the short term, and as described by the Cochrane review, the greatest effect is only moderate at 1-2 weeks and decreases from there, with small effects at 13 weeks and none at 26 weeks (Cochrane Database Syst Rev. 2015;10:CD005328).
As we have previously reported (Semin Arthritis Rheum. 2014;43:701-12), intra-articular corticosteroids are widely recommended by professional societies for the management of knee OA, although a specific formulation is not generally given. This compound may fill an important treatment gap by extending the efficacy of a treatment that is generally accepted as useful and safe for this common painful condition. Also, given the controversy surrounding other intra-articular therapies, it may provide a safe and effective alternative for patients who have not benefited from, or not tolerated, one or more traditional intra-articular steroid injection(s).
Amanda E. Nelson, MD, is with the division of rheumatology, allergy, and immunology and the Thurston Arthritis Research Center at the University of North Carolina, Chapel Hill. She is a consultant to GlaxoSmithKline and has received honoraria for online presentations for MedScape and QuantiaMD regarding OA treatment guidelines.
LAS VEGAS – The investigational agent FX006 brought improvements in pain and function in patients with knee osteoarthritis that were not only statistically significant but also clinically meaningful by three different yardsticks, according to Scott Kelley, MD.
FX006 (Zilretta) is an extended-release, microsphere-based formulation of triamcinolone acetonide for intra-articular injection now under review for marketing approval by the Food and Drug Administration, which has said it will render a decision in October, Dr. Kelley reported at the World Congress on Osteoarthritis.
He presented a post hoc pooled analysis of the 798 patients with knee OA who participated in two phase II randomized, double-blind clinical trials and in an identically designed pivotal phase III trial of a single 40-mg intra-articular injection of FX006. The three studies included 324 patients who got FX006, 212 who received a single 40-mg intra-articular injection of standard triamcinolone acetonide crystalline suspension, and 262 who got a placebo injection of 5 mL of saline.
All participants had radiographically documented symptomatic knee OA with baseline daily pain scores of 6-9 on a 0-10 scale, corresponding to pain in the moderate-to-severe range. Patients telephoned in their average daily pain scores every day during the studies, one of which lasted 12 weeks while the other two ran for 24 weeks. Patients also visited their clinician every 4 weeks for Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) assessments of pain, stiffness, and physical function.
This secondary analysis was undertaken to demonstrate that FX006 distinguishes itself from current nonsurgical treatments for knee OA, which typically achieve clinical effects that are small, transient, and not clinically relevant, Dr. Kelley said at the congress sponsored by the Osteoarthritis Research Society International.
“What’s different about this product formulation is it maintains a prolonged release of triamcinolone acetonide inside the synovial fluid. The pharmacology has demonstrated prolonged residence time in synovial fluid out to at least 12 weeks after intra-articular administration. In addition, it mitigates the peak plasma level after intra-articular administration, so it blunts the level of corticosteroid in plasma and has a lower systemic exposure over time,” he said.
The clinical relevance of the outcomes achieved in the pooled studies was assessed using three different metrics: the American Academy of Orthopaedic Surgeons (AAOS) criteria for determining whether a result represents a minimal clinically important improvement; the Outcomes Measures in Rheumatology–Osteoarthritis Research Society International (OMERACT-OARSI) “strict responder” definition; and the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT)–defined proportion of patients achieving substantial improvement in pain.
At the 4- and 8-week follow-up visits post injection, only the FX006 group achieved the AAOS threshold of improvement that’s deemed both statistically and clinically significant. Standard triamcinolone couldn’t reach that bar, even at week 4. This makes FX006 the first intra-articular treatment for knee OA to achieve this stringent standard for a clinically meaningful effect. By week 12, the improvement in pain in the FX006 group had slipped to the level of ‘‘statistically and possibly clinically significant.” At weeks 16-24 following a single injection, the FX006 results were no longer statistically or clinically significant.
A significantly greater percentage of the FX006 group met the OMERACT-OARSI strict responder definition of substantial pain improvement at weeks 4, 8, and 12, compared with the standard triamcinolone and placebo groups. The degree of pain improvement in the FX006 group remained superior to placebo through week 16. The OMERACT-OARSI definition of substantial improvement requires at least a 50% improvement in the WOMAC-A pain score plus an absolute improvement of 20 points or more on the WOMAC-A pain score or WOMAC-C physical function 100-point normalized scale.
Substantial clinical improvement as defined by the IMMPACT criteria requires at least a 50% improvement from baseline in the WOMAC-A pain score. Roughly 60% and 50% of the FX006 group met that standard at weeks 4 and 8, respectively, rates that were significantly higher than for standard triamcinolone. The FX006 group’s IMMPACT substantial improvement rate significantly exceeded that of placebo-treated controls throughout all 24 weeks.
These studies as well as the pooled analysis were funded by Flexion Therapeutics.
LAS VEGAS – The investigational agent FX006 brought improvements in pain and function in patients with knee osteoarthritis that were not only statistically significant but also clinically meaningful by three different yardsticks, according to Scott Kelley, MD.
FX006 (Zilretta) is an extended-release, microsphere-based formulation of triamcinolone acetonide for intra-articular injection now under review for marketing approval by the Food and Drug Administration, which has said it will render a decision in October, Dr. Kelley reported at the World Congress on Osteoarthritis.
He presented a post hoc pooled analysis of the 798 patients with knee OA who participated in two phase II randomized, double-blind clinical trials and in an identically designed pivotal phase III trial of a single 40-mg intra-articular injection of FX006. The three studies included 324 patients who got FX006, 212 who received a single 40-mg intra-articular injection of standard triamcinolone acetonide crystalline suspension, and 262 who got a placebo injection of 5 mL of saline.
All participants had radiographically documented symptomatic knee OA with baseline daily pain scores of 6-9 on a 0-10 scale, corresponding to pain in the moderate-to-severe range. Patients telephoned in their average daily pain scores every day during the studies, one of which lasted 12 weeks while the other two ran for 24 weeks. Patients also visited their clinician every 4 weeks for Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) assessments of pain, stiffness, and physical function.
