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For MD-IQ on Family Practice News, but a regular topic for Rheumatology News
No benefit found for routine inpatient rehab after knee replacement
A new randomized study from Australia suggests that for many patients, brief inpatient rehabilitation after knee replacement provides no benefits in several measures, compared with rehab at home.
However, “we are not concluding that there is no role for inpatient rehabilitation after knee arthroplasty,” said study coauthor Justine Naylor, PhD, of the University of New South Wales, Liverpool, Australia. “We are simply saying that for people who are otherwise well enough to be discharged directly home, inpatient rehabilitation does not provide more superior recovery across a range of outcomes.”
For the new study, conducted at two Australian hospitals during 2012-2015, researchers recruited patients aged 40 years or older with a primary diagnosis of osteoarthritis who were undergoing a primary unilateral knee arthroplasty and did not have complications such as a need for inpatient care in recovery beyond an initial 5 days after surgery.
The researchers randomly assigned 165 knee arthroplasty patients with uncomplicated cases to undergo either inpatient rehabilitation for 10 days and then recover at home for 6 weeks or a monitored 6-week home rehab program that began 2 weeks after surgery (JAMA. 2017;317[10]:1037-46).
A third group of 112 patients, 87 of whom were included in the primary analysis, were observed as they entered the home rehab protocol. They were in an initial group of 215 who declined to be randomized, mostly because they wanted to get home quickly after surgery.
The average age of all participants was 67 years, and just over two-thirds were women.
At 26 weeks, the researchers found that there was no significant difference in how the patients in the three groups fared on a 6-minute walk test (mean difference, −1.01 meters; 95% confidence interval, −25.56 to 23.55). They also found no significant difference in measurements of patient-reported pain and function (knee score mean difference, 2.06; 95% CI, −0.59 to 4.71), and quality of life (EQ-5D visual analog scale mean difference, 1.41; 95% CI, −6.42 to 3.60).
However, the patients did seem to have a preference. “Satisfaction with rehabilitation was significantly higher with inpatient rehab, average 92% vs. 83%, though both modes were well received overall,” Dr. Naylor said in an interview.
“Many patients who went to inpatient rehabilitation really enjoyed it,” she added. “We have observed that patients and carers like the convenience of inpatient rehab – a one-stop shop where patients get access to multiple clinicians, gyms, and other patients and do not have to prepare meals.”
However, she said, while “we have no doubt the inpatient rehabilitation environment is nurturing, there must also be advantages to being discharged directly home, otherwise we would have seen differences between the groups. It is possible that monitored home programs like the one provided in this study help people gain independence quickly and empower patients in their recovery.”
Dr. Naylor cautioned that inpatient rehabilitation does have potential benefits for certain patients, such as those who are the most impaired and those without someone available to care for them at home. “Future research could focus on what is best in those situations or, at least, design community-based programs [that] offer some of the perceived benefits of inpatient therapy,” she said. “In addition, we also need to know what the best rehabilitation approach is after hip arthroplasty.”
The study was funded by various sources, including a foundation grant. The study authors reported no relevant disclosures.
A new randomized study from Australia suggests that for many patients, brief inpatient rehabilitation after knee replacement provides no benefits in several measures, compared with rehab at home.
However, “we are not concluding that there is no role for inpatient rehabilitation after knee arthroplasty,” said study coauthor Justine Naylor, PhD, of the University of New South Wales, Liverpool, Australia. “We are simply saying that for people who are otherwise well enough to be discharged directly home, inpatient rehabilitation does not provide more superior recovery across a range of outcomes.”
For the new study, conducted at two Australian hospitals during 2012-2015, researchers recruited patients aged 40 years or older with a primary diagnosis of osteoarthritis who were undergoing a primary unilateral knee arthroplasty and did not have complications such as a need for inpatient care in recovery beyond an initial 5 days after surgery.
The researchers randomly assigned 165 knee arthroplasty patients with uncomplicated cases to undergo either inpatient rehabilitation for 10 days and then recover at home for 6 weeks or a monitored 6-week home rehab program that began 2 weeks after surgery (JAMA. 2017;317[10]:1037-46).
A third group of 112 patients, 87 of whom were included in the primary analysis, were observed as they entered the home rehab protocol. They were in an initial group of 215 who declined to be randomized, mostly because they wanted to get home quickly after surgery.
The average age of all participants was 67 years, and just over two-thirds were women.
At 26 weeks, the researchers found that there was no significant difference in how the patients in the three groups fared on a 6-minute walk test (mean difference, −1.01 meters; 95% confidence interval, −25.56 to 23.55). They also found no significant difference in measurements of patient-reported pain and function (knee score mean difference, 2.06; 95% CI, −0.59 to 4.71), and quality of life (EQ-5D visual analog scale mean difference, 1.41; 95% CI, −6.42 to 3.60).
However, the patients did seem to have a preference. “Satisfaction with rehabilitation was significantly higher with inpatient rehab, average 92% vs. 83%, though both modes were well received overall,” Dr. Naylor said in an interview.
“Many patients who went to inpatient rehabilitation really enjoyed it,” she added. “We have observed that patients and carers like the convenience of inpatient rehab – a one-stop shop where patients get access to multiple clinicians, gyms, and other patients and do not have to prepare meals.”
However, she said, while “we have no doubt the inpatient rehabilitation environment is nurturing, there must also be advantages to being discharged directly home, otherwise we would have seen differences between the groups. It is possible that monitored home programs like the one provided in this study help people gain independence quickly and empower patients in their recovery.”
Dr. Naylor cautioned that inpatient rehabilitation does have potential benefits for certain patients, such as those who are the most impaired and those without someone available to care for them at home. “Future research could focus on what is best in those situations or, at least, design community-based programs [that] offer some of the perceived benefits of inpatient therapy,” she said. “In addition, we also need to know what the best rehabilitation approach is after hip arthroplasty.”
The study was funded by various sources, including a foundation grant. The study authors reported no relevant disclosures.
A new randomized study from Australia suggests that for many patients, brief inpatient rehabilitation after knee replacement provides no benefits in several measures, compared with rehab at home.
However, “we are not concluding that there is no role for inpatient rehabilitation after knee arthroplasty,” said study coauthor Justine Naylor, PhD, of the University of New South Wales, Liverpool, Australia. “We are simply saying that for people who are otherwise well enough to be discharged directly home, inpatient rehabilitation does not provide more superior recovery across a range of outcomes.”
For the new study, conducted at two Australian hospitals during 2012-2015, researchers recruited patients aged 40 years or older with a primary diagnosis of osteoarthritis who were undergoing a primary unilateral knee arthroplasty and did not have complications such as a need for inpatient care in recovery beyond an initial 5 days after surgery.
The researchers randomly assigned 165 knee arthroplasty patients with uncomplicated cases to undergo either inpatient rehabilitation for 10 days and then recover at home for 6 weeks or a monitored 6-week home rehab program that began 2 weeks after surgery (JAMA. 2017;317[10]:1037-46).
A third group of 112 patients, 87 of whom were included in the primary analysis, were observed as they entered the home rehab protocol. They were in an initial group of 215 who declined to be randomized, mostly because they wanted to get home quickly after surgery.
The average age of all participants was 67 years, and just over two-thirds were women.
At 26 weeks, the researchers found that there was no significant difference in how the patients in the three groups fared on a 6-minute walk test (mean difference, −1.01 meters; 95% confidence interval, −25.56 to 23.55). They also found no significant difference in measurements of patient-reported pain and function (knee score mean difference, 2.06; 95% CI, −0.59 to 4.71), and quality of life (EQ-5D visual analog scale mean difference, 1.41; 95% CI, −6.42 to 3.60).
However, the patients did seem to have a preference. “Satisfaction with rehabilitation was significantly higher with inpatient rehab, average 92% vs. 83%, though both modes were well received overall,” Dr. Naylor said in an interview.
“Many patients who went to inpatient rehabilitation really enjoyed it,” she added. “We have observed that patients and carers like the convenience of inpatient rehab – a one-stop shop where patients get access to multiple clinicians, gyms, and other patients and do not have to prepare meals.”
However, she said, while “we have no doubt the inpatient rehabilitation environment is nurturing, there must also be advantages to being discharged directly home, otherwise we would have seen differences between the groups. It is possible that monitored home programs like the one provided in this study help people gain independence quickly and empower patients in their recovery.”
Dr. Naylor cautioned that inpatient rehabilitation does have potential benefits for certain patients, such as those who are the most impaired and those without someone available to care for them at home. “Future research could focus on what is best in those situations or, at least, design community-based programs [that] offer some of the perceived benefits of inpatient therapy,” she said. “In addition, we also need to know what the best rehabilitation approach is after hip arthroplasty.”
The study was funded by various sources, including a foundation grant. The study authors reported no relevant disclosures.
FROM JAMA
Key clinical point:
Major finding: There were no significant differences in the primary outcome of a 6-minute walk test at 26 weeks or in pain, function, and quality of life measures between patients randomized to inpatient or at-home rehab protocols.
Data source: A parallel, randomized controlled trial of 165 uncomplicated knee arthroplasty patients assigned to undergo either inpatient rehab for 10 days then in-home monitored rehab for 6 weeks or to a monitored 6-week home rehab 2 weeks after surgery. The study also included a third observational group of 112 patients (87 included in analysis) who underwent at-home rehab.
Disclosures: The study was funded by various sources, including a foundation grant. The study authors reported no relevant disclosures.
Rising arthritis prevalence driven by obesity
Rising obesity is driving an increase in arthritis prevalence, and the association is not appreciated because the impact of body mass index on joint disease is not fully understood, according to a study spanning four generations.
The proportion of people in more recent birth cohorts reporting arthritis symptoms indicates a successively greater prevalence of arthritis compared to earlier generations, based on an 18-year longitudinal study conducted by Elizabeth M. Badley, PhD, of Dalla Lana School of Public Health, University of Toronto, and her colleagues. The researchers compared the prevalence of arthritis across four birth cohorts: World War II (1935-1944; n = 1,598), older baby boomers (1945-1954; n = 2,208), younger baby boomers (1955-1964; n = 2,781) and Generation Xers (1965-1974; n = 2,230).
“Although our results do not represent projections as such, extrapolation of the trajectories of arthritis with age and comparison of the trajectories across cohorts suggest that current projections of the prevalence of arthritis … may be too low for obese individuals,” they concluded.
Using the World War II cohort as the reference group for comparison, the odds ratio for arthritis in Gen Xers was 3.2; for younger baby boomers it was 2.14; for older baby boomers, it was 1.48.
Furthermore, in all cohorts the age of onset of arthritis in obese individuals was earlier compared to those of normal weight.
“This has implications for the targeting of public health messages for the control and management of arthritis,” the researchers wrote (Arthritis Care Res. 2017. doi: 10.1002/acr.23213).
The authors noted that although the study participants were asked about arthritis in general it was likely the overall findings reflected an increasing prevalence of osteoarthritis.
And while the researchers could only speculate about the reasons for the higher prevalence of arthritis seen in recent cohorts, it was possible there had been “unrecognized changes over time in environmental or biologic exposures.”
The study was funded in part by a CIHR operating grant. No conflicts of interest were declared.
Rising obesity is driving an increase in arthritis prevalence, and the association is not appreciated because the impact of body mass index on joint disease is not fully understood, according to a study spanning four generations.
The proportion of people in more recent birth cohorts reporting arthritis symptoms indicates a successively greater prevalence of arthritis compared to earlier generations, based on an 18-year longitudinal study conducted by Elizabeth M. Badley, PhD, of Dalla Lana School of Public Health, University of Toronto, and her colleagues. The researchers compared the prevalence of arthritis across four birth cohorts: World War II (1935-1944; n = 1,598), older baby boomers (1945-1954; n = 2,208), younger baby boomers (1955-1964; n = 2,781) and Generation Xers (1965-1974; n = 2,230).
“Although our results do not represent projections as such, extrapolation of the trajectories of arthritis with age and comparison of the trajectories across cohorts suggest that current projections of the prevalence of arthritis … may be too low for obese individuals,” they concluded.
Using the World War II cohort as the reference group for comparison, the odds ratio for arthritis in Gen Xers was 3.2; for younger baby boomers it was 2.14; for older baby boomers, it was 1.48.
Furthermore, in all cohorts the age of onset of arthritis in obese individuals was earlier compared to those of normal weight.
“This has implications for the targeting of public health messages for the control and management of arthritis,” the researchers wrote (Arthritis Care Res. 2017. doi: 10.1002/acr.23213).
The authors noted that although the study participants were asked about arthritis in general it was likely the overall findings reflected an increasing prevalence of osteoarthritis.
And while the researchers could only speculate about the reasons for the higher prevalence of arthritis seen in recent cohorts, it was possible there had been “unrecognized changes over time in environmental or biologic exposures.”
The study was funded in part by a CIHR operating grant. No conflicts of interest were declared.
Rising obesity is driving an increase in arthritis prevalence, and the association is not appreciated because the impact of body mass index on joint disease is not fully understood, according to a study spanning four generations.
The proportion of people in more recent birth cohorts reporting arthritis symptoms indicates a successively greater prevalence of arthritis compared to earlier generations, based on an 18-year longitudinal study conducted by Elizabeth M. Badley, PhD, of Dalla Lana School of Public Health, University of Toronto, and her colleagues. The researchers compared the prevalence of arthritis across four birth cohorts: World War II (1935-1944; n = 1,598), older baby boomers (1945-1954; n = 2,208), younger baby boomers (1955-1964; n = 2,781) and Generation Xers (1965-1974; n = 2,230).
“Although our results do not represent projections as such, extrapolation of the trajectories of arthritis with age and comparison of the trajectories across cohorts suggest that current projections of the prevalence of arthritis … may be too low for obese individuals,” they concluded.
Using the World War II cohort as the reference group for comparison, the odds ratio for arthritis in Gen Xers was 3.2; for younger baby boomers it was 2.14; for older baby boomers, it was 1.48.
Furthermore, in all cohorts the age of onset of arthritis in obese individuals was earlier compared to those of normal weight.
“This has implications for the targeting of public health messages for the control and management of arthritis,” the researchers wrote (Arthritis Care Res. 2017. doi: 10.1002/acr.23213).
The authors noted that although the study participants were asked about arthritis in general it was likely the overall findings reflected an increasing prevalence of osteoarthritis.
And while the researchers could only speculate about the reasons for the higher prevalence of arthritis seen in recent cohorts, it was possible there had been “unrecognized changes over time in environmental or biologic exposures.”
The study was funded in part by a CIHR operating grant. No conflicts of interest were declared.
FROM ARTHRITIS CARE & RESEARCH
Key clinical point: The prevalence of arthritis in the general population is growing and increasing obesity appears to be a factor.
