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Hip pain predicts OA mortality beyond comorbidities
LIVERPOOL, ENGLAND – Hip pain increases all-cause mortality in people with OA by a third, according to data obtained from a large, community-based study.
The hazard ratio for all-cause mortality was 1.33 (95% confidence interval, 1.17-1.51) in people who self-reported hip pain over the course of up to 25 years’ follow-up. The presence of hip pain also increased the risk of cardiovascular mortality (HR, 1.22; 95% CI, 0.99-1.50).
The hazard ratios for all-cause and cardiovascular mortality in patients with radiographic hip pain were 1.04 (95% CI, 0.91-1.17) and 1.01(95% CI, 0.82-1.24), and the all-cause and cardiovascular mortality hazard ratios in patients with both hip pain and radiographic OA were 1.01 (95% CI, 0.87-1.18) and 1.01 (95% CI, 0.80-1.28).
These data support hip pain as a predictor of mortality, observed Dr. Cleveland, of the University of North Carolina at Chapel Hill. “While there have been a number of studies that have looked at osteoarthritis as a risk factor for mortality, a lot of these studies have looked at arthritis in general or have looked at specifically knee osteoarthritis.
“There have been only a handful of studies that have looked at hip osteoarthritis as a risk factor for mortality,” she added, and considered all together, the results have been equivocal.
The aim of the current study she presented at the congress sponsored by the Osteoarthritis Research Society International was to explore whether or not hip OA was associated with all-cause and cardiovascular disease–specific mortality, independent of any comorbidities. The comorbidities considered were cancer, liver disease, hypertension, type 2 diabetes mellitus, and cardiovascular disease.
Data on 3,919 people with and without hip OA were obtained from the Johnston County Osteoarthritis Project, a longitudinal cohort of white and African American residents aged 45 years or older. Enrollment was carried out in two waves, with 3,185 people recruited between 1990 and 1998 and 1,015 people recruited between 2003 and 2004. Only those with baseline and follow-up assessment data, including at least one hip radiograph, were included in the present analysis.
The mean age at recruitment was 62 years, 61% were women, and two-thirds were white. Around 17% (n = 655) had radiographic hip OA and hip pain (symptomatic OA) at baseline, 10% (n = 787) had radiographic OA alone, and 27% (n = 1,156) had hip pain alone. The remaining 45% (n = 1,321) had neither hip pain nor radiographic damage.
Over the course of up to 25 years’ follow-up, there were 1,762 deaths from any cause – 311 occurred in the group with symptomatic OA at baseline, 382 in the group with radiographic OA alone, 509 in those with hip pain alone, and 560 in those with neither hip pain nor radiographic OA.
Median survival was lowest in individuals with symptomatic OA, at 16.1 years, and highest in individuals without either, at 22.8 years. Median survival was similar for those with hip pain only (18.6 years) and with radiographic hip OA only (18.5 years).
Stratified by race, all-cause mortality was increased with hip pain alone, and was more pronounced in white patients (HR, 1.39) than in African American patients (HR, 1.24). Interestingly, the risk of all-cause death was lower in African American patients who had symptomatic hip OA than their white counterparts (HR, 0.78 and 1.16, respectively).
Furthermore, Dr. Cleveland reported that hip pain was strongly associated with all-cause mortality in those younger than 65 years (HR, 1.56) when compared with those who were 65 years and up (HR, 1.18). Of note, the risk of death was higher in younger patients with symptomatic hip pain than in older patients (HR, 1.33 and 0.88, respectively).
A 41% increased death risk was also observed in patients with hip pain who had a body mass index of 30 kg/m2 (HR, 1.41 vs. HR, 1.29 for those with hip pain and a body mass index of less than 30 kg/m2).
“Our results are independent of comorbidities and sociodemographic measures,” Dr. Cleveland said. “This suggests there are mechanisms beyond comorbidities in the link between radiographic hip OA and mortality risk.”
The Johnston County Osteoarthritis Project is funded by the Centers for Disease Control and Prevention and the National Institutes of Arthritis and Musculoskeletal and Skin Diseases. Dr. Cleveland had no conflicts of interest to report.
SOURCE: Cleveland RJ et al. Osteoarthritis Cartilage. 2018:26(1):S10-1. Abstract 1.
LIVERPOOL, ENGLAND – Hip pain increases all-cause mortality in people with OA by a third, according to data obtained from a large, community-based study.