This secondary analysis was undertaken to demonstrate that FX006 distinguishes itself from current nonsurgical treatments for knee OA, which typically achieve clinical effects that are small, transient, and not clinically relevant, Dr. Kelley said at the congress sponsored by the Osteoarthritis Research Society International.
“What’s different about this product formulation is it maintains a prolonged release of triamcinolone acetonide inside the synovial fluid. The pharmacology has demonstrated prolonged residence time in synovial fluid out to at least 12 weeks after intra-articular administration. In addition, it mitigates the peak plasma level after intra-articular administration, so it blunts the level of corticosteroid in plasma and has a lower systemic exposure over time,” he said.
The clinical relevance of the outcomes achieved in the pooled studies was assessed using three different metrics: the American Academy of Orthopaedic Surgeons (AAOS) criteria for determining whether a result represents a minimal clinically important improvement; the Outcomes Measures in Rheumatology–Osteoarthritis Research Society International (OMERACT-OARSI) “strict responder” definition; and the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT)–defined proportion of patients achieving substantial improvement in pain.
At the 4- and 8-week follow-up visits post injection, only the FX006 group achieved the AAOS threshold of improvement that’s deemed both statistically and clinically significant. Standard triamcinolone couldn’t reach that bar, even at week 4. This makes FX006 the first intra-articular treatment for knee OA to achieve this stringent standard for a clinically meaningful effect. By week 12, the improvement in pain in the FX006 group had slipped to the level of ‘‘statistically and possibly clinically significant.” At weeks 16-24 following a single injection, the FX006 results were no longer statistically or clinically significant.
A significantly greater percentage of the FX006 group met the OMERACT-OARSI strict responder definition of substantial pain improvement at weeks 4, 8, and 12, compared with the standard triamcinolone and placebo groups. The degree of pain improvement in the FX006 group remained superior to placebo through week 16. The OMERACT-OARSI definition of substantial improvement requires at least a 50% improvement in the WOMAC-A pain score plus an absolute improvement of 20 points or more on the WOMAC-A pain score or WOMAC-C physical function 100-point normalized scale.
Substantial clinical improvement as defined by the IMMPACT criteria requires at least a 50% improvement from baseline in the WOMAC-A pain score. Roughly 60% and 50% of the FX006 group met that standard at weeks 4 and 8, respectively, rates that were significantly higher than for standard triamcinolone. The FX006 group’s IMMPACT substantial improvement rate significantly exceeded that of placebo-treated controls throughout all 24 weeks.
These studies as well as the pooled analysis were funded by Flexion Therapeutics.
AT OARSI 2017
Key clinical point:
Major finding: The investigational extended-release formulation of triamcinolone, known as FX006 (Zilretta), is the first intra-articular treatment for knee OA to meet the American Academy of Orthopaedic Surgeons’ stringent standard for a clinically meaningful, as opposed to merely statistically significant, effect.
Data source: A post hoc pooled analysis of three randomized, double-blind clinical trials involving nearly 800 patients with knee osteoarthritis.
Disclosures: The pooled analysis was funded by Flexion Therapeutics and presented by a company officer.
Spontaneous coronary artery dissection: New insights
Washington – Patients with spontaneous coronary artery dissection as their presentation of acute coronary syndrome have a markedly better long-term survival rate than do patients with ACS in its various other forms, Rahul Potluri, MD, reported at the annual meeting of the American College of Cardiology.
In his retrospective cohort study of 182 U.K. patients diagnosed with spontaneous coronary artery dissection (SCAD) as the cause of their ACS and 32,981 controls with ACS without SCAD, the 15-year all-cause mortality rate was 10.4% in the SCAD group vs. 32.1% in the controls.
Although SCAD was first described in 1931, half of the roughly 1,500 cases reported in the medical literature have been published within the past 5 years. That makes this series of 182 SCAD patients with 15-year outcome data unique in providing the longest follow-up to date reported in a sizable patient series, said Dr. Potluri of the University of Alberta, Edmonton, and Aston University in Birmingham, England.
SCAD is a rupture in a coronary artery wall not related to atherosclerotic heart disease, trauma, or iatrogenic causes. The dissection is thought to result from an intimal tear or medial hemorrhage from the vasa vasorum, with subsequent accumulation of blood in a false lumen.
It’s not entirely unexpected that patients with SCAD have a better long-term prognosis than do those with ACS without SCAD, Dr. Potluri said. After all, patients with SCAD tend to be considerably younger: In Dr. Potluri’s series, the average age was younger than 52 years, vs. 66 years in controls. Plus they had lower levels of cardiovascular risk factors, and by definition they were free of atherosclerotic heart disease. But SCAD often occurs in conjunction with fibromuscular dysplasia, and the long-term health implications of that combination have not been well studied.
In a multivariate logistic regression analysis adjusted for age, sex, ethnicity, and comorbid conditions, the likelihood of dying within 5 years was 89% greater in the non-SCAD group. During follow-up, the non-SCAD ACS group was 4.1-fold more likely to have another ACS and 32% more likely to be diagnosed with heart failure.
SCAD was typically managed conservatively in Dr. Potluri’s series: In the SCAD group, 11% underwent PCI and 2.7% had CABG, compared with 51% and 10.7%, respectively, of controls.
“Conservative treatment appears to be safe in the SCAD patient population,” he said.
The prevalence of SCAD in his series of more than 33,000 patients admitted for ACS to U.K. hospitals in 2000-2014 was 0.54%. Dr. Potluri said that low figure likely reflects considerable underreporting due to the fact that some data were from the early 2000s, when SCAD was still largely below physicians’ radar.