Major finding: When researchers used the World War II cohort as the reference group for comparison, the odds ratio for arthritis in Gen Xers was 3.2; for younger baby boomers it was 2.14; for older baby boomers, it was 1.48.
Data source: A longitudinal analysis of data from the 1994/95 to 2010/11 National Population Health survey that included 8,817 participants in four birth cohorts.
Disclosures: The study was funded in part by a CIHR operating grant. No conflicts of interest were declared.
CDC: Greater activity limitations accompany rising arthritis prevalence
The number of adults with arthritis in the United States continues to rise, with the number projected to climb as high as 78 million by the year 2040. Some of the keys to stemming this rising tide are exercise, along with greater knowledge of how to manage symptoms, according to a new report from the Centers for Disease Control and Prevention.
“Arthritis is at an all-time high: more than 54 million people report a diagnosis of it, and alarmingly, more people with arthritis are suffering from it,” said Anne Schuchat, MD, acting director of the CDC, during a conference call regarding the agency’s latest Vital Signs report (MMWR Morb Mortal Wkly Rep. 2017 Mar 7. doi: org/10.15585/mmwr.mm6609e1). “Among adults with arthritis, the percentage whose lives are particularly limited has increased by about 20% since 2002, from about 36% in 2002 to 43% in 2015. We’re seeing this increase independent of aging of the population.”
“Physical activity can be the antidote for many people [and] can actually decrease pain and improve function by almost 40%,” Dr. Schuchat explained. “Right now, one in three adults with arthritis report being inactive [because of] pain or fear of pain or not knowing what exercise is safe for their joints.”
This inactivity can lead to arthritis patients developing other serious chronic conditions, such as heart disease, diabetes and obesity – conditions that all require physical activity in order to properly manage them. Arthritis alone puts an extraordinary financial burden on the domestic health care industry, as direct medical costs associated with the condition total roughly $81 billion per year, according to the CDC. Additionally, about half of all adults with heart disease or diabetes, and about one-third of obese adults, also have arthritis.
In addition to engaging in regular physical activity, the Vital Signs report also recommends that arthritis patients attend disease management education programs, which are available regionally but often go underutilized, largely due to lack of awareness about them or trepidation regarding how effective the programs really are. To combat this, the CDC is calling on health care providers to help them educate patients about these classes and spread the word about the steps that can be taken to manage arthritis. In 2017, the CDC is funding arthritis programs in 12 states (California, Kansas, Kentucky, Michigan, Missouri, Montana, New York, Oregon, Pennsylvania, Rhode Island, South Carolina, and Utah) to disseminate arthritis-appropriate evidence-based physical activity and self-management education interventions.
“Men or women with arthritis can reduce their symptoms by 10%-20% by participating in disease management education programs to acquire skills to better manage their symptoms. Right now, these programs are only reaching about 1 in 10 people with arthritis, but the classes are available in many community settings,” Dr. Schuchat said. “We know that adults with arthritis are significantly more likely to attend a disease management education program when a health care provider recommends it to them.”
When seeing patients with arthritis, Dr. Schuchat advised health care providers to recommend routine physical activity, such as walking, biking, swimming, and physical activity programs offered by local parks and recreation centers, as well as weight loss, in order to ease joint pain. The American College of Rheumatology and other professional organizations provide guidelines for discussing treatment options with patients. Providing treatment or additional services for depression or anxiety, which occur in about one-third of adult arthritis patients, may help individuals to better manage their arthritis symptoms.
The agency’s report derives from its analysis of 2013-2015 data from the National Health Interview Survey, which comprised a nationally representative sample of about 36,000 in-person interviews. The survey classifies individuals with physician-diagnosed arthritis as those who answered “yes” to the question “Have you ever been told by a doctor or other health professional that you have some form of arthritis, rheumatoid arthritis, gout, lupus, or fibromyalgia?”
The number of adults with arthritis in the United States continues to rise, with the number projected to climb as high as 78 million by the year 2040. Some of the keys to stemming this rising tide are exercise, along with greater knowledge of how to manage symptoms, according to a new report from the Centers for Disease Control and Prevention.
“Arthritis is at an all-time high: more than 54 million people report a diagnosis of it, and alarmingly, more people with arthritis are suffering from it,” said Anne Schuchat, MD, acting director of the CDC, during a conference call regarding the agency’s latest Vital Signs report (MMWR Morb Mortal Wkly Rep. 2017 Mar 7. doi: org/10.15585/mmwr.mm6609e1). “Among adults with arthritis, the percentage whose lives are particularly limited has increased by about 20% since 2002, from about 36% in 2002 to 43% in 2015. We’re seeing this increase independent of aging of the population.”
“Physical activity can be the antidote for many people [and] can actually decrease pain and improve function by almost 40%,” Dr. Schuchat explained. “Right now, one in three adults with arthritis report being inactive [because of] pain or fear of pain or not knowing what exercise is safe for their joints.”
This inactivity can lead to arthritis patients developing other serious chronic conditions, such as heart disease, diabetes and obesity – conditions that all require physical activity in order to properly manage them. Arthritis alone puts an extraordinary financial burden on the domestic health care industry, as direct medical costs associated with the condition total roughly $81 billion per year, according to the CDC. Additionally, about half of all adults with heart disease or diabetes, and about one-third of obese adults, also have arthritis.
In addition to engaging in regular physical activity, the Vital Signs report also recommends that arthritis patients attend disease management education programs, which are available regionally but often go underutilized, largely due to lack of awareness about them or trepidation regarding how effective the programs really are. To combat this, the CDC is calling on health care providers to help them educate patients about these classes and spread the word about the steps that can be taken to manage arthritis. In 2017, the CDC is funding arthritis programs in 12 states (California, Kansas, Kentucky, Michigan, Missouri, Montana, New York, Oregon, Pennsylvania, Rhode Island, South Carolina, and Utah) to disseminate arthritis-appropriate evidence-based physical activity and self-management education interventions.
“Men or women with arthritis can reduce their symptoms by 10%-20% by participating in disease management education programs to acquire skills to better manage their symptoms. Right now, these programs are only reaching about 1 in 10 people with arthritis, but the classes are available in many community settings,” Dr. Schuchat said. “We know that adults with arthritis are significantly more likely to attend a disease management education program when a health care provider recommends it to them.”
When seeing patients with arthritis, Dr. Schuchat advised health care providers to recommend routine physical activity, such as walking, biking, swimming, and physical activity programs offered by local parks and recreation centers, as well as weight loss, in order to ease joint pain. The American College of Rheumatology and other professional organizations provide guidelines for discussing treatment options with patients. Providing treatment or additional services for depression or anxiety, which occur in about one-third of adult arthritis patients, may help individuals to better manage their arthritis symptoms.
The agency’s report derives from its analysis of 2013-2015 data from the National Health Interview Survey, which comprised a nationally representative sample of about 36,000 in-person interviews. The survey classifies individuals with physician-diagnosed arthritis as those who answered “yes” to the question “Have you ever been told by a doctor or other health professional that you have some form of arthritis, rheumatoid arthritis, gout, lupus, or fibromyalgia?”
The number of adults with arthritis in the United States continues to rise, with the number projected to climb as high as 78 million by the year 2040. Some of the keys to stemming this rising tide are exercise, along with greater knowledge of how to manage symptoms, according to a new report from the Centers for Disease Control and Prevention.
“Arthritis is at an all-time high: more than 54 million people report a diagnosis of it, and alarmingly, more people with arthritis are suffering from it,” said Anne Schuchat, MD, acting director of the CDC, during a conference call regarding the agency’s latest Vital Signs report (MMWR Morb Mortal Wkly Rep. 2017 Mar 7. doi: org/10.15585/mmwr.mm6609e1). “Among adults with arthritis, the percentage whose lives are particularly limited has increased by about 20% since 2002, from about 36% in 2002 to 43% in 2015. We’re seeing this increase independent of aging of the population.”
“Physical activity can be the antidote for many people [and] can actually decrease pain and improve function by almost 40%,” Dr. Schuchat explained. “Right now, one in three adults with arthritis report being inactive [because of] pain or fear of pain or not knowing what exercise is safe for their joints.”
This inactivity can lead to arthritis patients developing other serious chronic conditions, such as heart disease, diabetes and obesity – conditions that all require physical activity in order to properly manage them. Arthritis alone puts an extraordinary financial burden on the domestic health care industry, as direct medical costs associated with the condition total roughly $81 billion per year, according to the CDC. Additionally, about half of all adults with heart disease or diabetes, and about one-third of obese adults, also have arthritis.
In addition to engaging in regular physical activity, the Vital Signs report also recommends that arthritis patients attend disease management education programs, which are available regionally but often go underutilized, largely due to lack of awareness about them or trepidation regarding how effective the programs really are. To combat this, the CDC is calling on health care providers to help them educate patients about these classes and spread the word about the steps that can be taken to manage arthritis. In 2017, the CDC is funding arthritis programs in 12 states (California, Kansas, Kentucky, Michigan, Missouri, Montana, New York, Oregon, Pennsylvania, Rhode Island, South Carolina, and Utah) to disseminate arthritis-appropriate evidence-based physical activity and self-management education interventions.
“Men or women with arthritis can reduce their symptoms by 10%-20% by participating in disease management education programs to acquire skills to better manage their symptoms. Right now, these programs are only reaching about 1 in 10 people with arthritis, but the classes are available in many community settings,” Dr. Schuchat said. “We know that adults with arthritis are significantly more likely to attend a disease management education program when a health care provider recommends it to them.”
When seeing patients with arthritis, Dr. Schuchat advised health care providers to recommend routine physical activity, such as walking, biking, swimming, and physical activity programs offered by local parks and recreation centers, as well as weight loss, in order to ease joint pain. The American College of Rheumatology and other professional organizations provide guidelines for discussing treatment options with patients. Providing treatment or additional services for depression or anxiety, which occur in about one-third of adult arthritis patients, may help individuals to better manage their arthritis symptoms.
The agency’s report derives from its analysis of 2013-2015 data from the National Health Interview Survey, which comprised a nationally representative sample of about 36,000 in-person interviews. The survey classifies individuals with physician-diagnosed arthritis as those who answered “yes” to the question “Have you ever been told by a doctor or other health professional that you have some form of arthritis, rheumatoid arthritis, gout, lupus, or fibromyalgia?”
FROM MMWR
Key clinical point:
Major finding: About 24 million American adults report being significantly limited due to their arthritis.
Data source: 2013-2015 data from the National Health Interview Survey.
Disclosures: No disclosures were reported.
Osteoarthritis in hip or knee can increase diabetes risk
Individuals who have osteoarthritis in the hip or knee are significantly more likely to develop diabetes than are people without the condition, according to findings from a population-based cohort study.
The relationship between osteoarthritis (OA) and new-onset diabetes was largely explained by the walking limitations brought on by OA, which was unsurprising to lead author Tetyana Kendzerska, MD, PhD, of the University of Toronto, who presented the study at the annual meeting of the Canadian Rheumatology Association.
But Dr. Kendzerska noted that even though “the World Health Organization has determined that osteoarthritis is the fastest growing chronic disease and the single most common cause of disability in older adults [and] the majority of people with OA have at least one other chronic condition – usually diabetes, high blood pressure, [or] heart disease ... few studies have examined the impact of OA on these other conditions, including on the development of diabetes.”
Dr. Kendzerska and her coauthors used existing data to study a population of 16,362 adults aged 55 or older who did not have diabetes at baseline enrollment during 1996-1998 and were then followed until 2014 for a median period of 13 years. The adults’ median age was 68 years and median body mass index was 25.3 kg/m2; 61% were female. Cox regression modeling was used to quantify any association found between osteoarthritis and diabetes.
A total of 1,637 (10%) had hip osteoarthritis, 2,431 (15%) had knee osteoarthritis, and 3,908 (24%) had some type of walking limitation. Over the course of the follow-up period, 3,539 (22%) developed diabetes. The risk for diabetes was significantly elevated in particular for individuals with two hip or knee joints with OA, where the hazard ratio was 1.25 (95% CI, 1.08-1.44; P = .003) for hips and 1.16 (95% CI, 1.04-1.29; P = .008) for knees, after adjustment for baseline age, sex, income, body mass index, preexisting hypertension and cardiovascular disease, and prior primary care exposure. However, further adjustment to the comparisons for walking limitation attenuated the relationships so that they were no longer statistically significant.
The next steps for research may be to assess the impact of evidence-based osteoarthritis care on mobility and metabolic derangements, she said.
Previous “studies have been limited by a number of methodological limitations, [such as] cross-sectional design or failure to control for other factors that may explain a relationship. Our study has addressed these limitations and thus provides important evidence to suggest that osteoarthritis-related difficulty walking contributes causally to the development of diabetes [but] now we need studies to show if effective treatment of hip and knee osteoarthritis can reduce diabetes risk.”
The Canadian Institutes of Health Research funded the study. Dr. Kendzerska did not report any relevant financial disclosures.
Individuals who have osteoarthritis in the hip or knee are significantly more likely to develop diabetes than are people without the condition, according to findings from a population-based cohort study.
The relationship between osteoarthritis (OA) and new-onset diabetes was largely explained by the walking limitations brought on by OA, which was unsurprising to lead author Tetyana Kendzerska, MD, PhD, of the University of Toronto, who presented the study at the annual meeting of the Canadian Rheumatology Association.
But Dr. Kendzerska noted that even though “the World Health Organization has determined that osteoarthritis is the fastest growing chronic disease and the single most common cause of disability in older adults [and] the majority of people with OA have at least one other chronic condition – usually diabetes, high blood pressure, [or] heart disease ... few studies have examined the impact of OA on these other conditions, including on the development of diabetes.”
Dr. Kendzerska and her coauthors used existing data to study a population of 16,362 adults aged 55 or older who did not have diabetes at baseline enrollment during 1996-1998 and were then followed until 2014 for a median period of 13 years. The adults’ median age was 68 years and median body mass index was 25.3 kg/m2; 61% were female. Cox regression modeling was used to quantify any association found between osteoarthritis and diabetes.
A total of 1,637 (10%) had hip osteoarthritis, 2,431 (15%) had knee osteoarthritis, and 3,908 (24%) had some type of walking limitation. Over the course of the follow-up period, 3,539 (22%) developed diabetes. The risk for diabetes was significantly elevated in particular for individuals with two hip or knee joints with OA, where the hazard ratio was 1.25 (95% CI, 1.08-1.44; P = .003) for hips and 1.16 (95% CI, 1.04-1.29; P = .008) for knees, after adjustment for baseline age, sex, income, body mass index, preexisting hypertension and cardiovascular disease, and prior primary care exposure. However, further adjustment to the comparisons for walking limitation attenuated the relationships so that they were no longer statistically significant.