The hazard ratio for all-cause mortality was 1.33 (95% confidence interval, 1.17-1.51) in people who self-reported hip pain over the course of up to 25 years’ follow-up. The presence of hip pain also increased the risk of cardiovascular mortality (HR, 1.22; 95% CI, 0.99-1.50).
The hazard ratios for all-cause and cardiovascular mortality in patients with radiographic hip pain were 1.04 (95% CI, 0.91-1.17) and 1.01(95% CI, 0.82-1.24), and the all-cause and cardiovascular mortality hazard ratios in patients with both hip pain and radiographic OA were 1.01 (95% CI, 0.87-1.18) and 1.01 (95% CI, 0.80-1.28).
These data support hip pain as a predictor of mortality, observed Dr. Cleveland, of the University of North Carolina at Chapel Hill. “While there have been a number of studies that have looked at osteoarthritis as a risk factor for mortality, a lot of these studies have looked at arthritis in general or have looked at specifically knee osteoarthritis.
“There have been only a handful of studies that have looked at hip osteoarthritis as a risk factor for mortality,” she added, and considered all together, the results have been equivocal.
The aim of the current study she presented at the congress sponsored by the Osteoarthritis Research Society International was to explore whether or not hip OA was associated with all-cause and cardiovascular disease–specific mortality, independent of any comorbidities. The comorbidities considered were cancer, liver disease, hypertension, type 2 diabetes mellitus, and cardiovascular disease.
Data on 3,919 people with and without hip OA were obtained from the Johnston County Osteoarthritis Project, a longitudinal cohort of white and African American residents aged 45 years or older. Enrollment was carried out in two waves, with 3,185 people recruited between 1990 and 1998 and 1,015 people recruited between 2003 and 2004. Only those with baseline and follow-up assessment data, including at least one hip radiograph, were included in the present analysis.
The mean age at recruitment was 62 years, 61% were women, and two-thirds were white. Around 17% (n = 655) had radiographic hip OA and hip pain (symptomatic OA) at baseline, 10% (n = 787) had radiographic OA alone, and 27% (n = 1,156) had hip pain alone. The remaining 45% (n = 1,321) had neither hip pain nor radiographic damage.
Over the course of up to 25 years’ follow-up, there were 1,762 deaths from any cause – 311 occurred in the group with symptomatic OA at baseline, 382 in the group with radiographic OA alone, 509 in those with hip pain alone, and 560 in those with neither hip pain nor radiographic OA.
Median survival was lowest in individuals with symptomatic OA, at 16.1 years, and highest in individuals without either, at 22.8 years. Median survival was similar for those with hip pain only (18.6 years) and with radiographic hip OA only (18.5 years).
Stratified by race, all-cause mortality was increased with hip pain alone, and was more pronounced in white patients (HR, 1.39) than in African American patients (HR, 1.24). Interestingly, the risk of all-cause death was lower in African American patients who had symptomatic hip OA than their white counterparts (HR, 0.78 and 1.16, respectively).
Furthermore, Dr. Cleveland reported that hip pain was strongly associated with all-cause mortality in those younger than 65 years (HR, 1.56) when compared with those who were 65 years and up (HR, 1.18). Of note, the risk of death was higher in younger patients with symptomatic hip pain than in older patients (HR, 1.33 and 0.88, respectively).
A 41% increased death risk was also observed in patients with hip pain who had a body mass index of 30 kg/m2 (HR, 1.41 vs. HR, 1.29 for those with hip pain and a body mass index of less than 30 kg/m2).
“Our results are independent of comorbidities and sociodemographic measures,” Dr. Cleveland said. “This suggests there are mechanisms beyond comorbidities in the link between radiographic hip OA and mortality risk.”
The Johnston County Osteoarthritis Project is funded by the Centers for Disease Control and Prevention and the National Institutes of Arthritis and Musculoskeletal and Skin Diseases. Dr. Cleveland had no conflicts of interest to report.
SOURCE: Cleveland RJ et al. Osteoarthritis Cartilage. 2018:26(1):S10-1. Abstract 1.
LIVERPOOL, ENGLAND – Hip pain increases all-cause mortality in people with OA by a third, according to data obtained from a large, community-based study.
The hazard ratio for all-cause mortality was 1.33 (95% confidence interval, 1.17-1.51) in people who self-reported hip pain over the course of up to 25 years’ follow-up. The presence of hip pain also increased the risk of cardiovascular mortality (HR, 1.22; 95% CI, 0.99-1.50).