Dr. Potluri is an authority on big data analytics in medical research. He formed his 182-patient SCAD series using ACALM (Algorithm for Comorbidity, Associations, Length of Stay, and Mortality), an analytic tool he developed years ago as a medical student. At the time of his SCAD study, the ACALM registry included anonymous, deidentified data on 1.8 million U.K. patients. The ACALM methodology utilizes a form of artificial intelligence known as novel field derivation to analyze huge amalgamated data sets. This is made possible by the fact that all U.K. hospitals report patient data in an identical standardized way, which is not the case in the United States.
Dr. Potluri has previously applied the ACALM methodology to a variety of other health care issues, including studies of an association between hyperlipidemia and breast cancer, the relationship between cardiovascular disease and mental health, and the so-called weekend effect, whereby U.K. patients hospitalized for cardiovascular reasons on the weekend have higher mortality than do those admitted on weekdays.
THE ACALM registry now exceeds 4 million patients. Dr. Potluri said he plans to analyze this full group to develop a large, comprehensive SCAD patient registry. This will enable investigators to evaluate potential psychosocial risk factors for SCAD, the role of fibromuscular dysplasia and connective tissue diseases, and other practical questions.
He reported having no financial conflicts regarding his study.
Washington – Patients with spontaneous coronary artery dissection as their presentation of acute coronary syndrome have a markedly better long-term survival rate than do patients with ACS in its various other forms, Rahul Potluri, MD, reported at the annual meeting of the American College of Cardiology.
In his retrospective cohort study of 182 U.K. patients diagnosed with spontaneous coronary artery dissection (SCAD) as the cause of their ACS and 32,981 controls with ACS without SCAD, the 15-year all-cause mortality rate was 10.4% in the SCAD group vs. 32.1% in the controls.
Although SCAD was first described in 1931, half of the roughly 1,500 cases reported in the medical literature have been published within the past 5 years. That makes this series of 182 SCAD patients with 15-year outcome data unique in providing the longest follow-up to date reported in a sizable patient series, said Dr. Potluri of the University of Alberta, Edmonton, and Aston University in Birmingham, England.
SCAD is a rupture in a coronary artery wall not related to atherosclerotic heart disease, trauma, or iatrogenic causes. The dissection is thought to result from an intimal tear or medial hemorrhage from the vasa vasorum, with subsequent accumulation of blood in a false lumen.
It’s not entirely unexpected that patients with SCAD have a better long-term prognosis than do those with ACS without SCAD, Dr. Potluri said. After all, patients with SCAD tend to be considerably younger: In Dr. Potluri’s series, the average age was younger than 52 years, vs. 66 years in controls. Plus they had lower levels of cardiovascular risk factors, and by definition they were free of atherosclerotic heart disease. But SCAD often occurs in conjunction with fibromuscular dysplasia, and the long-term health implications of that combination have not been well studied.
In a multivariate logistic regression analysis adjusted for age, sex, ethnicity, and comorbid conditions, the likelihood of dying within 5 years was 89% greater in the non-SCAD group. During follow-up, the non-SCAD ACS group was 4.1-fold more likely to have another ACS and 32% more likely to be diagnosed with heart failure.
SCAD was typically managed conservatively in Dr. Potluri’s series: In the SCAD group, 11% underwent PCI and 2.7% had CABG, compared with 51% and 10.7%, respectively, of controls.
“Conservative treatment appears to be safe in the SCAD patient population,” he said.
The prevalence of SCAD in his series of more than 33,000 patients admitted for ACS to U.K. hospitals in 2000-2014 was 0.54%. Dr. Potluri said that low figure likely reflects considerable underreporting due to the fact that some data were from the early 2000s, when SCAD was still largely below physicians’ radar.
Dr. Potluri is an authority on big data analytics in medical research. He formed his 182-patient SCAD series using ACALM (Algorithm for Comorbidity, Associations, Length of Stay, and Mortality), an analytic tool he developed years ago as a medical student. At the time of his SCAD study, the ACALM registry included anonymous, deidentified data on 1.8 million U.K. patients. The ACALM methodology utilizes a form of artificial intelligence known as novel field derivation to analyze huge amalgamated data sets. This is made possible by the fact that all U.K. hospitals report patient data in an identical standardized way, which is not the case in the United States.
Dr. Potluri has previously applied the ACALM methodology to a variety of other health care issues, including studies of an association between hyperlipidemia and breast cancer, the relationship between cardiovascular disease and mental health, and the so-called weekend effect, whereby U.K. patients hospitalized for cardiovascular reasons on the weekend have higher mortality than do those admitted on weekdays.
THE ACALM registry now exceeds 4 million patients. Dr. Potluri said he plans to analyze this full group to develop a large, comprehensive SCAD patient registry. This will enable investigators to evaluate potential psychosocial risk factors for SCAD, the role of fibromuscular dysplasia and connective tissue diseases, and other practical questions.
He reported having no financial conflicts regarding his study.
Washington – Patients with spontaneous coronary artery dissection as their presentation of acute coronary syndrome have a markedly better long-term survival rate than do patients with ACS in its various other forms, Rahul Potluri, MD, reported at the annual meeting of the American College of Cardiology.
In his retrospective cohort study of 182 U.K. patients diagnosed with spontaneous coronary artery dissection (SCAD) as the cause of their ACS and 32,981 controls with ACS without SCAD, the 15-year all-cause mortality rate was 10.4% in the SCAD group vs. 32.1% in the controls.
Although SCAD was first described in 1931, half of the roughly 1,500 cases reported in the medical literature have been published within the past 5 years. That makes this series of 182 SCAD patients with 15-year outcome data unique in providing the longest follow-up to date reported in a sizable patient series, said Dr. Potluri of the University of Alberta, Edmonton, and Aston University in Birmingham, England.
SCAD is a rupture in a coronary artery wall not related to atherosclerotic heart disease, trauma, or iatrogenic causes. The dissection is thought to result from an intimal tear or medial hemorrhage from the vasa vasorum, with subsequent accumulation of blood in a false lumen.