The next steps for research may be to assess the impact of evidence-based osteoarthritis care on mobility and metabolic derangements, she said.
Previous “studies have been limited by a number of methodological limitations, [such as] cross-sectional design or failure to control for other factors that may explain a relationship. Our study has addressed these limitations and thus provides important evidence to suggest that osteoarthritis-related difficulty walking contributes causally to the development of diabetes [but] now we need studies to show if effective treatment of hip and knee osteoarthritis can reduce diabetes risk.”
The Canadian Institutes of Health Research funded the study. Dr. Kendzerska did not report any relevant financial disclosures.
Individuals who have osteoarthritis in the hip or knee are significantly more likely to develop diabetes than are people without the condition, according to findings from a population-based cohort study.
The relationship between osteoarthritis (OA) and new-onset diabetes was largely explained by the walking limitations brought on by OA, which was unsurprising to lead author Tetyana Kendzerska, MD, PhD, of the University of Toronto, who presented the study at the annual meeting of the Canadian Rheumatology Association.
But Dr. Kendzerska noted that even though “the World Health Organization has determined that osteoarthritis is the fastest growing chronic disease and the single most common cause of disability in older adults [and] the majority of people with OA have at least one other chronic condition – usually diabetes, high blood pressure, [or] heart disease ... few studies have examined the impact of OA on these other conditions, including on the development of diabetes.”
Dr. Kendzerska and her coauthors used existing data to study a population of 16,362 adults aged 55 or older who did not have diabetes at baseline enrollment during 1996-1998 and were then followed until 2014 for a median period of 13 years. The adults’ median age was 68 years and median body mass index was 25.3 kg/m2; 61% were female. Cox regression modeling was used to quantify any association found between osteoarthritis and diabetes.
A total of 1,637 (10%) had hip osteoarthritis, 2,431 (15%) had knee osteoarthritis, and 3,908 (24%) had some type of walking limitation. Over the course of the follow-up period, 3,539 (22%) developed diabetes. The risk for diabetes was significantly elevated in particular for individuals with two hip or knee joints with OA, where the hazard ratio was 1.25 (95% CI, 1.08-1.44; P = .003) for hips and 1.16 (95% CI, 1.04-1.29; P = .008) for knees, after adjustment for baseline age, sex, income, body mass index, preexisting hypertension and cardiovascular disease, and prior primary care exposure. However, further adjustment to the comparisons for walking limitation attenuated the relationships so that they were no longer statistically significant.
The next steps for research may be to assess the impact of evidence-based osteoarthritis care on mobility and metabolic derangements, she said.
Previous “studies have been limited by a number of methodological limitations, [such as] cross-sectional design or failure to control for other factors that may explain a relationship. Our study has addressed these limitations and thus provides important evidence to suggest that osteoarthritis-related difficulty walking contributes causally to the development of diabetes [but] now we need studies to show if effective treatment of hip and knee osteoarthritis can reduce diabetes risk.”
The Canadian Institutes of Health Research funded the study. Dr. Kendzerska did not report any relevant financial disclosures.
FROM THE CRA SCIENTIFIC CONFERENCE
Key clinical point:
Major finding: The risk for diabetes was significantly elevated for individuals with two hip or knee joints with OA, where the hazard ratio was 1.25 (95% CI, 1.08-1.44; P = .003) for hips and 1.16 (95% CI, 1.04-1.29; P = .008) for knees.
Data source: Population-based cohort study of 16,362 individuals without diabetes at baseline.
Disclosures: The Canadian Institutes of Health Research funded the study. Dr. Kendzerska did not report any relevant financial disclosures.
Thigh muscle weakness predicts knee osteoarthritis in women only
Weakness in the lower thigh muscles is a stronger risk factor for knee osteoarthritis in women than in men, possibly because of the greater influence that high body mass index has on thigh muscle strength in women, according to new case-control study findings.
The findings, published online Feb. 8 in Arthritis Care & Research (doi: 10.1002/acr.23182), come from a study enrolling 161 patients with radiographic knee osteoarthritis and 186 controls without arthritis at baseline who were observed over a 4-year period in the ongoing multicenter Osteoarthritis Initiative cohort study. About 60% of patients and controls were women.
They found that lower muscle-specific strength in these areas significantly increased the risk of incident knee osteoarthritis in women, with odds ratios of 1.47 (95% confidence interval, 1.10-1.96) for knee flexors and 1.41 (95% CI, 1.06-1.89) for extensors. This relationship was not significant in men, and in women, the relationship lost statistical significance after adjustment for high body mass index (BMI). Lower specific strength was associated with higher BMI in women (r = –0.29, P less than .001), but not in men.
“The lower muscle-specific strength in the presence of higher BMI in women (possibly driven by greater intramuscular adiposity), but not in men, may provide a possible explanation” for the differences in knee osteoarthritis incidence in men and women with muscle strength deficits, Dr. Culvenor and colleagues wrote in their analysis.
“The response of thigh muscle to variations in BMI differed between men and women, with apparently more contractile tissue (and strength) being present in men with greater BMI, and apparently more noncontractile (adipose) tissue in women with greater BMI,” the researchers concluded.
The Osteoarthritis Initiative is cofunded by the National Institutes of Health and a consortium of pharmacological manufacturers. The work for this analysis also received funding from Paracelsus Medical University and the European Union Seventh Framework Programme. Three of the study’s seven coauthors disclosed extensive financial relationships, including employment, with Chondrometrics GmbH, a company that provides MRI analysis services, among other firms, while four disclosed no commercial conflicts.
Weakness in the lower thigh muscles is a stronger risk factor for knee osteoarthritis in women than in men, possibly because of the greater influence that high body mass index has on thigh muscle strength in women, according to new case-control study findings.
The findings, published online Feb. 8 in Arthritis Care & Research (doi: 10.1002/acr.23182), come from a study enrolling 161 patients with radiographic knee osteoarthritis and 186 controls without arthritis at baseline who were observed over a 4-year period in the ongoing multicenter Osteoarthritis Initiative cohort study. About 60% of patients and controls were women.
They found that lower muscle-specific strength in these areas significantly increased the risk of incident knee osteoarthritis in women, with odds ratios of 1.47 (95% confidence interval, 1.10-1.96) for knee flexors and 1.41 (95% CI, 1.06-1.89) for extensors. This relationship was not significant in men, and in women, the relationship lost statistical significance after adjustment for high body mass index (BMI). Lower specific strength was associated with higher BMI in women (r = –0.29, P less than .001), but not in men.
“The lower muscle-specific strength in the presence of higher BMI in women (possibly driven by greater intramuscular adiposity), but not in men, may provide a possible explanation” for the differences in knee osteoarthritis incidence in men and women with muscle strength deficits, Dr. Culvenor and colleagues wrote in their analysis.
“The response of thigh muscle to variations in BMI differed between men and women, with apparently more contractile tissue (and strength) being present in men with greater BMI, and apparently more noncontractile (adipose) tissue in women with greater BMI,” the researchers concluded.
The Osteoarthritis Initiative is cofunded by the National Institutes of Health and a consortium of pharmacological manufacturers. The work for this analysis also received funding from Paracelsus Medical University and the European Union Seventh Framework Programme. Three of the study’s seven coauthors disclosed extensive financial relationships, including employment, with Chondrometrics GmbH, a company that provides MRI analysis services, among other firms, while four disclosed no commercial conflicts.
Weakness in the lower thigh muscles is a stronger risk factor for knee osteoarthritis in women than in men, possibly because of the greater influence that high body mass index has on thigh muscle strength in women, according to new case-control study findings.
The findings, published online Feb. 8 in Arthritis Care & Research (doi: 10.1002/acr.23182), come from a study enrolling 161 patients with radiographic knee osteoarthritis and 186 controls without arthritis at baseline who were observed over a 4-year period in the ongoing multicenter Osteoarthritis Initiative cohort study. About 60% of patients and controls were women.
They found that lower muscle-specific strength in these areas significantly increased the risk of incident knee osteoarthritis in women, with odds ratios of 1.47 (95% confidence interval, 1.10-1.96) for knee flexors and 1.41 (95% CI, 1.06-1.89) for extensors. This relationship was not significant in men, and in women, the relationship lost statistical significance after adjustment for high body mass index (BMI). Lower specific strength was associated with higher BMI in women (r = –0.29, P less than .001), but not in men.
“The lower muscle-specific strength in the presence of higher BMI in women (possibly driven by greater intramuscular adiposity), but not in men, may provide a possible explanation” for the differences in knee osteoarthritis incidence in men and women with muscle strength deficits, Dr. Culvenor and colleagues wrote in their analysis.
“The response of thigh muscle to variations in BMI differed between men and women, with apparently more contractile tissue (and strength) being present in men with greater BMI, and apparently more noncontractile (adipose) tissue in women with greater BMI,” the researchers concluded.
The Osteoarthritis Initiative is cofunded by the National Institutes of Health and a consortium of pharmacological manufacturers. The work for this analysis also received funding from Paracelsus Medical University and the European Union Seventh Framework Programme. Three of the study’s seven coauthors disclosed extensive financial relationships, including employment, with Chondrometrics GmbH, a company that provides MRI analysis services, among other firms, while four disclosed no commercial conflicts.
FROM ARTHRITIS CARE & RESEARCH
Key clinical point:
Major finding: Weaker thigh muscle significantly increased the risk of incident knee osteoarthritis in women, but after adjusting for BMI the relationship lost significance.
Data source: Men and women (n = 161) with knee osteoarthritis and matched controls (n = 186) without osteoarthritis at baseline who were recruited from a multisite longitudinal cohort.
Disclosures: The Osteoarthritis Initiative is cofunded by the National Institutes of Health and a consortium of pharmacological manufacturers. The work for this analysis also received funding from Paracelsus Medical University and the European Union Seventh Framework Programme. Three of the study’s seven coauthors disclosed extensive financial relationships, including employment, with Chondrometrics GmbH, a company that provides MRI analysis services, among other firms, while four disclosed no commercial conflicts.
Lyme arthritis changes its immune response profile if it persists after antibiotics
The persistence of Lyme arthritis after treatment with antibiotics comes with a shift from an immune response expected for bacterial infection to one characterized by chronic inflammation, synovial proliferation, and breakdown of wound repair processes, according to an analysis of microRNA expression in patients before, during, and after infection.
Based on the findings, investigators led by Robert B. Lochhead, PhD, of Massachusetts General Hospital, Boston, said that they “suspect that, in humans, genetic variables determine whether the response to B. burgdorferi infection elicits an appropriate wound repair response … or a maladaptive inflammatory cellular response and arrest of wound repair processes.”
The investigators studied synovial fluid or tissue from 32 patients with LA who were representative of the spectrum of disease severity and treatment responses seen in this disease. In 18 patients for whom synovial fluid samples were available, 5 illustrated the differences in miRNA expression that occur from the time before any antibiotic treatment to the time after antibiotic treatment that successfully resolves arthritis symptoms, and 13 showed how an incomplete response to antibiotic treatment can affect miRNA expression. The expression profile of miRNA in synovial tissue samples from another 14 patients who underwent arthroscopic synovectomies 4-48 months after oral and intravenous antibiotics demonstrated the change in immune response seen in postinfectious LA.
The group of five patients with synovial fluid samples who were referred prior to antibiotic therapy when they had active B. burgdorferi infection (group 1) had a history of mild to severe knee swelling and pain for a median duration of 1 month prior to evaluation and the start of antibiotic treatment. A 1-month course of oral doxycycline resolved arthritis in three of the patients, and the other two continued to have marked knee swelling that later resolved after 1 month of IV ceftriaxone. Of six different miRNAs that the investigators measured, five were at low levels in these patients. The lone exception was a hematopoietic-specific miRNA, miR-223, which is abundantly expressed in polymorphonuclear lymphocytes (PMNs) and is associated with downregulation of acute inflammation and tissue remodeling.
In the group of 13 who still had joint swelling despite oral or IV antibiotics (group 2), only 2 had resolution of their swelling after IV antibiotics. Most of the remaining 11 had successful treatment with methotrexate. The synovial fluid samples for seven patients were collected after oral antibiotics but before IV antibiotics, and in the other six the samples were collected after both therapies. These 13 patients had significantly lower white blood cell counts in synovial fluid, fewer PMNs, and greater percentages of lymphocytes and monocytes than did group 1 patients. The five miRNAs that were found at low levels among the patients in group 1 were higher in these patients, which “suggested that the nature of the arthritis had changed after spirochetal killing.” The higher miR-223 levels seen in group 1 also occurred in group 2.
A separate analysis of synovial fluid samples from four patients with osteoarthritis and six patients with RA showed that levels of the six miRNAs from RA patients were similar to those of patients from group 2, and the low levels that were observed for most of the miRNAs in group 1 were similar to those seen in OA patients.
The investigators found that the five miRNAs with elevated levels in group 2 patients, but not miR-223, were positively correlated with arthritis duration after start of oral antibiotic therapy. B. burgdorferi IgG antibody titers negatively correlated with some of the elevated miRNAs in group 2.
The investigators analyzed a larger set of miRNAs in the synovial tissue samples obtained from 14 patients who underwent synovectomies for treatment of persistent synovitis a median of 15.5 months after they had undergone 2-3 months of antibiotic therapy (group 3). Some of the miRNAs overexpressed in these postinfectious LA samples, relative to samples from five OA patients, were associated with proliferative, tumor-associated responses and regulation of inflammatory processes. However, miRNAs overexpressed in tissues from OA patients relative to postinfectious LA patients were thought to affect genes that control tissue remodeling and cell proliferation, but not inflammation. The “distinct oncogenic miRNA profile” exhibited by postinfectious synovial tissue, according to the investigators, showed that “in these patients, the transition to the postinfectious phase was blocked by chronic inflammation, which stalled the wound repair process.”
The investigators concluded that “miRNAs hold promise as potential biomarkers to identify LA patients who are developing maladaptive immune responses during the period of infection. In such patients, it will be important to learn whether simultaneous treatment with antibiotics and DMARDs, rather than sequential treatment with these medications, will reduce the period of therapy and improve outcome, creating a new paradigm in treatment of this form of chronic inflammatory arthritis.”
The study was supported by grants from the National Institutes of Health, the Lucius N. Littauer Foundation, the Roland Foundation, the Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital, the Rheumatology Research Foundation, and the English, Bonter, Mitchell Foundation.
The persistence of Lyme arthritis after treatment with antibiotics comes with a shift from an immune response expected for bacterial infection to one characterized by chronic inflammation, synovial proliferation, and breakdown of wound repair processes, according to an analysis of microRNA expression in patients before, during, and after infection.