The hazard ratios for all-cause and cardiovascular mortality in patients with radiographic hip pain were 1.04 (95% CI, 0.91-1.17) and 1.01(95% CI, 0.82-1.24), and the all-cause and cardiovascular mortality hazard ratios in patients with both hip pain and radiographic OA were 1.01 (95% CI, 0.87-1.18) and 1.01 (95% CI, 0.80-1.28).
These data support hip pain as a predictor of mortality, observed Dr. Cleveland, of the University of North Carolina at Chapel Hill. “While there have been a number of studies that have looked at osteoarthritis as a risk factor for mortality, a lot of these studies have looked at arthritis in general or have looked at specifically knee osteoarthritis.
“There have been only a handful of studies that have looked at hip osteoarthritis as a risk factor for mortality,” she added, and considered all together, the results have been equivocal.
The aim of the current study she presented at the congress sponsored by the Osteoarthritis Research Society International was to explore whether or not hip OA was associated with all-cause and cardiovascular disease–specific mortality, independent of any comorbidities. The comorbidities considered were cancer, liver disease, hypertension, type 2 diabetes mellitus, and cardiovascular disease.
Data on 3,919 people with and without hip OA were obtained from the Johnston County Osteoarthritis Project, a longitudinal cohort of white and African American residents aged 45 years or older. Enrollment was carried out in two waves, with 3,185 people recruited between 1990 and 1998 and 1,015 people recruited between 2003 and 2004. Only those with baseline and follow-up assessment data, including at least one hip radiograph, were included in the present analysis.
The mean age at recruitment was 62 years, 61% were women, and two-thirds were white. Around 17% (n = 655) had radiographic hip OA and hip pain (symptomatic OA) at baseline, 10% (n = 787) had radiographic OA alone, and 27% (n = 1,156) had hip pain alone. The remaining 45% (n = 1,321) had neither hip pain nor radiographic damage.
Over the course of up to 25 years’ follow-up, there were 1,762 deaths from any cause – 311 occurred in the group with symptomatic OA at baseline, 382 in the group with radiographic OA alone, 509 in those with hip pain alone, and 560 in those with neither hip pain nor radiographic OA.
Median survival was lowest in individuals with symptomatic OA, at 16.1 years, and highest in individuals without either, at 22.8 years. Median survival was similar for those with hip pain only (18.6 years) and with radiographic hip OA only (18.5 years).
Stratified by race, all-cause mortality was increased with hip pain alone, and was more pronounced in white patients (HR, 1.39) than in African American patients (HR, 1.24). Interestingly, the risk of all-cause death was lower in African American patients who had symptomatic hip OA than their white counterparts (HR, 0.78 and 1.16, respectively).
Furthermore, Dr. Cleveland reported that hip pain was strongly associated with all-cause mortality in those younger than 65 years (HR, 1.56) when compared with those who were 65 years and up (HR, 1.18). Of note, the risk of death was higher in younger patients with symptomatic hip pain than in older patients (HR, 1.33 and 0.88, respectively).
A 41% increased death risk was also observed in patients with hip pain who had a body mass index of 30 kg/m2 (HR, 1.41 vs. HR, 1.29 for those with hip pain and a body mass index of less than 30 kg/m2).
“Our results are independent of comorbidities and sociodemographic measures,” Dr. Cleveland said. “This suggests there are mechanisms beyond comorbidities in the link between radiographic hip OA and mortality risk.”
The Johnston County Osteoarthritis Project is funded by the Centers for Disease Control and Prevention and the National Institutes of Arthritis and Musculoskeletal and Skin Diseases. Dr. Cleveland had no conflicts of interest to report.
SOURCE: Cleveland RJ et al. Osteoarthritis Cartilage. 2018:26(1):S10-1. Abstract 1.
REPORTING FROM OARSI 2018
Key clinical point: Hip pain is a predictor of mortality in patients with OA and is independent of any comorbidities.
Major finding: The hazard ratios for all-cause and cardiovascular mortality in patients with hip pain were 1.33 and 1.22.
Study details: A longitudinal cohort study of almost 4,000 people, with up to 25 years’ follow-up.
Disclosures: The Johnston County Osteoarthritis Project is funded by the Centers for Disease Control and Prevention and the National Institutes of Arthritis and Musculoskeletal and Skin Diseases. Dr. Cleveland had no conflicts of interest to report.
Source: Cleveland RJ et al. Osteoarthritis Cartilage. 2018 Apr:26(1):S10-1. Abstract 1
Post-traumatic osteoarthritis needs to be prevention focus
, Jackie Whittaker, PT, PhD, said at the World Congress of Osteoarthritis.