It’s not entirely unexpected that patients with SCAD have a better long-term prognosis than do those with ACS without SCAD, Dr. Potluri said. After all, patients with SCAD tend to be considerably younger: In Dr. Potluri’s series, the average age was younger than 52 years, vs. 66 years in controls. Plus they had lower levels of cardiovascular risk factors, and by definition they were free of atherosclerotic heart disease. But SCAD often occurs in conjunction with fibromuscular dysplasia, and the long-term health implications of that combination have not been well studied.
In a multivariate logistic regression analysis adjusted for age, sex, ethnicity, and comorbid conditions, the likelihood of dying within 5 years was 89% greater in the non-SCAD group. During follow-up, the non-SCAD ACS group was 4.1-fold more likely to have another ACS and 32% more likely to be diagnosed with heart failure.
SCAD was typically managed conservatively in Dr. Potluri’s series: In the SCAD group, 11% underwent PCI and 2.7% had CABG, compared with 51% and 10.7%, respectively, of controls.
“Conservative treatment appears to be safe in the SCAD patient population,” he said.
The prevalence of SCAD in his series of more than 33,000 patients admitted for ACS to U.K. hospitals in 2000-2014 was 0.54%. Dr. Potluri said that low figure likely reflects considerable underreporting due to the fact that some data were from the early 2000s, when SCAD was still largely below physicians’ radar.
Dr. Potluri is an authority on big data analytics in medical research. He formed his 182-patient SCAD series using ACALM (Algorithm for Comorbidity, Associations, Length of Stay, and Mortality), an analytic tool he developed years ago as a medical student. At the time of his SCAD study, the ACALM registry included anonymous, deidentified data on 1.8 million U.K. patients. The ACALM methodology utilizes a form of artificial intelligence known as novel field derivation to analyze huge amalgamated data sets. This is made possible by the fact that all U.K. hospitals report patient data in an identical standardized way, which is not the case in the United States.
Dr. Potluri has previously applied the ACALM methodology to a variety of other health care issues, including studies of an association between hyperlipidemia and breast cancer, the relationship between cardiovascular disease and mental health, and the so-called weekend effect, whereby U.K. patients hospitalized for cardiovascular reasons on the weekend have higher mortality than do those admitted on weekdays.
THE ACALM registry now exceeds 4 million patients. Dr. Potluri said he plans to analyze this full group to develop a large, comprehensive SCAD patient registry. This will enable investigators to evaluate potential psychosocial risk factors for SCAD, the role of fibromuscular dysplasia and connective tissue diseases, and other practical questions.
He reported having no financial conflicts regarding his study.
At ACC 17
Key clinical point:
Major finding: The 15-year all-cause mortality rate was 10% in patients with spontaneous coronary artery dissection, compared with 32% in those with ACS without spontaneous coronary artery dissection.
Data source: A retrospective cohort study including 15-year outcomes for 182 patients with spontaneous coronary artery dissection and more than 32,000 controls with ACS without dissection.
Disclosures: The study presenter reported having no financial conflicts.
Knee osteoarthritis linked to premature mortality
LAS VEGAS – Knee osteoarthritis was independently associated with increased risk of premature mortality in the largest-ever meta-analysis to examine the issue, Kirsten M. Leyland, PhD, reported at the World Congress on Osteoarthritis.
The meta-analysis used individual patient-level data on 11,954 participants in six prospective observational cohort studies conducted in four countries. The key finding: Subjects with symptomatic and radiographically confirmed knee OA were at 17% greater risk of premature mortality, compared with pain-free, radiographically negative participants, independent of age, sex, and race, according to Dr. Leyland, a musculoskeletal epidemiologist at the University of Oxford (England).
The six prospective cohort studies included in the new analysis are well known in the field of osteoarthritis research: the Framingham (Mass.) Osteoarthritis Study, the Rotterdam (the Netherlands) Study, the Multicenter Osteoarthritis Study (MOST), the Johnston County (N.C.) Osteoarthritis Project, the Tasmanian Older Adult Cohort Study, and the Chingford (U.K.) 1000 Women Study. These studies feature 7.4-23.7 years of prospective follow-up.
In an interview, Dr. Leyland said that the current analysis uses all-cause mortality as the outcome because causes of death are recorded differently in the countries where the studies are taking place. It will take several more years for statisticians to harmonize the cause-of-death data and draw definitive conclusions; however, preliminary analysis suggests the causes of premature mortality in the knee OA patients are disproportionately cardiovascular, she added.
Dr. Leyland reported having no financial conflicts regarding the study, which was supported by Arthritis Research UK.
LAS VEGAS – Knee osteoarthritis was independently associated with increased risk of premature mortality in the largest-ever meta-analysis to examine the issue, Kirsten M. Leyland, PhD, reported at the World Congress on Osteoarthritis.
The meta-analysis used individual patient-level data on 11,954 participants in six prospective observational cohort studies conducted in four countries. The key finding: Subjects with symptomatic and radiographically confirmed knee OA were at 17% greater risk of premature mortality, compared with pain-free, radiographically negative participants, independent of age, sex, and race, according to Dr. Leyland, a musculoskeletal epidemiologist at the University of Oxford (England).
The six prospective cohort studies included in the new analysis are well known in the field of osteoarthritis research: the Framingham (Mass.) Osteoarthritis Study, the Rotterdam (the Netherlands) Study, the Multicenter Osteoarthritis Study (MOST), the Johnston County (N.C.) Osteoarthritis Project, the Tasmanian Older Adult Cohort Study, and the Chingford (U.K.) 1000 Women Study. These studies feature 7.4-23.7 years of prospective follow-up.
In an interview, Dr. Leyland said that the current analysis uses all-cause mortality as the outcome because causes of death are recorded differently in the countries where the studies are taking place. It will take several more years for statisticians to harmonize the cause-of-death data and draw definitive conclusions; however, preliminary analysis suggests the causes of premature mortality in the knee OA patients are disproportionately cardiovascular, she added.
Dr. Leyland reported having no financial conflicts regarding the study, which was supported by Arthritis Research UK.