Based on the findings, investigators led by Robert B. Lochhead, PhD, of Massachusetts General Hospital, Boston, said that they “suspect that, in humans, genetic variables determine whether the response to B. burgdorferi infection elicits an appropriate wound repair response … or a maladaptive inflammatory cellular response and arrest of wound repair processes.”
The investigators studied synovial fluid or tissue from 32 patients with LA who were representative of the spectrum of disease severity and treatment responses seen in this disease. In 18 patients for whom synovial fluid samples were available, 5 illustrated the differences in miRNA expression that occur from the time before any antibiotic treatment to the time after antibiotic treatment that successfully resolves arthritis symptoms, and 13 showed how an incomplete response to antibiotic treatment can affect miRNA expression. The expression profile of miRNA in synovial tissue samples from another 14 patients who underwent arthroscopic synovectomies 4-48 months after oral and intravenous antibiotics demonstrated the change in immune response seen in postinfectious LA.
The group of five patients with synovial fluid samples who were referred prior to antibiotic therapy when they had active B. burgdorferi infection (group 1) had a history of mild to severe knee swelling and pain for a median duration of 1 month prior to evaluation and the start of antibiotic treatment. A 1-month course of oral doxycycline resolved arthritis in three of the patients, and the other two continued to have marked knee swelling that later resolved after 1 month of IV ceftriaxone. Of six different miRNAs that the investigators measured, five were at low levels in these patients. The lone exception was a hematopoietic-specific miRNA, miR-223, which is abundantly expressed in polymorphonuclear lymphocytes (PMNs) and is associated with downregulation of acute inflammation and tissue remodeling.
In the group of 13 who still had joint swelling despite oral or IV antibiotics (group 2), only 2 had resolution of their swelling after IV antibiotics. Most of the remaining 11 had successful treatment with methotrexate. The synovial fluid samples for seven patients were collected after oral antibiotics but before IV antibiotics, and in the other six the samples were collected after both therapies. These 13 patients had significantly lower white blood cell counts in synovial fluid, fewer PMNs, and greater percentages of lymphocytes and monocytes than did group 1 patients. The five miRNAs that were found at low levels among the patients in group 1 were higher in these patients, which “suggested that the nature of the arthritis had changed after spirochetal killing.” The higher miR-223 levels seen in group 1 also occurred in group 2.
A separate analysis of synovial fluid samples from four patients with osteoarthritis and six patients with RA showed that levels of the six miRNAs from RA patients were similar to those of patients from group 2, and the low levels that were observed for most of the miRNAs in group 1 were similar to those seen in OA patients.
The investigators found that the five miRNAs with elevated levels in group 2 patients, but not miR-223, were positively correlated with arthritis duration after start of oral antibiotic therapy. B. burgdorferi IgG antibody titers negatively correlated with some of the elevated miRNAs in group 2.
The investigators analyzed a larger set of miRNAs in the synovial tissue samples obtained from 14 patients who underwent synovectomies for treatment of persistent synovitis a median of 15.5 months after they had undergone 2-3 months of antibiotic therapy (group 3). Some of the miRNAs overexpressed in these postinfectious LA samples, relative to samples from five OA patients, were associated with proliferative, tumor-associated responses and regulation of inflammatory processes. However, miRNAs overexpressed in tissues from OA patients relative to postinfectious LA patients were thought to affect genes that control tissue remodeling and cell proliferation, but not inflammation. The “distinct oncogenic miRNA profile” exhibited by postinfectious synovial tissue, according to the investigators, showed that “in these patients, the transition to the postinfectious phase was blocked by chronic inflammation, which stalled the wound repair process.”
The investigators concluded that “miRNAs hold promise as potential biomarkers to identify LA patients who are developing maladaptive immune responses during the period of infection. In such patients, it will be important to learn whether simultaneous treatment with antibiotics and DMARDs, rather than sequential treatment with these medications, will reduce the period of therapy and improve outcome, creating a new paradigm in treatment of this form of chronic inflammatory arthritis.”
The study was supported by grants from the National Institutes of Health, the Lucius N. Littauer Foundation, the Roland Foundation, the Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital, the Rheumatology Research Foundation, and the English, Bonter, Mitchell Foundation.
The persistence of Lyme arthritis after treatment with antibiotics comes with a shift from an immune response expected for bacterial infection to one characterized by chronic inflammation, synovial proliferation, and breakdown of wound repair processes, according to an analysis of microRNA expression in patients before, during, and after infection.
Based on the findings, investigators led by Robert B. Lochhead, PhD, of Massachusetts General Hospital, Boston, said that they “suspect that, in humans, genetic variables determine whether the response to B. burgdorferi infection elicits an appropriate wound repair response … or a maladaptive inflammatory cellular response and arrest of wound repair processes.”
The investigators studied synovial fluid or tissue from 32 patients with LA who were representative of the spectrum of disease severity and treatment responses seen in this disease. In 18 patients for whom synovial fluid samples were available, 5 illustrated the differences in miRNA expression that occur from the time before any antibiotic treatment to the time after antibiotic treatment that successfully resolves arthritis symptoms, and 13 showed how an incomplete response to antibiotic treatment can affect miRNA expression. The expression profile of miRNA in synovial tissue samples from another 14 patients who underwent arthroscopic synovectomies 4-48 months after oral and intravenous antibiotics demonstrated the change in immune response seen in postinfectious LA.
The group of five patients with synovial fluid samples who were referred prior to antibiotic therapy when they had active B. burgdorferi infection (group 1) had a history of mild to severe knee swelling and pain for a median duration of 1 month prior to evaluation and the start of antibiotic treatment. A 1-month course of oral doxycycline resolved arthritis in three of the patients, and the other two continued to have marked knee swelling that later resolved after 1 month of IV ceftriaxone. Of six different miRNAs that the investigators measured, five were at low levels in these patients. The lone exception was a hematopoietic-specific miRNA, miR-223, which is abundantly expressed in polymorphonuclear lymphocytes (PMNs) and is associated with downregulation of acute inflammation and tissue remodeling.
In the group of 13 who still had joint swelling despite oral or IV antibiotics (group 2), only 2 had resolution of their swelling after IV antibiotics. Most of the remaining 11 had successful treatment with methotrexate. The synovial fluid samples for seven patients were collected after oral antibiotics but before IV antibiotics, and in the other six the samples were collected after both therapies. These 13 patients had significantly lower white blood cell counts in synovial fluid, fewer PMNs, and greater percentages of lymphocytes and monocytes than did group 1 patients. The five miRNAs that were found at low levels among the patients in group 1 were higher in these patients, which “suggested that the nature of the arthritis had changed after spirochetal killing.” The higher miR-223 levels seen in group 1 also occurred in group 2.
A separate analysis of synovial fluid samples from four patients with osteoarthritis and six patients with RA showed that levels of the six miRNAs from RA patients were similar to those of patients from group 2, and the low levels that were observed for most of the miRNAs in group 1 were similar to those seen in OA patients.
The investigators found that the five miRNAs with elevated levels in group 2 patients, but not miR-223, were positively correlated with arthritis duration after start of oral antibiotic therapy. B. burgdorferi IgG antibody titers negatively correlated with some of the elevated miRNAs in group 2.
The investigators analyzed a larger set of miRNAs in the synovial tissue samples obtained from 14 patients who underwent synovectomies for treatment of persistent synovitis a median of 15.5 months after they had undergone 2-3 months of antibiotic therapy (group 3). Some of the miRNAs overexpressed in these postinfectious LA samples, relative to samples from five OA patients, were associated with proliferative, tumor-associated responses and regulation of inflammatory processes. However, miRNAs overexpressed in tissues from OA patients relative to postinfectious LA patients were thought to affect genes that control tissue remodeling and cell proliferation, but not inflammation. The “distinct oncogenic miRNA profile” exhibited by postinfectious synovial tissue, according to the investigators, showed that “in these patients, the transition to the postinfectious phase was blocked by chronic inflammation, which stalled the wound repair process.”
The investigators concluded that “miRNAs hold promise as potential biomarkers to identify LA patients who are developing maladaptive immune responses during the period of infection. In such patients, it will be important to learn whether simultaneous treatment with antibiotics and DMARDs, rather than sequential treatment with these medications, will reduce the period of therapy and improve outcome, creating a new paradigm in treatment of this form of chronic inflammatory arthritis.”
The study was supported by grants from the National Institutes of Health, the Lucius N. Littauer Foundation, the Roland Foundation, the Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital, the Rheumatology Research Foundation, and the English, Bonter, Mitchell Foundation.
Key clinical point:
Major finding: miRNAs overexpressed in synovial tissue samples from 14 patients with postinfectious Lyme arthritis, relative to samples from five OA patients, were associated with proliferative, tumor-associated responses and regulation of inflammatory processes.
Data source: A retrospective study of synovial fluid or tissue samples from 32 patients with Lyme arthritis.
Disclosures: The study was supported by grants from the National Institutes of Health, the Lucius N. Littauer Foundation, the Roland Foundation, the Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital, the Rheumatology Research Foundation, and the English, Bonter, Mitchell Foundation.
OA drug development needs patient-focused approach to biomarkers and outcome measures
Advances in our understanding of the development and treatment of osteoarthritis have led to renewed interest in leveraging these insights to establish more ways to evaluate potential drug candidates in clinical trials, particularly through the use of qualified biomarkers as meaningful outcome measures.
It is with this goal in mind that the Arthritis Foundation and the Food and Drug Administration held the Accelerating Osteoarthritis Clinical Trials Workshop in Atlanta in February 2016,1 to discuss ways of enhancing the likelihood of successful OA trials, including possible “qualification” of biomarkers that can be used as endpoints in trials of OA treatments. Clinical trial endpoints would ideally be known to be clinically meaningful to the patient (such as pain, fatigue, functional status, etc.)2 and would reflect treatments that enable patients to feel and function better.
Patient engagement in different steps of the development process might be possible through patient registries, social media communities, smart phones, and wearable devices to be used as tools for capturing patient perceptions and mobility. These means for capturing dynamic data about domains of high interest to OA patients may lead to the development of better outcome measures that can be used as clinical trial endpoints.4 Researchers at the workshop presented new ways in which they are beginning to specialize in these techniques and methods that will be useful for turning the patient experience into usable data to aid in precision medicine.
Imaging outcomes and biomarkers are attractive for their potential to demonstrate an effect on the structural and pathophysiologic elements of OA in the time frame of a clinical trial, but rely on well-characterized relationships between those structural and pathophysiologic elements of OA and the clinical outcomes of OA. A recent advance is data showing that semiquantitative knee joint features, including cartilage thickness and surface area, meniscal morphology, and bone marrow lesions, were associated with clinically relevant OA progression and could be potentially useful as measures of efficacy in clinical trials of disease-modifying interventions.5 Being able to describe the clinical benefit to be expected from such changes is essential to use these outcomes in the benefit-risk assessment. How to include structural outcomes in OA trials will depend on the level of information available to characterize clinical benefit. With less information, structural outcomes may still be useful as adjunct or secondary endpoints. To be used as the primary endpoint to support approval, a high level of characterization would be needed about the relationship of the endpoint to anticipated clinical benefit. The FDA recommends that sponsors proposing such a primary endpoint should engage with the agency early in the development program.
Another option discussed was to study an accelerated OA population, that is, subjects (prior to joint replacement) with a history of trauma to a joint and other injuries predictive of early OA. In that setting, the study duration needed to demonstrate the relationship of structural and clinical outcomes may be more feasible.
A third option discussed was an end-stage OA trial that could enroll subjects who meet criteria for joint replacement. Such a study could possibly have outcomes that include delay in time to surgery, reduction in need for surgery, and clinical outcomes, such as need for concomitant analgesics, patient pain, and patient function. In any OA population, demonstrating a treatment’s effectiveness on clinical outcomes could be the sole basis for approval, in the context of an acceptable safety profile.
Dr. Niskar is national scientific director of the Arthritis Foundation. Dr. Yim is supervisory associate director of the division of pulmonary, allergy, and rheumatology products in the Office of New Drugs at the FDA’s Center for Drug Evaluation and Research. Dr. Kraus is professor of medicine, pathology, and orthopedic surgery at Duke University, Durham, N.C., and is a faculty member of the Duke Molecular Physiology Institute. Dr. Tuan is director of the Center for Cellular and Molecular Engineering and Distinguished Professor of Orthopedic Surgery at the University of Pittsburgh.
Dr. Niskar reports that the Arthritis Foundation received a donation from Samumed and a cosponsorship grant from the FDA to implement the Accelerating OA Clinical Trials Workshop. Dr. Kraus reports an Arthritis Foundation Delivering on Discovery Award that is outside of this editorial. Dr. Yim and Dr. Tuan disclosed no conflicts. Dr. Yim is relaying her personal views in this editorial, and they are not intended to convey official FDA policy, and no official support or endorsement by the FDA is provided or should be inferred. Samumed did not have a role in the writing of this editorial.
References
1. Bioworld. 2016;27:1-4.
2. Osteoarthritis Cartilage. 2015 May;23[5]:677-85.
3. Clinical Trials Transformation Initiative. PG engagement across the research & development continuum. 2015.
4. Sci Transl Med. 2016;8:336ps11.
5. Arthritis Rheumatol. 2016 Oct;68[10]:2422-31.
Advances in our understanding of the development and treatment of osteoarthritis have led to renewed interest in leveraging these insights to establish more ways to evaluate potential drug candidates in clinical trials, particularly through the use of qualified biomarkers as meaningful outcome measures.
It is with this goal in mind that the Arthritis Foundation and the Food and Drug Administration held the Accelerating Osteoarthritis Clinical Trials Workshop in Atlanta in February 2016,1 to discuss ways of enhancing the likelihood of successful OA trials, including possible “qualification” of biomarkers that can be used as endpoints in trials of OA treatments. Clinical trial endpoints would ideally be known to be clinically meaningful to the patient (such as pain, fatigue, functional status, etc.)2 and would reflect treatments that enable patients to feel and function better.
Patient engagement in different steps of the development process might be possible through patient registries, social media communities, smart phones, and wearable devices to be used as tools for capturing patient perceptions and mobility. These means for capturing dynamic data about domains of high interest to OA patients may lead to the development of better outcome measures that can be used as clinical trial endpoints.4 Researchers at the workshop presented new ways in which they are beginning to specialize in these techniques and methods that will be useful for turning the patient experience into usable data to aid in precision medicine.
Imaging outcomes and biomarkers are attractive for their potential to demonstrate an effect on the structural and pathophysiologic elements of OA in the time frame of a clinical trial, but rely on well-characterized relationships between those structural and pathophysiologic elements of OA and the clinical outcomes of OA. A recent advance is data showing that semiquantitative knee joint features, including cartilage thickness and surface area, meniscal morphology, and bone marrow lesions, were associated with clinically relevant OA progression and could be potentially useful as measures of efficacy in clinical trials of disease-modifying interventions.5 Being able to describe the clinical benefit to be expected from such changes is essential to use these outcomes in the benefit-risk assessment. How to include structural outcomes in OA trials will depend on the level of information available to characterize clinical benefit. With less information, structural outcomes may still be useful as adjunct or secondary endpoints. To be used as the primary endpoint to support approval, a high level of characterization would be needed about the relationship of the endpoint to anticipated clinical benefit. The FDA recommends that sponsors proposing such a primary endpoint should engage with the agency early in the development program.
Another option discussed was to study an accelerated OA population, that is, subjects (prior to joint replacement) with a history of trauma to a joint and other injuries predictive of early OA. In that setting, the study duration needed to demonstrate the relationship of structural and clinical outcomes may be more feasible.
A third option discussed was an end-stage OA trial that could enroll subjects who meet criteria for joint replacement. Such a study could possibly have outcomes that include delay in time to surgery, reduction in need for surgery, and clinical outcomes, such as need for concomitant analgesics, patient pain, and patient function. In any OA population, demonstrating a treatment’s effectiveness on clinical outcomes could be the sole basis for approval, in the context of an acceptable safety profile.
Dr. Niskar is national scientific director of the Arthritis Foundation. Dr. Yim is supervisory associate director of the division of pulmonary, allergy, and rheumatology products in the Office of New Drugs at the FDA’s Center for Drug Evaluation and Research. Dr. Kraus is professor of medicine, pathology, and orthopedic surgery at Duke University, Durham, N.C., and is a faculty member of the Duke Molecular Physiology Institute. Dr. Tuan is director of the Center for Cellular and Molecular Engineering and Distinguished Professor of Orthopedic Surgery at the University of Pittsburgh.
Dr. Niskar reports that the Arthritis Foundation received a donation from Samumed and a cosponsorship grant from the FDA to implement the Accelerating OA Clinical Trials Workshop. Dr. Kraus reports an Arthritis Foundation Delivering on Discovery Award that is outside of this editorial. Dr. Yim and Dr. Tuan disclosed no conflicts. Dr. Yim is relaying her personal views in this editorial, and they are not intended to convey official FDA policy, and no official support or endorsement by the FDA is provided or should be inferred. Samumed did not have a role in the writing of this editorial.
References
1. Bioworld. 2016;27:1-4.
2. Osteoarthritis Cartilage. 2015 May;23[5]:677-85.
3. Clinical Trials Transformation Initiative. PG engagement across the research & development continuum. 2015.
4. Sci Transl Med. 2016;8:336ps11.
5. Arthritis Rheumatol. 2016 Oct;68[10]:2422-31.
Advances in our understanding of the development and treatment of osteoarthritis have led to renewed interest in leveraging these insights to establish more ways to evaluate potential drug candidates in clinical trials, particularly through the use of qualified biomarkers as meaningful outcome measures.
It is with this goal in mind that the Arthritis Foundation and the Food and Drug Administration held the Accelerating Osteoarthritis Clinical Trials Workshop in Atlanta in February 2016,1 to discuss ways of enhancing the likelihood of successful OA trials, including possible “qualification” of biomarkers that can be used as endpoints in trials of OA treatments. Clinical trial endpoints would ideally be known to be clinically meaningful to the patient (such as pain, fatigue, functional status, etc.)2 and would reflect treatments that enable patients to feel and function better.
Patient engagement in different steps of the development process might be possible through patient registries, social media communities, smart phones, and wearable devices to be used as tools for capturing patient perceptions and mobility. These means for capturing dynamic data about domains of high interest to OA patients may lead to the development of better outcome measures that can be used as clinical trial endpoints.4 Researchers at the workshop presented new ways in which they are beginning to specialize in these techniques and methods that will be useful for turning the patient experience into usable data to aid in precision medicine.
Imaging outcomes and biomarkers are attractive for their potential to demonstrate an effect on the structural and pathophysiologic elements of OA in the time frame of a clinical trial, but rely on well-characterized relationships between those structural and pathophysiologic elements of OA and the clinical outcomes of OA. A recent advance is data showing that semiquantitative knee joint features, including cartilage thickness and surface area, meniscal morphology, and bone marrow lesions, were associated with clinically relevant OA progression and could be potentially useful as measures of efficacy in clinical trials of disease-modifying interventions.5 Being able to describe the clinical benefit to be expected from such changes is essential to use these outcomes in the benefit-risk assessment. How to include structural outcomes in OA trials will depend on the level of information available to characterize clinical benefit. With less information, structural outcomes may still be useful as adjunct or secondary endpoints. To be used as the primary endpoint to support approval, a high level of characterization would be needed about the relationship of the endpoint to anticipated clinical benefit. The FDA recommends that sponsors proposing such a primary endpoint should engage with the agency early in the development program.
Another option discussed was to study an accelerated OA population, that is, subjects (prior to joint replacement) with a history of trauma to a joint and other injuries predictive of early OA. In that setting, the study duration needed to demonstrate the relationship of structural and clinical outcomes may be more feasible.
A third option discussed was an end-stage OA trial that could enroll subjects who meet criteria for joint replacement. Such a study could possibly have outcomes that include delay in time to surgery, reduction in need for surgery, and clinical outcomes, such as need for concomitant analgesics, patient pain, and patient function. In any OA population, demonstrating a treatment’s effectiveness on clinical outcomes could be the sole basis for approval, in the context of an acceptable safety profile.
Dr. Niskar is national scientific director of the Arthritis Foundation. Dr. Yim is supervisory associate director of the division of pulmonary, allergy, and rheumatology products in the Office of New Drugs at the FDA’s Center for Drug Evaluation and Research. Dr. Kraus is professor of medicine, pathology, and orthopedic surgery at Duke University, Durham, N.C., and is a faculty member of the Duke Molecular Physiology Institute. Dr. Tuan is director of the Center for Cellular and Molecular Engineering and Distinguished Professor of Orthopedic Surgery at the University of Pittsburgh.
Dr. Niskar reports that the Arthritis Foundation received a donation from Samumed and a cosponsorship grant from the FDA to implement the Accelerating OA Clinical Trials Workshop. Dr. Kraus reports an Arthritis Foundation Delivering on Discovery Award that is outside of this editorial. Dr. Yim and Dr. Tuan disclosed no conflicts. Dr. Yim is relaying her personal views in this editorial, and they are not intended to convey official FDA policy, and no official support or endorsement by the FDA is provided or should be inferred. Samumed did not have a role in the writing of this editorial.
References
1. Bioworld. 2016;27:1-4.
2. Osteoarthritis Cartilage. 2015 May;23[5]:677-85.
3. Clinical Trials Transformation Initiative. PG engagement across the research & development continuum. 2015.
4. Sci Transl Med. 2016;8:336ps11.
5. Arthritis Rheumatol. 2016 Oct;68[10]:2422-31.
Fiber may play role in lessening knee pain, OA development
Consumption of dietary fiber at the recommended average intake of 25 g per day was associated with lower risks of developing symptomatic knee osteoarthritis and moderate or severe knee pain over 4-8 years in two separate analyses of Osteoarthritis Initiative participants conducted by investigators at Boston University.
The studies are the first to describe an association between total dietary fiber and lower risk of symptomatic OA and pain worsening in the knee, as well as a lower risk of moderate and severe pain patterns. The lowered risks were partially mediated by body mass index (BMI) but persisted even after adjustment for the variable.
In both studies, the investigators estimated dietary fiber intake by using a validated food frequency questionnaire at baseline that summed the fibers from grains, fruits and vegetables, and nuts and legumes.
Fiber and symptomatic knee OA
At the end of 4 years of follow-up, Dr. Dai and her colleagues identified 152 knees with incident radiographic OA (defined as a knee newly developing a Kellgren and Lawrence grade of 2 or higher), 869 knees with incident symptomatic OA (defined as new onset of both radiographic OA and a painful knee on most days in past month), and 1,964 knees with pain worsening as defined by an increase of at least 14% of the baseline Western Ontario and McMaster Universities (WOMAC) Index pain subscale score at each annual exam. This analysis excluded 540 people who were lost to follow-up and 205 who had invalid caloric intake recordings, leaving 4,051 in the study. The outcomes also excluded people with prevalent radiographic or symptomatic knee OA or knee pain worsening at baseline.
There was a significant trend for lower risk of both symptomatic OA (P less than .002) and pain worsening (P = .005) across four quartiles of daily total dietary fiber intake (mean of 9.1 g, 13 g, 16 g, and 21.9 g in quartiles 1-4). Quartile 4 daily intake was associated with a statistically significant 30% reduction (95% confidence interval, 6%-48%) in the odds of symptomatic knee OA and a 19% reduction (95% CI, 6%-29%) in the odds of pain worsening. Both comparisons were adjusted for age, sex, race, total energy intake, education, smoking status, physical activity, intake of other dietary factors (including polyunsaturated fat and other fats, vitamin C, vitamin D, vitamin E, vitamin K, dairy products, sweets, and soda), and nonsteroidal anti-inflammatory drug use (for the pain-worsening comparison).
Even though approximately 34% of the association between total fiber intake and symptomatic OA and 22% of the association between total fiber intake and pain worsening were mediated through reduced BMI, further adjustment of the comparisons for baseline BMI yielded similarly significant results.
The investigators found no associations between total dietary fiber intake and radiographic knee OA or for other fiber intake with either symptomatic or radiographic knee OA.
“The strongest protection was suggested at the highest quartile, which is in line with the current dietary guidelines for daily fiber intake. For older people [aged 51 years and older], for women it’s 22 g per day and for men it’s 28 g per day,” Dr. Dai said at the meeting.
Fiber and knee pain trajectories
Dr. Dai and her associates identified distinct, relatively homogeneous clusters of WOMAC pain trajectories over the 8-year study course in patients with and without radiographic knee OA at baseline in the Arthritis Care & Research study, and then examined their relationship to participants’ total dietary fiber intake, divided into quartiles (Arthritis Res Care. 2016; Nov 29. doi: 10.1002/acr.23158). The investigators found four pain trajectory patterns, including no pain (34.5%), mild pain (38.1%), moderate pain (21.2%), and severe pain (6.2%).
Individuals who consumed the most total fiber also had the highest representation in the no pain pattern (38.1%) and the lowest representation in the severe pain pattern (4.3%). A high total fiber intake was associated with lower risk of having a moderate or severe pain pattern when compared with those in the no pain trajectory (both P for trend less than .01). Intake of fiber in the highest quartile was associated with a 24% lower likelihood (95% CI, 7%-39%) of belonging to the moderate pain pattern and a 44% lower likelihood (95% CI, 2%-59%) of being in the severe pain pattern, compared with individuals in the lowest intake quartile.
The same four pain trajectory patterns existed in individuals with radiographic knee OA at baseline, but the proportions were shifted slightly lower for no pain (26.1%) and higher for severe pain (7.9%). There was an even greater effect magnitude for the association between dietary total fiber and moderate or severe pain pattern among individuals with radiographic knee OA at baseline. Similar results were found for participants without radiographic knee OA at baseline. The relationships between total dietary fiber intake and pain patterns were somewhat attenuated after adjustment for depression scores and BMI at baseline but still remained statistically significant.
In each of the comparisons and sensitivity analyses, the highest quartile of cereal grain fiber intake was also significant on its own in lowering risk for being in the moderate or severe pain trajectory patterns. However, no significant results were found for fiber from fruits and vegetables or from nuts and legumes.
The studies were supported by grants from the National Institutes of Health. None of the authors had conflicts of interest to disclose.
Consumption of dietary fiber at the recommended average intake of 25 g per day was associated with lower risks of developing symptomatic knee osteoarthritis and moderate or severe knee pain over 4-8 years in two separate analyses of Osteoarthritis Initiative participants conducted by investigators at Boston University.
The studies are the first to describe an association between total dietary fiber and lower risk of symptomatic OA and pain worsening in the knee, as well as a lower risk of moderate and severe pain patterns. The lowered risks were partially mediated by body mass index (BMI) but persisted even after adjustment for the variable.
In both studies, the investigators estimated dietary fiber intake by using a validated food frequency questionnaire at baseline that summed the fibers from grains, fruits and vegetables, and nuts and legumes.
Fiber and symptomatic knee OA
At the end of 4 years of follow-up, Dr. Dai and her colleagues identified 152 knees with incident radiographic OA (defined as a knee newly developing a Kellgren and Lawrence grade of 2 or higher), 869 knees with incident symptomatic OA (defined as new onset of both radiographic OA and a painful knee on most days in past month), and 1,964 knees with pain worsening as defined by an increase of at least 14% of the baseline Western Ontario and McMaster Universities (WOMAC) Index pain subscale score at each annual exam. This analysis excluded 540 people who were lost to follow-up and 205 who had invalid caloric intake recordings, leaving 4,051 in the study. The outcomes also excluded people with prevalent radiographic or symptomatic knee OA or knee pain worsening at baseline.
There was a significant trend for lower risk of both symptomatic OA (P less than .002) and pain worsening (P = .005) across four quartiles of daily total dietary fiber intake (mean of 9.1 g, 13 g, 16 g, and 21.9 g in quartiles 1-4). Quartile 4 daily intake was associated with a statistically significant 30% reduction (95% confidence interval, 6%-48%) in the odds of symptomatic knee OA and a 19% reduction (95% CI, 6%-29%) in the odds of pain worsening. Both comparisons were adjusted for age, sex, race, total energy intake, education, smoking status, physical activity, intake of other dietary factors (including polyunsaturated fat and other fats, vitamin C, vitamin D, vitamin E, vitamin K, dairy products, sweets, and soda), and nonsteroidal anti-inflammatory drug use (for the pain-worsening comparison).
Even though approximately 34% of the association between total fiber intake and symptomatic OA and 22% of the association between total fiber intake and pain worsening were mediated through reduced BMI, further adjustment of the comparisons for baseline BMI yielded similarly significant results.
The investigators found no associations between total dietary fiber intake and radiographic knee OA or for other fiber intake with either symptomatic or radiographic knee OA.
“The strongest protection was suggested at the highest quartile, which is in line with the current dietary guidelines for daily fiber intake. For older people [aged 51 years and older], for women it’s 22 g per day and for men it’s 28 g per day,” Dr. Dai said at the meeting.
Fiber and knee pain trajectories
Dr. Dai and her associates identified distinct, relatively homogeneous clusters of WOMAC pain trajectories over the 8-year study course in patients with and without radiographic knee OA at baseline in the Arthritis Care & Research study, and then examined their relationship to participants’ total dietary fiber intake, divided into quartiles (Arthritis Res Care. 2016; Nov 29. doi: 10.1002/acr.23158). The investigators found four pain trajectory patterns, including no pain (34.5%), mild pain (38.1%), moderate pain (21.2%), and severe pain (6.2%).