LAS VEGAS – Knee osteoarthritis was independently associated with increased risk of premature mortality in the largest-ever meta-analysis to examine the issue, Kirsten M. Leyland, PhD, reported at the World Congress on Osteoarthritis.
The meta-analysis used individual patient-level data on 11,954 participants in six prospective observational cohort studies conducted in four countries. The key finding: Subjects with symptomatic and radiographically confirmed knee OA were at 17% greater risk of premature mortality, compared with pain-free, radiographically negative participants, independent of age, sex, and race, according to Dr. Leyland, a musculoskeletal epidemiologist at the University of Oxford (England).
The six prospective cohort studies included in the new analysis are well known in the field of osteoarthritis research: the Framingham (Mass.) Osteoarthritis Study, the Rotterdam (the Netherlands) Study, the Multicenter Osteoarthritis Study (MOST), the Johnston County (N.C.) Osteoarthritis Project, the Tasmanian Older Adult Cohort Study, and the Chingford (U.K.) 1000 Women Study. These studies feature 7.4-23.7 years of prospective follow-up.
In an interview, Dr. Leyland said that the current analysis uses all-cause mortality as the outcome because causes of death are recorded differently in the countries where the studies are taking place. It will take several more years for statisticians to harmonize the cause-of-death data and draw definitive conclusions; however, preliminary analysis suggests the causes of premature mortality in the knee OA patients are disproportionately cardiovascular, she added.
Dr. Leyland reported having no financial conflicts regarding the study, which was supported by Arthritis Research UK.
AT OARSI 2017
Key clinical point:
Major finding: Knee osteoarthritis is independently associated with a 17% increased likelihood of premature mortality.
Data source: This meta-analysis harmonized individual patient-level data drawn from six major prospective, population-based cohort studies worldwide.
Disclosures: The presenter reported having no financial conflicts regarding the study, which was supported by Arthritis Research UK.
Digoxin and heart failure mortality: The Swedes weigh in
WASHINGTON – The use of digoxin by Swedish Heart Failure Registry participants with heart failure with reduced ejection fraction was associated with significantly increased risk of all-cause mortality if they had concomitant paroxysmal atrial fibrillation or were in normal sinus rhythm, Gianluigi Savarese, MD, reported at the annual meeting of the American College of Cardiology.
In contrast, digoxin in Swedish patients with heart failure with reduced ejection fraction (HFrEF) and permanent atrial fibrillation (AF) was associated with a reduced risk of heart failure hospitalization but had no impact on mortality, added Dr. Savarese of the Karolinska Institute in Stockholm.
The Swedish Heart Failure Registry includes the majority of heart failure patients in that country. Data on 80 variables gets collected for each participant.
Dr. Savarese reported on 23,708 Swedes with HFrEF, 18% of whom were on digoxin. In a multivariate Cox regression analysis adjusted for numerous potential confounders, the use of digoxin was associated with an 8% increased risk of all-cause mortality and a 10% lower risk of heart failure hospitalizations during up to 11 years of follow-up.
In the 12,162 patients with HFrEF and comorbid AF, 30% of whom were on digoxin, the drug was associated with a 12% reduction in heart failure hospitalizations and had no effect on all-cause mortality.
In contrast, among patients with HFrEF without AF, 5% of whom were taking digoxin, use of the drug was associated with an adjusted 31% increase in mortality risk. But digoxin didn’t affect the risk of heart failure hospitalization one way or the other in this group.
Stratifying subjects by their type of AF, the use of digoxin in patients with HFrEF and permanent AF was associated with a 16% reduction in risk of heart failure hospitalization with no impact on mortality. In contrast, among the 2,723 patients with HFrEF and paroxysmal AF, digoxin was associated with a 29% increase in the risk of mortality and no effect on hospitalization.
Current ACC/American Heart Association heart failure guidelines give digoxin a strong Class IIa recommendation for reducing heart failure hospitalizations in patients with HFrEF. European Society of Cardiology guidelines provide a Class IIb recommendation for digoxin to reduce the risk of hospitalization in patients with symptomatic HFrEF in normal sinus rhythm.
Dr. Savarese said he and his coinvestigators decided to examine the impact of digoxin in the Swedish Heart Failure Registry because despite the guideline support for the drug’s use, recent years have brought conflicting data regarding digoxin’s impact on mortality. For example, a meta-analysis of nine studies in more than 235,000 AF patients, seven studies in patients with heart failure, and three in patients with both disorders showed that digoxin was associated with a 29% increased mortality risk in AF patients and a 14% increase in those with heart failure (Eur Heart J. 2015 Jul 21;36[28]:1831-8).
Moreover, at a late-breaking clinical trial session elsewhere at ACC 17, a secondary analysis of the roughly 18,000-patient ARISTOTLE trial came down emphatically on the side of avoiding the venerable drug in patients with AF, where it was found to be associated with a fourfold increased risk of sudden death.
Session comoderator Lee R. Goldberg, MD, medical director of the University of Pennsylvania Heart Failure and Transplantation Program in Philadelphia, observed that the use of digoxin has become quite controversial. He posed a question to Dr. Savarese: “Every few months someone writes the last paper on digoxin as they look at thousands of patients, and then there’s always a new paper. If you were to rewrite the guidelines now, what would you recommend for digoxin?”
Dr. Savarese replied that the current guidelines rely heavily upon the results of a 20-year-old randomized, double-blind, placebo-controlled trial of digoxin in heart failure (N Engl J Med. 1997 Feb 20;336[8]:525-33). Those study participants look nothing at all like the heart failure patients physicians see today in clinical practice. Hardly any of them were on what today is guideline-directed medical therapy with a beta-blocker or mineralocorticoid receptor antagonist. So the trial’s applicability is dubious.
“Our Swedish data are observational. They are hypothesis-generating. They should drive trialists to design a new trial of digoxin. But I think we all know that’s not going to happen. So actually I don’t think there is still space for a IIb or IIa recommendation for digoxin in the guidelines,” Dr. Savarese said.