Individuals who consumed the most total fiber also had the highest representation in the no pain pattern (38.1%) and the lowest representation in the severe pain pattern (4.3%). A high total fiber intake was associated with lower risk of having a moderate or severe pain pattern when compared with those in the no pain trajectory (both P for trend less than .01). Intake of fiber in the highest quartile was associated with a 24% lower likelihood (95% CI, 7%-39%) of belonging to the moderate pain pattern and a 44% lower likelihood (95% CI, 2%-59%) of being in the severe pain pattern, compared with individuals in the lowest intake quartile.
The same four pain trajectory patterns existed in individuals with radiographic knee OA at baseline, but the proportions were shifted slightly lower for no pain (26.1%) and higher for severe pain (7.9%). There was an even greater effect magnitude for the association between dietary total fiber and moderate or severe pain pattern among individuals with radiographic knee OA at baseline. Similar results were found for participants without radiographic knee OA at baseline. The relationships between total dietary fiber intake and pain patterns were somewhat attenuated after adjustment for depression scores and BMI at baseline but still remained statistically significant.
In each of the comparisons and sensitivity analyses, the highest quartile of cereal grain fiber intake was also significant on its own in lowering risk for being in the moderate or severe pain trajectory patterns. However, no significant results were found for fiber from fruits and vegetables or from nuts and legumes.
The studies were supported by grants from the National Institutes of Health. None of the authors had conflicts of interest to disclose.
Consumption of dietary fiber at the recommended average intake of 25 g per day was associated with lower risks of developing symptomatic knee osteoarthritis and moderate or severe knee pain over 4-8 years in two separate analyses of Osteoarthritis Initiative participants conducted by investigators at Boston University.
The studies are the first to describe an association between total dietary fiber and lower risk of symptomatic OA and pain worsening in the knee, as well as a lower risk of moderate and severe pain patterns. The lowered risks were partially mediated by body mass index (BMI) but persisted even after adjustment for the variable.
In both studies, the investigators estimated dietary fiber intake by using a validated food frequency questionnaire at baseline that summed the fibers from grains, fruits and vegetables, and nuts and legumes.
Fiber and symptomatic knee OA
At the end of 4 years of follow-up, Dr. Dai and her colleagues identified 152 knees with incident radiographic OA (defined as a knee newly developing a Kellgren and Lawrence grade of 2 or higher), 869 knees with incident symptomatic OA (defined as new onset of both radiographic OA and a painful knee on most days in past month), and 1,964 knees with pain worsening as defined by an increase of at least 14% of the baseline Western Ontario and McMaster Universities (WOMAC) Index pain subscale score at each annual exam. This analysis excluded 540 people who were lost to follow-up and 205 who had invalid caloric intake recordings, leaving 4,051 in the study. The outcomes also excluded people with prevalent radiographic or symptomatic knee OA or knee pain worsening at baseline.
There was a significant trend for lower risk of both symptomatic OA (P less than .002) and pain worsening (P = .005) across four quartiles of daily total dietary fiber intake (mean of 9.1 g, 13 g, 16 g, and 21.9 g in quartiles 1-4). Quartile 4 daily intake was associated with a statistically significant 30% reduction (95% confidence interval, 6%-48%) in the odds of symptomatic knee OA and a 19% reduction (95% CI, 6%-29%) in the odds of pain worsening. Both comparisons were adjusted for age, sex, race, total energy intake, education, smoking status, physical activity, intake of other dietary factors (including polyunsaturated fat and other fats, vitamin C, vitamin D, vitamin E, vitamin K, dairy products, sweets, and soda), and nonsteroidal anti-inflammatory drug use (for the pain-worsening comparison).
Even though approximately 34% of the association between total fiber intake and symptomatic OA and 22% of the association between total fiber intake and pain worsening were mediated through reduced BMI, further adjustment of the comparisons for baseline BMI yielded similarly significant results.
The investigators found no associations between total dietary fiber intake and radiographic knee OA or for other fiber intake with either symptomatic or radiographic knee OA.
“The strongest protection was suggested at the highest quartile, which is in line with the current dietary guidelines for daily fiber intake. For older people [aged 51 years and older], for women it’s 22 g per day and for men it’s 28 g per day,” Dr. Dai said at the meeting.
Fiber and knee pain trajectories
Dr. Dai and her associates identified distinct, relatively homogeneous clusters of WOMAC pain trajectories over the 8-year study course in patients with and without radiographic knee OA at baseline in the Arthritis Care & Research study, and then examined their relationship to participants’ total dietary fiber intake, divided into quartiles (Arthritis Res Care. 2016; Nov 29. doi: 10.1002/acr.23158). The investigators found four pain trajectory patterns, including no pain (34.5%), mild pain (38.1%), moderate pain (21.2%), and severe pain (6.2%).
Individuals who consumed the most total fiber also had the highest representation in the no pain pattern (38.1%) and the lowest representation in the severe pain pattern (4.3%). A high total fiber intake was associated with lower risk of having a moderate or severe pain pattern when compared with those in the no pain trajectory (both P for trend less than .01). Intake of fiber in the highest quartile was associated with a 24% lower likelihood (95% CI, 7%-39%) of belonging to the moderate pain pattern and a 44% lower likelihood (95% CI, 2%-59%) of being in the severe pain pattern, compared with individuals in the lowest intake quartile.
The same four pain trajectory patterns existed in individuals with radiographic knee OA at baseline, but the proportions were shifted slightly lower for no pain (26.1%) and higher for severe pain (7.9%). There was an even greater effect magnitude for the association between dietary total fiber and moderate or severe pain pattern among individuals with radiographic knee OA at baseline. Similar results were found for participants without radiographic knee OA at baseline. The relationships between total dietary fiber intake and pain patterns were somewhat attenuated after adjustment for depression scores and BMI at baseline but still remained statistically significant.
In each of the comparisons and sensitivity analyses, the highest quartile of cereal grain fiber intake was also significant on its own in lowering risk for being in the moderate or severe pain trajectory patterns. However, no significant results were found for fiber from fruits and vegetables or from nuts and legumes.
The studies were supported by grants from the National Institutes of Health. None of the authors had conflicts of interest to disclose.
FROM ARTHRITIS CARE & RESEARCH AND THE ACR ANNUAL MEETING
Key clinical point:
Major finding: The highest quartile of daily dietary fiber intake was associated with a statistically significant 30% reduction (95% CI, 6%-48%) in the odds of symptomatic knee OA and a 19% reduction (95% CI, 6%-29%) in the odds of pain worsening.
Data source: Two analyses of the prospective, multicenter Osteoarthritis Initiative cohort of 4,796 men and women aged 45-79 years with or at risk for knee osteoarthritis.
Disclosures: The studies were supported by grants from the National Institutes of Health. None of the authors had conflicts of interest to disclose.
VIDEO: Celecoxib just as safe as naproxen or ibuprofen in OA and RA
WASHINGTON – Celecoxib conferred a 53% decreased risk of overall mortality upon patients with rheumatoid arthritis when compared with naproxen – a surprise finding in a subanalysis of the newly released PRECISION study of anti-inflammatory drugs in arthritis.
But it’s tough to know what to make of the difference, according to the investigators at the annual meeting of the American College of Rheumatology. Although statistically significant, the mortality finding was based on just 45 events: 30 among those taking naproxen and 15 among those taking celecoxib.
“While I would say we were surprised to see this, we really can’t say what it means – or if it means anything,” primary investigator Daniel Solomon, MD, said in an interview. “This is a finding we will continue to investigate and look at, but at this point it’s not enough to base any prescribing decisions on.”
PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen) enrolled more than 24,000 patients with osteoarthritis or rheumatoid arthritis. They were randomized to celecoxib, naproxen, or ibuprofen for a mean of 20 months, with an additional mean follow-up of 34 months.
The primary outcome was the first occurrence of an adverse event from the Antiplatelet Trialists Collaboration criteria (APTC; death from cardiovascular causes, nonfatal heart attack, or nonfatal stroke). Secondary outcomes included:
• Major cardiovascular events (heart attack, stroke, cardiovascular death, revascularization, and hospitalization for unstable angina or transient ischemic attack).
• Renal events (acute kidney injury, including hospitalization for renal failure).
• Gastrointestinal events (hemorrhage, perforation, gastroduodenal ulcer, anemia of gastrointestinal origin, and gastric outlet obstruction.
The main PRECISION findings were released Nov. 13 at the annual meeting of the American Heart Association and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2016 Nov 13. doi: 10.1056/NEJMoa1611593).
Overall, celecoxib was just as safe as were the other drugs on the APTC endpoint, which occurred in about 2% of each groups. The study found significantly decreased risks of both GI and renal events with celecoxib, compared with either naproxen or ibuprofen. Celecoxib and naproxen were equivalent with regard to GI and renal events.
The subanalysis, released at the ACR meeting, adds important disease-specific context to the overall PRECISION results.
“We wanted to really delve into the subtle differences in how these two patient groups responded to these medications,” said PRECISION coinvestigator Elaine Husni, MD, vice chair of the department of rheumatic and immunologic diseases at the Cleveland Clinic.
“We learned that each of these NSAIDs has a unique safety profile that can be different in different groups. And in general, celecoxib seems less risky than the others.”
The cohort subanalysis broke down these endpoints among 21,600 patients with osteoarthritis and 2,400 with rheumatoid arthritis.
Among patients with osteoarthritis, celecoxib was also associated with a 16% decreased risk of a major adverse cardiovascular event, compared with ibuprofen. GI events were also less likely in this group: Celecoxib was associated with a 32% decreased risk, compared with ibuprofen, and a 27% decreased risk, compared with naproxen.
Renal outcomes were almost identical in all of the medications in both groups, Dr. Husni said.
In addition to the adverse event outcomes, the subanalysis examined how well patients responded to their assigned NSAID. There were also some subtle differences seen here, Dr. Solomon and Dr. Husni said.
For patients with RA, ibuprofen was slightly, but significantly, more effective than either celecoxib or ibuprofen at controlling pain as measured by a visual analog pain scale. Patients with osteoarthritis responded equally well to all of the drugs.
RA patients also responded best to ibuprofen as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). Again, patients with osteoarthritis responded equally well to all of the medications.
The overall findings, as well as the subanalysis, should be reassuring to both physicians and patients, said Dr. Solomon, chief of the section of clinical sciences in the divisions of rheumatology and pharmacoepidemiology at Brigham and Women’s Hospital, Boston.
“I can now stand in front of patients and say with confidence, ‘Each of these drugs is fairly safe, and together we can choose the one that will be best for you, based on your own individual history and your own individual risk factors.’ I feel good about that.”
Pfizer funded the trial. Dr. Husni has research grants from Genzyme/Sanofi on a knee osteoarthritis trial related to hyaluronic acid injections. Dr. Solomon has research grants from Pfizer on non-NSAID related topics. He also receives royalties from UpToDate on chapters related to NSAIDs and selective COX-2 inhibitors.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
msullivan@frontlinemedcom.com
On Twitter @alz_gal
WASHINGTON – Celecoxib conferred a 53% decreased risk of overall mortality upon patients with rheumatoid arthritis when compared with naproxen – a surprise finding in a subanalysis of the newly released PRECISION study of anti-inflammatory drugs in arthritis.
But it’s tough to know what to make of the difference, according to the investigators at the annual meeting of the American College of Rheumatology. Although statistically significant, the mortality finding was based on just 45 events: 30 among those taking naproxen and 15 among those taking celecoxib.
“While I would say we were surprised to see this, we really can’t say what it means – or if it means anything,” primary investigator Daniel Solomon, MD, said in an interview. “This is a finding we will continue to investigate and look at, but at this point it’s not enough to base any prescribing decisions on.”
PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen) enrolled more than 24,000 patients with osteoarthritis or rheumatoid arthritis. They were randomized to celecoxib, naproxen, or ibuprofen for a mean of 20 months, with an additional mean follow-up of 34 months.
The primary outcome was the first occurrence of an adverse event from the Antiplatelet Trialists Collaboration criteria (APTC; death from cardiovascular causes, nonfatal heart attack, or nonfatal stroke). Secondary outcomes included:
• Major cardiovascular events (heart attack, stroke, cardiovascular death, revascularization, and hospitalization for unstable angina or transient ischemic attack).
• Renal events (acute kidney injury, including hospitalization for renal failure).
• Gastrointestinal events (hemorrhage, perforation, gastroduodenal ulcer, anemia of gastrointestinal origin, and gastric outlet obstruction.
The main PRECISION findings were released Nov. 13 at the annual meeting of the American Heart Association and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2016 Nov 13. doi: 10.1056/NEJMoa1611593).
Overall, celecoxib was just as safe as were the other drugs on the APTC endpoint, which occurred in about 2% of each groups. The study found significantly decreased risks of both GI and renal events with celecoxib, compared with either naproxen or ibuprofen. Celecoxib and naproxen were equivalent with regard to GI and renal events.
The subanalysis, released at the ACR meeting, adds important disease-specific context to the overall PRECISION results.
“We wanted to really delve into the subtle differences in how these two patient groups responded to these medications,” said PRECISION coinvestigator Elaine Husni, MD, vice chair of the department of rheumatic and immunologic diseases at the Cleveland Clinic.
“We learned that each of these NSAIDs has a unique safety profile that can be different in different groups. And in general, celecoxib seems less risky than the others.”
The cohort subanalysis broke down these endpoints among 21,600 patients with osteoarthritis and 2,400 with rheumatoid arthritis.
Among patients with osteoarthritis, celecoxib was also associated with a 16% decreased risk of a major adverse cardiovascular event, compared with ibuprofen. GI events were also less likely in this group: Celecoxib was associated with a 32% decreased risk, compared with ibuprofen, and a 27% decreased risk, compared with naproxen.
Renal outcomes were almost identical in all of the medications in both groups, Dr. Husni said.
In addition to the adverse event outcomes, the subanalysis examined how well patients responded to their assigned NSAID. There were also some subtle differences seen here, Dr. Solomon and Dr. Husni said.
For patients with RA, ibuprofen was slightly, but significantly, more effective than either celecoxib or ibuprofen at controlling pain as measured by a visual analog pain scale. Patients with osteoarthritis responded equally well to all of the drugs.
RA patients also responded best to ibuprofen as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). Again, patients with osteoarthritis responded equally well to all of the medications.
The overall findings, as well as the subanalysis, should be reassuring to both physicians and patients, said Dr. Solomon, chief of the section of clinical sciences in the divisions of rheumatology and pharmacoepidemiology at Brigham and Women’s Hospital, Boston.