He reported having no financial conflicts.
WASHINGTON – The use of digoxin by Swedish Heart Failure Registry participants with heart failure with reduced ejection fraction was associated with significantly increased risk of all-cause mortality if they had concomitant paroxysmal atrial fibrillation or were in normal sinus rhythm, Gianluigi Savarese, MD, reported at the annual meeting of the American College of Cardiology.
In contrast, digoxin in Swedish patients with heart failure with reduced ejection fraction (HFrEF) and permanent atrial fibrillation (AF) was associated with a reduced risk of heart failure hospitalization but had no impact on mortality, added Dr. Savarese of the Karolinska Institute in Stockholm.
The Swedish Heart Failure Registry includes the majority of heart failure patients in that country. Data on 80 variables gets collected for each participant.
Dr. Savarese reported on 23,708 Swedes with HFrEF, 18% of whom were on digoxin. In a multivariate Cox regression analysis adjusted for numerous potential confounders, the use of digoxin was associated with an 8% increased risk of all-cause mortality and a 10% lower risk of heart failure hospitalizations during up to 11 years of follow-up.
In the 12,162 patients with HFrEF and comorbid AF, 30% of whom were on digoxin, the drug was associated with a 12% reduction in heart failure hospitalizations and had no effect on all-cause mortality.
In contrast, among patients with HFrEF without AF, 5% of whom were taking digoxin, use of the drug was associated with an adjusted 31% increase in mortality risk. But digoxin didn’t affect the risk of heart failure hospitalization one way or the other in this group.
Stratifying subjects by their type of AF, the use of digoxin in patients with HFrEF and permanent AF was associated with a 16% reduction in risk of heart failure hospitalization with no impact on mortality. In contrast, among the 2,723 patients with HFrEF and paroxysmal AF, digoxin was associated with a 29% increase in the risk of mortality and no effect on hospitalization.
Current ACC/American Heart Association heart failure guidelines give digoxin a strong Class IIa recommendation for reducing heart failure hospitalizations in patients with HFrEF. European Society of Cardiology guidelines provide a Class IIb recommendation for digoxin to reduce the risk of hospitalization in patients with symptomatic HFrEF in normal sinus rhythm.
Dr. Savarese said he and his coinvestigators decided to examine the impact of digoxin in the Swedish Heart Failure Registry because despite the guideline support for the drug’s use, recent years have brought conflicting data regarding digoxin’s impact on mortality. For example, a meta-analysis of nine studies in more than 235,000 AF patients, seven studies in patients with heart failure, and three in patients with both disorders showed that digoxin was associated with a 29% increased mortality risk in AF patients and a 14% increase in those with heart failure (Eur Heart J. 2015 Jul 21;36[28]:1831-8).
Moreover, at a late-breaking clinical trial session elsewhere at ACC 17, a secondary analysis of the roughly 18,000-patient ARISTOTLE trial came down emphatically on the side of avoiding the venerable drug in patients with AF, where it was found to be associated with a fourfold increased risk of sudden death.
Session comoderator Lee R. Goldberg, MD, medical director of the University of Pennsylvania Heart Failure and Transplantation Program in Philadelphia, observed that the use of digoxin has become quite controversial. He posed a question to Dr. Savarese: “Every few months someone writes the last paper on digoxin as they look at thousands of patients, and then there’s always a new paper. If you were to rewrite the guidelines now, what would you recommend for digoxin?”
Dr. Savarese replied that the current guidelines rely heavily upon the results of a 20-year-old randomized, double-blind, placebo-controlled trial of digoxin in heart failure (N Engl J Med. 1997 Feb 20;336[8]:525-33). Those study participants look nothing at all like the heart failure patients physicians see today in clinical practice. Hardly any of them were on what today is guideline-directed medical therapy with a beta-blocker or mineralocorticoid receptor antagonist. So the trial’s applicability is dubious.
“Our Swedish data are observational. They are hypothesis-generating. They should drive trialists to design a new trial of digoxin. But I think we all know that’s not going to happen. So actually I don’t think there is still space for a IIb or IIa recommendation for digoxin in the guidelines,” Dr. Savarese said.
He reported having no financial conflicts.
WASHINGTON – The use of digoxin by Swedish Heart Failure Registry participants with heart failure with reduced ejection fraction was associated with significantly increased risk of all-cause mortality if they had concomitant paroxysmal atrial fibrillation or were in normal sinus rhythm, Gianluigi Savarese, MD, reported at the annual meeting of the American College of Cardiology.
In contrast, digoxin in Swedish patients with heart failure with reduced ejection fraction (HFrEF) and permanent atrial fibrillation (AF) was associated with a reduced risk of heart failure hospitalization but had no impact on mortality, added Dr. Savarese of the Karolinska Institute in Stockholm.
The Swedish Heart Failure Registry includes the majority of heart failure patients in that country. Data on 80 variables gets collected for each participant.
Dr. Savarese reported on 23,708 Swedes with HFrEF, 18% of whom were on digoxin. In a multivariate Cox regression analysis adjusted for numerous potential confounders, the use of digoxin was associated with an 8% increased risk of all-cause mortality and a 10% lower risk of heart failure hospitalizations during up to 11 years of follow-up.
In the 12,162 patients with HFrEF and comorbid AF, 30% of whom were on digoxin, the drug was associated with a 12% reduction in heart failure hospitalizations and had no effect on all-cause mortality.
In contrast, among patients with HFrEF without AF, 5% of whom were taking digoxin, use of the drug was associated with an adjusted 31% increase in mortality risk. But digoxin didn’t affect the risk of heart failure hospitalization one way or the other in this group.
Stratifying subjects by their type of AF, the use of digoxin in patients with HFrEF and permanent AF was associated with a 16% reduction in risk of heart failure hospitalization with no impact on mortality. In contrast, among the 2,723 patients with HFrEF and paroxysmal AF, digoxin was associated with a 29% increase in the risk of mortality and no effect on hospitalization.
Current ACC/American Heart Association heart failure guidelines give digoxin a strong Class IIa recommendation for reducing heart failure hospitalizations in patients with HFrEF. European Society of Cardiology guidelines provide a Class IIb recommendation for digoxin to reduce the risk of hospitalization in patients with symptomatic HFrEF in normal sinus rhythm.
Dr. Savarese said he and his coinvestigators decided to examine the impact of digoxin in the Swedish Heart Failure Registry because despite the guideline support for the drug’s use, recent years have brought conflicting data regarding digoxin’s impact on mortality. For example, a meta-analysis of nine studies in more than 235,000 AF patients, seven studies in patients with heart failure, and three in patients with both disorders showed that digoxin was associated with a 29% increased mortality risk in AF patients and a 14% increase in those with heart failure (Eur Heart J. 2015 Jul 21;36[28]:1831-8).
Moreover, at a late-breaking clinical trial session elsewhere at ACC 17, a secondary analysis of the roughly 18,000-patient ARISTOTLE trial came down emphatically on the side of avoiding the venerable drug in patients with AF, where it was found to be associated with a fourfold increased risk of sudden death.
Session comoderator Lee R. Goldberg, MD, medical director of the University of Pennsylvania Heart Failure and Transplantation Program in Philadelphia, observed that the use of digoxin has become quite controversial. He posed a question to Dr. Savarese: “Every few months someone writes the last paper on digoxin as they look at thousands of patients, and then there’s always a new paper. If you were to rewrite the guidelines now, what would you recommend for digoxin?”
Dr. Savarese replied that the current guidelines rely heavily upon the results of a 20-year-old randomized, double-blind, placebo-controlled trial of digoxin in heart failure (N Engl J Med. 1997 Feb 20;336[8]:525-33). Those study participants look nothing at all like the heart failure patients physicians see today in clinical practice. Hardly any of them were on what today is guideline-directed medical therapy with a beta-blocker or mineralocorticoid receptor antagonist. So the trial’s applicability is dubious.
“Our Swedish data are observational. They are hypothesis-generating. They should drive trialists to design a new trial of digoxin. But I think we all know that’s not going to happen. So actually I don’t think there is still space for a IIb or IIa recommendation for digoxin in the guidelines,” Dr. Savarese said.
He reported having no financial conflicts.
AT ACC 17
Key clinical point:
Major finding: The use of digoxin in patients with heart failure with reduced ejection fraction was associated with significantly increased risk of all-cause mortality if they had concomitant paroxysmal atrial fibrillation or were in normal sinus rhythm.
Data source: An observational study of nearly 24,000 patients enrolled in the Swedish Heart Failure Registry, 18% of whom were on digoxin.
Disclosures: The study presenter reported having no financial conflicts.
Address procrastination, disorganization in hoarding disorder
SAN FRANCISCO – Procrastination, disorganization, indecisiveness, and perfectionism each are significant independent predictors of hoarding severity, even though none of these associated factors is included in the DSM-5 diagnostic criteria for hoarding disorder, according to Sanjaya Saxena, MD.
Of these four associated factors, disorganization and procrastination had the strongest correlation with hoarding severity in his study. Patients meeting the DSM-5 criteria for hoarding disorder scored significantly higher on measures of disorganization and procrastination than did patients with nonhoarding obsessive-compulsive disorder or anxiety disorders, said Dr. Saxena, professor of psychiatry and director of the obsessive-compulsive disorders program at the University of California, San Diego.
The DSM-5 lists as the core symptoms of hoarding disorder difficulty in discarding possessions; perceived need to save items; excessive acquisition, clutter, and resultant distress; and impaired functioning. But while procrastination, disorganization, perfectionism, and indecisiveness aren’t included in the diagnostic criteria, Dr. Saxena said he and some other experts have considered those features to be characteristic of affected individuals. So he decided to formally test the strength of the associations.
He reported on 21 patients with hoarding disorder and 13 controls with nonhoarding OCD or an anxiety disorder. All subjects completed a battery of assessment tools, including the Beck Depression Inventory, the Beck Anxiety Inventory, the Frost Multidimensional Perfectionism Scale, the Frost Indecisiveness Scale, the Adult Inventory of Procrastination Scale, and three different measures of hoarding severity. Participants also completed a disorganization index based on their answers to three questions drawn from the Swanson, Nolan, and Pelham (SNAP-IV) Rating Scale: How often did you have difficulty organizing tasks and activities as a child? How disorganized are you in your thinking, planning, and time management? And how disorganized are your belongings at home?
Neither disorganization, procrastination, perfectionism, nor indecisiveness turned out to be associated with severity of nonhoarding OCD or anxiety disorder symptoms. Surprisingly, no significant differences were found between hoarding disorder patients and controls on the measures of indecisiveness or perfectionism, Dr. Saxena said. And the two groups did not differ in their levels of anxiety and depression.
However, levels of procrastination and disorganization were strongly correlated with hoarding severity as assessed via the Saving Inventory – Revised, the UCLA Hoarding Severity Scale, and the Hoarding Rating Scale. The hoarding disorder group’s average score on the disorganization index was 5.67, more than twice that of the 2.67 in the control group. And patients with hoarding disorder had an average Adult Inventory of Procrastination score of 50.9 out of a possible maximum of 75 points, compared with 41 in controls.
In a multivariate regression analysis, age and level of depression collectively explained 23.5% of the variance in hoarding severity scores in the study population. Disorganization independently explained an additional 29.9% of the variance, and procrastination accounted for another 19.1%, Dr. Saxena reported.
He reported having no financial conflicts regarding his study, which was funded by the university’s department of psychiatry.
SAN FRANCISCO – Procrastination, disorganization, indecisiveness, and perfectionism each are significant independent predictors of hoarding severity, even though none of these associated factors is included in the DSM-5 diagnostic criteria for hoarding disorder, according to Sanjaya Saxena, MD.