“I can now stand in front of patients and say with confidence, ‘Each of these drugs is fairly safe, and together we can choose the one that will be best for you, based on your own individual history and your own individual risk factors.’ I feel good about that.”
Pfizer funded the trial. Dr. Husni has research grants from Genzyme/Sanofi on a knee osteoarthritis trial related to hyaluronic acid injections. Dr. Solomon has research grants from Pfizer on non-NSAID related topics. He also receives royalties from UpToDate on chapters related to NSAIDs and selective COX-2 inhibitors.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
msullivan@frontlinemedcom.com
On Twitter @alz_gal
WASHINGTON – Celecoxib conferred a 53% decreased risk of overall mortality upon patients with rheumatoid arthritis when compared with naproxen – a surprise finding in a subanalysis of the newly released PRECISION study of anti-inflammatory drugs in arthritis.
But it’s tough to know what to make of the difference, according to the investigators at the annual meeting of the American College of Rheumatology. Although statistically significant, the mortality finding was based on just 45 events: 30 among those taking naproxen and 15 among those taking celecoxib.
“While I would say we were surprised to see this, we really can’t say what it means – or if it means anything,” primary investigator Daniel Solomon, MD, said in an interview. “This is a finding we will continue to investigate and look at, but at this point it’s not enough to base any prescribing decisions on.”
PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen) enrolled more than 24,000 patients with osteoarthritis or rheumatoid arthritis. They were randomized to celecoxib, naproxen, or ibuprofen for a mean of 20 months, with an additional mean follow-up of 34 months.
The primary outcome was the first occurrence of an adverse event from the Antiplatelet Trialists Collaboration criteria (APTC; death from cardiovascular causes, nonfatal heart attack, or nonfatal stroke). Secondary outcomes included:
• Major cardiovascular events (heart attack, stroke, cardiovascular death, revascularization, and hospitalization for unstable angina or transient ischemic attack).
• Renal events (acute kidney injury, including hospitalization for renal failure).
• Gastrointestinal events (hemorrhage, perforation, gastroduodenal ulcer, anemia of gastrointestinal origin, and gastric outlet obstruction.
The main PRECISION findings were released Nov. 13 at the annual meeting of the American Heart Association and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2016 Nov 13. doi: 10.1056/NEJMoa1611593).
Overall, celecoxib was just as safe as were the other drugs on the APTC endpoint, which occurred in about 2% of each groups. The study found significantly decreased risks of both GI and renal events with celecoxib, compared with either naproxen or ibuprofen. Celecoxib and naproxen were equivalent with regard to GI and renal events.
The subanalysis, released at the ACR meeting, adds important disease-specific context to the overall PRECISION results.
“We wanted to really delve into the subtle differences in how these two patient groups responded to these medications,” said PRECISION coinvestigator Elaine Husni, MD, vice chair of the department of rheumatic and immunologic diseases at the Cleveland Clinic.
“We learned that each of these NSAIDs has a unique safety profile that can be different in different groups. And in general, celecoxib seems less risky than the others.”
The cohort subanalysis broke down these endpoints among 21,600 patients with osteoarthritis and 2,400 with rheumatoid arthritis.
Among patients with osteoarthritis, celecoxib was also associated with a 16% decreased risk of a major adverse cardiovascular event, compared with ibuprofen. GI events were also less likely in this group: Celecoxib was associated with a 32% decreased risk, compared with ibuprofen, and a 27% decreased risk, compared with naproxen.
Renal outcomes were almost identical in all of the medications in both groups, Dr. Husni said.
In addition to the adverse event outcomes, the subanalysis examined how well patients responded to their assigned NSAID. There were also some subtle differences seen here, Dr. Solomon and Dr. Husni said.
For patients with RA, ibuprofen was slightly, but significantly, more effective than either celecoxib or ibuprofen at controlling pain as measured by a visual analog pain scale. Patients with osteoarthritis responded equally well to all of the drugs.
RA patients also responded best to ibuprofen as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). Again, patients with osteoarthritis responded equally well to all of the medications.
The overall findings, as well as the subanalysis, should be reassuring to both physicians and patients, said Dr. Solomon, chief of the section of clinical sciences in the divisions of rheumatology and pharmacoepidemiology at Brigham and Women’s Hospital, Boston.
“I can now stand in front of patients and say with confidence, ‘Each of these drugs is fairly safe, and together we can choose the one that will be best for you, based on your own individual history and your own individual risk factors.’ I feel good about that.”
Pfizer funded the trial. Dr. Husni has research grants from Genzyme/Sanofi on a knee osteoarthritis trial related to hyaluronic acid injections. Dr. Solomon has research grants from Pfizer on non-NSAID related topics. He also receives royalties from UpToDate on chapters related to NSAIDs and selective COX-2 inhibitors.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
msullivan@frontlinemedcom.com
On Twitter @alz_gal
AT THE ACR ANNUAL MEETING
Key clinical point:
Major finding: Compared with naproxen, celecoxib was associated with a 53% lower risk of overall mortality, although the clinical impact of that finding remains unknown.
Data source: PRECISION, which randomized more than 24,000 patients to celecoxib, ibuprofen, or naproxen.
Disclosures: Pfizer funded the trial. Dr. Husni has research grants from Genzyme/Sanofi on a knee osteoarthritis trial related to hyaluronic acid injections. Dr. Solomon has research grants from Pfizer on non-NSAID related topics. He also receives royalties from UpToDate on chapters related to NSAIDs and selective COX-2 inhibitors.
VIDEO: PRECISION exonerates celecoxib: cardiovascular risk is no worse than that of nonselective NSAIDs
NEW ORLEANS – The cardiovascular safety profile of the nonsteroidal anti-inflammatory drug (NSAID) celecoxib, a selective inhibitor of COX-2, is no worse than those of the nonselective NSAIDs naproxen and ibuprofen, according to a trial reported at the American Heart Association scientific sessions.
The trial, known as PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen Or Naproxen) was undertaken after another selective COX-2 inhibitor, rofecoxib (Vioxx), was withdrawn from the market because of associated cardiovascular events. It compared the three drugs among more than 24,000 patients with painful arthritis and elevated cardiovascular risk.
Main results showed that 2%-3% of patients experienced a cardiovascular event (cardiovascular death, myocardial infarction, or stroke) during a follow-up approaching 3 years, regardless of which drug they were assigned to take, with the slight differences falling within predefined margins for noninferiority of celecoxib, investigators reported in a session and related press conference.
Additionally, celecoxib yielded a lower rate of gastrointestinal events when compared with each of the other drugs and a lower rate of renal events when compared with ibuprofen.
“After the withdrawal of rofecoxib, everybody thought they knew the answer, that COX-2 inhibitors had an unfavorable cardiovascular profile,” commented first author Steven E. Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic in Ohio. “We didn’t find that. And this is the type of study that once again teaches us that if we jump to conclusions about this based on mechanistic considerations, we often make very bad decisions.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Efforts are under way to disseminate the PRECISION findings to rheumatologists and other groups who do much of the NSAID prescribing.
“Any time you have something that has findings like the findings we have, it takes some time to trickle down to the prescribers. It’s going to be our job to communicate both the value and the important limitations of the trial so that people can make informed decisions about which of these drugs to use and in whom,” Dr. Nissen said.
A cautionary view
“The investigators addressed an extremely important question, which is what is the cardiovascular safety of agents that we administer for a general medical condition over the long term,” commented invited discussant Elliott M. Antman, MD, a senior physician at Brigham and Women’s Hospital and associate dean for Clinical and Translational Research at Harvard Medical School in Boston. “We don’t see a lot of trials like that, but we do need this information.”
“This is not a comparison of drugs; this is a comparison of drug regimens because the investigators were able to increase the dose to control the subjects’ pain,” Dr. Antman elaborated. “And they were able to increase the dose of naproxen and ibuprofen comparatively more than they could for celecoxib,” which was capped at 200 mg per day at most study sites.
Furthermore, only about one-fifth of the patients studied had known heart disease. “We know that the more likely a person is to have atherosclerosis, the more likely they are to experience harm from COX-2 inhibition,” he said. “So given the profile of the patients in this trial, it’s unlikely that we would have been able to detect that signal of harm from COX-2 inhibition, particularly at this dose.”
Dr. Antman also had concerns about the impact on concomitant aspirin therapy (the benefit of which can be affected by nonselective NSAIDs) and about possible differences in the reasons for dropouts that may have biased findings toward celecoxib. “I believe we need more information in order to more completely interpret this trial,” he summarized.
For now, he advised physicians to follow guidance put forth by the American Heart Association: Avoid NSAIDs in patients with known heart disease, and if one must use them, try to use the lowest-risk drug in the lowest dose needed for the shortest period of time.
In the future, “we should actually break out of the mold of assigning everybody in the trial a common phenotype and reporting the average result, but instead take a precision medicine approach, where we look at the polymorphisms in the COX enzyme, look at the polymorphisms in the ability to metabolize these drugs, and actually see if we can be more precise,” Dr. Antman maintained. “Finally, there is an urgent clinical need for the development of novel analgesics and other therapeutics to avoid the cardiovascular risk from all NSAIDs.”
Trial details
Patients were eligible for PRECISION, a Pfizer-funded trial, if they had osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk.
In all, 24,081 patients from 926 centers globally were randomly assigned to double-blind treatment with celecoxib, naproxen, or ibuprofen, all of which are now available as generics in the United States.
“Patients were randomized to the FDA-approved doses of these drugs, and they could have their dose increased if they had unrelieved pain up to the maximum allowed by regulatory authorities in the local jurisdictions where the study was done,” Dr. Nissen noted, pointing out that studies initially generating some concern about celecoxib used a supratherapeutic dose of 800 mg daily.
As COX-2 inhibitors are less likely than nonselective NSAIDs to cause ulcers, which might affect compliance and outcomes, all patients additionally received esomeprazole for gastroprotection “to try to level the playing field,” he explained.
The mean treatment duration was 20.3 months, and the mean follow-up duration was 34.1 months, according to data reported at the meeting and simultaneously published (N Engl J Med. 2016 Nov 13. doi: 10.1056/NEJMoa1611593). On average, the daily dose of drug received was 209 mg for celecoxib, 852 mg for naproxen, and 2,045 mg for ibuprofen.
In intention-to-treat analyses, the rate of the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke was 2.3% in the celecoxib group, 2.5% in the naproxen group, and 2.7% in the ibuprofen group. The hazard ratio was 0.93 for celecoxib versus naproxen (P less than .001 for noninferiority) and 0.85 for celecoxib versus ibuprofen (P less than .001 for noninferiority).
Differences were more marked in the on-treatment population. Here, the rate of the primary outcome was 1.7% in the celecoxib group, 1.8% in the naproxen group, and 1.9% in the ibuprofen group. The HR was 0.90 for celecoxib versus naproxen (P less than .001 for noninferiority) and 0.81 for celecoxib versus ibuprofen (P less than .001 for noninferiority).
Secondary outcomes, which tested for superiority, showed that the rate of major adverse cardiovascular events was 15% higher in the ibuprofen group as compared with the celecoxib group in the intent-to-treat population. The difference translated to a near-significant reduction in risk with the latter (HR, 0.87; P = .06) that appeared greater in the on-treatment population.
However, Dr. Nissen cautioned that he could not state that celecoxib was superior. “Secondary and tertiary endpoints in a clinical trial are hypothesis generating, and they are not considered definitive evidence,” he commented. At the same time, “the FDA is going to have to deal with that because what do they do with labeling? What do they do with over-the-counter access to these various drugs?”
The rate of all-cause mortality was 25% higher with naproxen than with celecoxib (HR, 0.80; P = .052).
The rate of gastrointestinal events was 54% higher with ibuprofen (HR, 0.65; P = .002) and 41% higher with naproxen (HR, 0.71; P = .01) as compared with celecoxib. And the rate of renal events was 64% higher with ibuprofen than with celecoxib (HR, 0.61; P = .004).
In a post hoc analysis of global safety, the rate of serious cardiovascular, gastrointestinal, and renal events was 28% higher with ibuprofen (HR, 0.78; P less than .001) and 15% higher with naproxen (HR, 0.87; P = .03) than with celecoxib.
Of note, the findings for the primary endpoint were similar regardless of whether patients were taking low-dose aspirin or not. “There was no interaction with aspirin use,” Dr. Nissen stated. “This was not about the interference of ibuprofen or naproxen with aspirin use.”
Analyses of pain relief using a visual analogue scale showed no clinically meaningful differences, suggesting that the drug doses used were equally analgesic, he said. Stopping of study drug because of lack of efficacy was slightly more common in the celecoxib group.
“We didn’t study the low-dose, intermittent use of these drugs that most of the public engages in, and it’s really important that we crisply communicate that to the public because somebody who takes occasionally ibuprofen or naproxen for a headache should not look at these comparative data in a way that should necessarily influence their behavior. We just don’t know the answer,” cautioned Dr. Nissen, who disclosed that he received grant support from Pfizer during the conduct of the trial.
But the findings are relevant for individuals who take over-the-counter NSAIDs at doses exceeding the label, a phenomenon known as dose creep. “We need to reemphasize to the public that the labeled over-the-counter dose is what you should take. You shouldn’t double up or triple up on the drugs because the issue of high-dose therapy, which is what we studied, suggests that there are really potentially important gastrointestinal, renal, and cardiovascular risks,” he said.
NEW ORLEANS – The cardiovascular safety profile of the nonsteroidal anti-inflammatory drug (NSAID) celecoxib, a selective inhibitor of COX-2, is no worse than those of the nonselective NSAIDs naproxen and ibuprofen, according to a trial reported at the American Heart Association scientific sessions.
The trial, known as PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen Or Naproxen) was undertaken after another selective COX-2 inhibitor, rofecoxib (Vioxx), was withdrawn from the market because of associated cardiovascular events. It compared the three drugs among more than 24,000 patients with painful arthritis and elevated cardiovascular risk.
Main results showed that 2%-3% of patients experienced a cardiovascular event (cardiovascular death, myocardial infarction, or stroke) during a follow-up approaching 3 years, regardless of which drug they were assigned to take, with the slight differences falling within predefined margins for noninferiority of celecoxib, investigators reported in a session and related press conference.
Additionally, celecoxib yielded a lower rate of gastrointestinal events when compared with each of the other drugs and a lower rate of renal events when compared with ibuprofen.
“After the withdrawal of rofecoxib, everybody thought they knew the answer, that COX-2 inhibitors had an unfavorable cardiovascular profile,” commented first author Steven E. Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic in Ohio. “We didn’t find that. And this is the type of study that once again teaches us that if we jump to conclusions about this based on mechanistic considerations, we often make very bad decisions.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Efforts are under way to disseminate the PRECISION findings to rheumatologists and other groups who do much of the NSAID prescribing.
“Any time you have something that has findings like the findings we have, it takes some time to trickle down to the prescribers. It’s going to be our job to communicate both the value and the important limitations of the trial so that people can make informed decisions about which of these drugs to use and in whom,” Dr. Nissen said.
A cautionary view
“The investigators addressed an extremely important question, which is what is the cardiovascular safety of agents that we administer for a general medical condition over the long term,” commented invited discussant Elliott M. Antman, MD, a senior physician at Brigham and Women’s Hospital and associate dean for Clinical and Translational Research at Harvard Medical School in Boston. “We don’t see a lot of trials like that, but we do need this information.”
“This is not a comparison of drugs; this is a comparison of drug regimens because the investigators were able to increase the dose to control the subjects’ pain,” Dr. Antman elaborated. “And they were able to increase the dose of naproxen and ibuprofen comparatively more than they could for celecoxib,” which was capped at 200 mg per day at most study sites.
Furthermore, only about one-fifth of the patients studied had known heart disease. “We know that the more likely a person is to have atherosclerosis, the more likely they are to experience harm from COX-2 inhibition,” he said. “So given the profile of the patients in this trial, it’s unlikely that we would have been able to detect that signal of harm from COX-2 inhibition, particularly at this dose.”
Dr. Antman also had concerns about the impact on concomitant aspirin therapy (the benefit of which can be affected by nonselective NSAIDs) and about possible differences in the reasons for dropouts that may have biased findings toward celecoxib. “I believe we need more information in order to more completely interpret this trial,” he summarized.
For now, he advised physicians to follow guidance put forth by the American Heart Association: Avoid NSAIDs in patients with known heart disease, and if one must use them, try to use the lowest-risk drug in the lowest dose needed for the shortest period of time.
In the future, “we should actually break out of the mold of assigning everybody in the trial a common phenotype and reporting the average result, but instead take a precision medicine approach, where we look at the polymorphisms in the COX enzyme, look at the polymorphisms in the ability to metabolize these drugs, and actually see if we can be more precise,” Dr. Antman maintained. “Finally, there is an urgent clinical need for the development of novel analgesics and other therapeutics to avoid the cardiovascular risk from all NSAIDs.”
Trial details
Patients were eligible for PRECISION, a Pfizer-funded trial, if they had osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk.
In all, 24,081 patients from 926 centers globally were randomly assigned to double-blind treatment with celecoxib, naproxen, or ibuprofen, all of which are now available as generics in the United States.
“Patients were randomized to the FDA-approved doses of these drugs, and they could have their dose increased if they had unrelieved pain up to the maximum allowed by regulatory authorities in the local jurisdictions where the study was done,” Dr. Nissen noted, pointing out that studies initially generating some concern about celecoxib used a supratherapeutic dose of 800 mg daily.
As COX-2 inhibitors are less likely than nonselective NSAIDs to cause ulcers, which might affect compliance and outcomes, all patients additionally received esomeprazole for gastroprotection “to try to level the playing field,” he explained.
The mean treatment duration was 20.3 months, and the mean follow-up duration was 34.1 months, according to data reported at the meeting and simultaneously published (N Engl J Med. 2016 Nov 13. doi: 10.1056/NEJMoa1611593). On average, the daily dose of drug received was 209 mg for celecoxib, 852 mg for naproxen, and 2,045 mg for ibuprofen.
In intention-to-treat analyses, the rate of the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke was 2.3% in the celecoxib group, 2.5% in the naproxen group, and 2.7% in the ibuprofen group. The hazard ratio was 0.93 for celecoxib versus naproxen (P less than .001 for noninferiority) and 0.85 for celecoxib versus ibuprofen (P less than .001 for noninferiority).
Differences were more marked in the on-treatment population. Here, the rate of the primary outcome was 1.7% in the celecoxib group, 1.8% in the naproxen group, and 1.9% in the ibuprofen group. The HR was 0.90 for celecoxib versus naproxen (P less than .001 for noninferiority) and 0.81 for celecoxib versus ibuprofen (P less than .001 for noninferiority).
Secondary outcomes, which tested for superiority, showed that the rate of major adverse cardiovascular events was 15% higher in the ibuprofen group as compared with the celecoxib group in the intent-to-treat population. The difference translated to a near-significant reduction in risk with the latter (HR, 0.87; P = .06) that appeared greater in the on-treatment population.
However, Dr. Nissen cautioned that he could not state that celecoxib was superior. “Secondary and tertiary endpoints in a clinical trial are hypothesis generating, and they are not considered definitive evidence,” he commented. At the same time, “the FDA is going to have to deal with that because what do they do with labeling? What do they do with over-the-counter access to these various drugs?”
The rate of all-cause mortality was 25% higher with naproxen than with celecoxib (HR, 0.80; P = .052).
The rate of gastrointestinal events was 54% higher with ibuprofen (HR, 0.65; P = .002) and 41% higher with naproxen (HR, 0.71; P = .01) as compared with celecoxib. And the rate of renal events was 64% higher with ibuprofen than with celecoxib (HR, 0.61; P = .004).
In a post hoc analysis of global safety, the rate of serious cardiovascular, gastrointestinal, and renal events was 28% higher with ibuprofen (HR, 0.78; P less than .001) and 15% higher with naproxen (HR, 0.87; P = .03) than with celecoxib.
Of note, the findings for the primary endpoint were similar regardless of whether patients were taking low-dose aspirin or not. “There was no interaction with aspirin use,” Dr. Nissen stated. “This was not about the interference of ibuprofen or naproxen with aspirin use.”
Analyses of pain relief using a visual analogue scale showed no clinically meaningful differences, suggesting that the drug doses used were equally analgesic, he said. Stopping of study drug because of lack of efficacy was slightly more common in the celecoxib group.
“We didn’t study the low-dose, intermittent use of these drugs that most of the public engages in, and it’s really important that we crisply communicate that to the public because somebody who takes occasionally ibuprofen or naproxen for a headache should not look at these comparative data in a way that should necessarily influence their behavior. We just don’t know the answer,” cautioned Dr. Nissen, who disclosed that he received grant support from Pfizer during the conduct of the trial.
But the findings are relevant for individuals who take over-the-counter NSAIDs at doses exceeding the label, a phenomenon known as dose creep. “We need to reemphasize to the public that the labeled over-the-counter dose is what you should take. You shouldn’t double up or triple up on the drugs because the issue of high-dose therapy, which is what we studied, suggests that there are really potentially important gastrointestinal, renal, and cardiovascular risks,” he said.
NEW ORLEANS – The cardiovascular safety profile of the nonsteroidal anti-inflammatory drug (NSAID) celecoxib, a selective inhibitor of COX-2, is no worse than those of the nonselective NSAIDs naproxen and ibuprofen, according to a trial reported at the American Heart Association scientific sessions.
The trial, known as PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen Or Naproxen) was undertaken after another selective COX-2 inhibitor, rofecoxib (Vioxx), was withdrawn from the market because of associated cardiovascular events. It compared the three drugs among more than 24,000 patients with painful arthritis and elevated cardiovascular risk.
Main results showed that 2%-3% of patients experienced a cardiovascular event (cardiovascular death, myocardial infarction, or stroke) during a follow-up approaching 3 years, regardless of which drug they were assigned to take, with the slight differences falling within predefined margins for noninferiority of celecoxib, investigators reported in a session and related press conference.
Additionally, celecoxib yielded a lower rate of gastrointestinal events when compared with each of the other drugs and a lower rate of renal events when compared with ibuprofen.
“After the withdrawal of rofecoxib, everybody thought they knew the answer, that COX-2 inhibitors had an unfavorable cardiovascular profile,” commented first author Steven E. Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic in Ohio. “We didn’t find that. And this is the type of study that once again teaches us that if we jump to conclusions about this based on mechanistic considerations, we often make very bad decisions.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Efforts are under way to disseminate the PRECISION findings to rheumatologists and other groups who do much of the NSAID prescribing.
“Any time you have something that has findings like the findings we have, it takes some time to trickle down to the prescribers. It’s going to be our job to communicate both the value and the important limitations of the trial so that people can make informed decisions about which of these drugs to use and in whom,” Dr. Nissen said.
A cautionary view
“The investigators addressed an extremely important question, which is what is the cardiovascular safety of agents that we administer for a general medical condition over the long term,” commented invited discussant Elliott M. Antman, MD, a senior physician at Brigham and Women’s Hospital and associate dean for Clinical and Translational Research at Harvard Medical School in Boston. “We don’t see a lot of trials like that, but we do need this information.”
“This is not a comparison of drugs; this is a comparison of drug regimens because the investigators were able to increase the dose to control the subjects’ pain,” Dr. Antman elaborated. “And they were able to increase the dose of naproxen and ibuprofen comparatively more than they could for celecoxib,” which was capped at 200 mg per day at most study sites.
Furthermore, only about one-fifth of the patients studied had known heart disease. “We know that the more likely a person is to have atherosclerosis, the more likely they are to experience harm from COX-2 inhibition,” he said. “So given the profile of the patients in this trial, it’s unlikely that we would have been able to detect that signal of harm from COX-2 inhibition, particularly at this dose.”
Dr. Antman also had concerns about the impact on concomitant aspirin therapy (the benefit of which can be affected by nonselective NSAIDs) and about possible differences in the reasons for dropouts that may have biased findings toward celecoxib. “I believe we need more information in order to more completely interpret this trial,” he summarized.
For now, he advised physicians to follow guidance put forth by the American Heart Association: Avoid NSAIDs in patients with known heart disease, and if one must use them, try to use the lowest-risk drug in the lowest dose needed for the shortest period of time.
In the future, “we should actually break out of the mold of assigning everybody in the trial a common phenotype and reporting the average result, but instead take a precision medicine approach, where we look at the polymorphisms in the COX enzyme, look at the polymorphisms in the ability to metabolize these drugs, and actually see if we can be more precise,” Dr. Antman maintained. “Finally, there is an urgent clinical need for the development of novel analgesics and other therapeutics to avoid the cardiovascular risk from all NSAIDs.”
Trial details
Patients were eligible for PRECISION, a Pfizer-funded trial, if they had osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk.
In all, 24,081 patients from 926 centers globally were randomly assigned to double-blind treatment with celecoxib, naproxen, or ibuprofen, all of which are now available as generics in the United States.
“Patients were randomized to the FDA-approved doses of these drugs, and they could have their dose increased if they had unrelieved pain up to the maximum allowed by regulatory authorities in the local jurisdictions where the study was done,” Dr. Nissen noted, pointing out that studies initially generating some concern about celecoxib used a supratherapeutic dose of 800 mg daily.
As COX-2 inhibitors are less likely than nonselective NSAIDs to cause ulcers, which might affect compliance and outcomes, all patients additionally received esomeprazole for gastroprotection “to try to level the playing field,” he explained.
The mean treatment duration was 20.3 months, and the mean follow-up duration was 34.1 months, according to data reported at the meeting and simultaneously published (N Engl J Med. 2016 Nov 13. doi: 10.1056/NEJMoa1611593). On average, the daily dose of drug received was 209 mg for celecoxib, 852 mg for naproxen, and 2,045 mg for ibuprofen.
In intention-to-treat analyses, the rate of the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke was 2.3% in the celecoxib group, 2.5% in the naproxen group, and 2.7% in the ibuprofen group. The hazard ratio was 0.93 for celecoxib versus naproxen (P less than .001 for noninferiority) and 0.85 for celecoxib versus ibuprofen (P less than .001 for noninferiority).
Differences were more marked in the on-treatment population. Here, the rate of the primary outcome was 1.7% in the celecoxib group, 1.8% in the naproxen group, and 1.9% in the ibuprofen group. The HR was 0.90 for celecoxib versus naproxen (P less than .001 for noninferiority) and 0.81 for celecoxib versus ibuprofen (P less than .001 for noninferiority).
Secondary outcomes, which tested for superiority, showed that the rate of major adverse cardiovascular events was 15% higher in the ibuprofen group as compared with the celecoxib group in the intent-to-treat population. The difference translated to a near-significant reduction in risk with the latter (HR, 0.87; P = .06) that appeared greater in the on-treatment population.
However, Dr. Nissen cautioned that he could not state that celecoxib was superior. “Secondary and tertiary endpoints in a clinical trial are hypothesis generating, and they are not considered definitive evidence,” he commented. At the same time, “the FDA is going to have to deal with that because what do they do with labeling? What do they do with over-the-counter access to these various drugs?”
The rate of all-cause mortality was 25% higher with naproxen than with celecoxib (HR, 0.80; P = .052).
The rate of gastrointestinal events was 54% higher with ibuprofen (HR, 0.65; P = .002) and 41% higher with naproxen (HR, 0.71; P = .01) as compared with celecoxib. And the rate of renal events was 64% higher with ibuprofen than with celecoxib (HR, 0.61; P = .004).
In a post hoc analysis of global safety, the rate of serious cardiovascular, gastrointestinal, and renal events was 28% higher with ibuprofen (HR, 0.78; P less than .001) and 15% higher with naproxen (HR, 0.87; P = .03) than with celecoxib.
Of note, the findings for the primary endpoint were similar regardless of whether patients were taking low-dose aspirin or not. “There was no interaction with aspirin use,” Dr. Nissen stated. “This was not about the interference of ibuprofen or naproxen with aspirin use.”
Analyses of pain relief using a visual analogue scale showed no clinically meaningful differences, suggesting that the drug doses used were equally analgesic, he said. Stopping of study drug because of lack of efficacy was slightly more common in the celecoxib group.
“We didn’t study the low-dose, intermittent use of these drugs that most of the public engages in, and it’s really important that we crisply communicate that to the public because somebody who takes occasionally ibuprofen or naproxen for a headache should not look at these comparative data in a way that should necessarily influence their behavior. We just don’t know the answer,” cautioned Dr. Nissen, who disclosed that he received grant support from Pfizer during the conduct of the trial.
But the findings are relevant for individuals who take over-the-counter NSAIDs at doses exceeding the label, a phenomenon known as dose creep. “We need to reemphasize to the public that the labeled over-the-counter dose is what you should take. You shouldn’t double up or triple up on the drugs because the issue of high-dose therapy, which is what we studied, suggests that there are really potentially important gastrointestinal, renal, and cardiovascular risks,” he said.
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: The rate of the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke was 2.3% with celecoxib, 2.5% with naproxen, and 2.7% with ibuprofen (P less than .001 for noninferiority).
Data source: A randomized, controlled trial among 24,081 patients who required NSAIDs for painful arthritis and were at increased cardiovascular risk (PRECISION trial).
Disclosures: Dr. Nissen disclosed that he received grant support from Pfizer during the conduct of the trial. The trial was funded by Pfizer.