Of these four associated factors, disorganization and procrastination had the strongest correlation with hoarding severity in his study. Patients meeting the DSM-5 criteria for hoarding disorder scored significantly higher on measures of disorganization and procrastination than did patients with nonhoarding obsessive-compulsive disorder or anxiety disorders, said Dr. Saxena, professor of psychiatry and director of the obsessive-compulsive disorders program at the University of California, San Diego.
The DSM-5 lists as the core symptoms of hoarding disorder difficulty in discarding possessions; perceived need to save items; excessive acquisition, clutter, and resultant distress; and impaired functioning. But while procrastination, disorganization, perfectionism, and indecisiveness aren’t included in the diagnostic criteria, Dr. Saxena said he and some other experts have considered those features to be characteristic of affected individuals. So he decided to formally test the strength of the associations.
He reported on 21 patients with hoarding disorder and 13 controls with nonhoarding OCD or an anxiety disorder. All subjects completed a battery of assessment tools, including the Beck Depression Inventory, the Beck Anxiety Inventory, the Frost Multidimensional Perfectionism Scale, the Frost Indecisiveness Scale, the Adult Inventory of Procrastination Scale, and three different measures of hoarding severity. Participants also completed a disorganization index based on their answers to three questions drawn from the Swanson, Nolan, and Pelham (SNAP-IV) Rating Scale: How often did you have difficulty organizing tasks and activities as a child? How disorganized are you in your thinking, planning, and time management? And how disorganized are your belongings at home?
Neither disorganization, procrastination, perfectionism, nor indecisiveness turned out to be associated with severity of nonhoarding OCD or anxiety disorder symptoms. Surprisingly, no significant differences were found between hoarding disorder patients and controls on the measures of indecisiveness or perfectionism, Dr. Saxena said. And the two groups did not differ in their levels of anxiety and depression.
However, levels of procrastination and disorganization were strongly correlated with hoarding severity as assessed via the Saving Inventory – Revised, the UCLA Hoarding Severity Scale, and the Hoarding Rating Scale. The hoarding disorder group’s average score on the disorganization index was 5.67, more than twice that of the 2.67 in the control group. And patients with hoarding disorder had an average Adult Inventory of Procrastination score of 50.9 out of a possible maximum of 75 points, compared with 41 in controls.
In a multivariate regression analysis, age and level of depression collectively explained 23.5% of the variance in hoarding severity scores in the study population. Disorganization independently explained an additional 29.9% of the variance, and procrastination accounted for another 19.1%, Dr. Saxena reported.
He reported having no financial conflicts regarding his study, which was funded by the university’s department of psychiatry.
SAN FRANCISCO – Procrastination, disorganization, indecisiveness, and perfectionism each are significant independent predictors of hoarding severity, even though none of these associated factors is included in the DSM-5 diagnostic criteria for hoarding disorder, according to Sanjaya Saxena, MD.
Of these four associated factors, disorganization and procrastination had the strongest correlation with hoarding severity in his study. Patients meeting the DSM-5 criteria for hoarding disorder scored significantly higher on measures of disorganization and procrastination than did patients with nonhoarding obsessive-compulsive disorder or anxiety disorders, said Dr. Saxena, professor of psychiatry and director of the obsessive-compulsive disorders program at the University of California, San Diego.
The DSM-5 lists as the core symptoms of hoarding disorder difficulty in discarding possessions; perceived need to save items; excessive acquisition, clutter, and resultant distress; and impaired functioning. But while procrastination, disorganization, perfectionism, and indecisiveness aren’t included in the diagnostic criteria, Dr. Saxena said he and some other experts have considered those features to be characteristic of affected individuals. So he decided to formally test the strength of the associations.
He reported on 21 patients with hoarding disorder and 13 controls with nonhoarding OCD or an anxiety disorder. All subjects completed a battery of assessment tools, including the Beck Depression Inventory, the Beck Anxiety Inventory, the Frost Multidimensional Perfectionism Scale, the Frost Indecisiveness Scale, the Adult Inventory of Procrastination Scale, and three different measures of hoarding severity. Participants also completed a disorganization index based on their answers to three questions drawn from the Swanson, Nolan, and Pelham (SNAP-IV) Rating Scale: How often did you have difficulty organizing tasks and activities as a child? How disorganized are you in your thinking, planning, and time management? And how disorganized are your belongings at home?
Neither disorganization, procrastination, perfectionism, nor indecisiveness turned out to be associated with severity of nonhoarding OCD or anxiety disorder symptoms. Surprisingly, no significant differences were found between hoarding disorder patients and controls on the measures of indecisiveness or perfectionism, Dr. Saxena said. And the two groups did not differ in their levels of anxiety and depression.
However, levels of procrastination and disorganization were strongly correlated with hoarding severity as assessed via the Saving Inventory – Revised, the UCLA Hoarding Severity Scale, and the Hoarding Rating Scale. The hoarding disorder group’s average score on the disorganization index was 5.67, more than twice that of the 2.67 in the control group. And patients with hoarding disorder had an average Adult Inventory of Procrastination score of 50.9 out of a possible maximum of 75 points, compared with 41 in controls.
In a multivariate regression analysis, age and level of depression collectively explained 23.5% of the variance in hoarding severity scores in the study population. Disorganization independently explained an additional 29.9% of the variance, and procrastination accounted for another 19.1%, Dr. Saxena reported.
He reported having no financial conflicts regarding his study, which was funded by the university’s department of psychiatry.
AT THE ANXIETY AND DEPRESSION CONFERENCE 2017
Key clinical point:
Major finding: Severity of procrastination explained 30% of the variance in hoarding severity scores between patients with hoarding disorder and controls with nonhoarding obsessive-compulsive disorder or an anxiety disorder.
Data source: A cross-sectional study involving 21 patients with hoarding disorder and 13 controls, all of whom completed a battery of tests assessing anxiety, depression, hoarding severity, disorganization, procrastination, indecisiveness, and perfectionism.
Disclosures: The presenter reported having no financial conflicts regarding the study, which was funded by a university psychiatry department.