“We all know that the burden of this disease is enormous and it’s expanding at an alarming rate,” she said at the congress, sponsored by the Osteoarthritis Research Society International.
“The only way that we have at this moment to try to reduce the burden of this disease is to shift our approach to management upstream and focus on prevention,” said Dr. Whittaker, who is an associate professor and research director at the University of Alberta, Edmonton, Canada.
According to the World Health Organization, OA is expected to become the fourth leading cause of disability worldwide by 2020. Furthermore, there will be a projected rise in prevalence from 12% to 25% in North America by 2030.
Dr. Whittaker suggested that it was time to try to identify those at risk of developing OA, such as after a joint injury, and ran through some suggestions on how posttraumatic OA (PTOA) might be preventable.
Secondary prevention of posttraumatic osteoarthritis
The prevention of PTOA can be split into primary, secondary and tertiary prevention, with primary prevention trying to prevent injuries from occurring in the first place.
“Strategies aimed at identifying and slowing down the onset of symptomatic osteoarthritis in preclinical populations would be referred to as secondary prevention,” Dr. Whittaker explained, adding that tertiary prevention would then be strategies aimed at improving function and reducing disability in those who already have symptomatic PTOA.
While there are programs that address primary and tertiary prevention – such as Footy First, an exercise training program adopted by the Australian Football League to reduce the risk of common leg injuries and the Good Life with osteoArthritis in Denmark (GLA:D®) education and supervised exercise program for those with symptomatic OA – there is more of a gap for secondary prevention.
Some of the first steps to developing a secondary prevention model would be to determine the extent of PTOA after joint injury and then identify risk factors or causal mechanisms. Then, prevention strategies could be developed and tested before implementation and effectiveness studies are performed.
Performing the necessary prospective cohort studies, however, is when things get challenging – PTOA can take 10–15 years to manifest and studies would potentially need to run for long periods of time, which comes at a cost. Other challenges are that there is no commonly agree definition. PTOA is multifactorial, and because people may be in their 20s, there could be other contributing factors to the disease course.
Identifying modifiable risk factors
There are a “fair number” of prospective and retrospective studies that have been done to try to identify patients at risk for OA after joint injury. Several have looked at unmodifiable risk factors, such as age and sex, and the type of injury. Others have looked at potentially modifiable factors such as the treatment approach and avoiding re-injury, joint mechanics and strength, body composition and aerobic fitness and behavioral characteristics such as physical activity and return to sport.
Data from the Alberta Youth PrE-OA Study, an ongoing longitudinal cohort study, have shown that structural changes consistent with OA are not unique to tears in the anterior cruciate ligament or to meniscal tears, which are known to up the risk of PTOA. Furthermore, the odds of having MRI-defined OA 3–10 years after a knee injury varies by the injury history, type, and surgery.
Other findings from the Alberta Youth PrE-OA Study data have shown that previously injured subjects have a 30% risk for re-injury, with weaker knee extensors and flexors and poorer dynamic balance than uninjured study participants. The results have also shown that there is reduced physical activity and avoidance in those who have been injured.
Who is the population at risk?
“Although the supporting evidence and the level of evidence for some of the risk factors is not as thorough as we would like it, there are some common themes across the literature, that are consistent to what we see in clinical practice, and what we know from primary and tertiary prevention,” Dr. Whittaker said. “Based upon that, we can start to hypothesize who’s at greatest risk of developing posttraumatic osteoarthritis and what we might start doing about it right now.”
Dr. Whittaker proposed the following risk factors could be used to “build a profile” of someone at risk of PTOA:
- Having sustained an anterior cruciate ligament (ACL) tear with or without a damaged meniscus
- Elevated body mass index (BMI) or adiposity, and low grade systemic inflammation
- Weak knee muscles, and poor dynamic balance
- Reduced or disengaged from physical activity
- Insufficient rehabilitation, pain or stiffness, or fear of movement
There is also an argument for nutrition being involved, Dr. Whittaker said, with levels of micronutrients such as vitamins D and K and calcium playing an integral role in bone health.
What could secondary prevention look like?
“So, with this risk profile, what can be done?” Dr. Whittaker asked rhetorically. Exercise therapy is key, and increasing the muscle strength of the knee and lower extremity are an important component of this strategy. Strength alone may not be enough, so exercise programs will need to increase the neuromuscular control of functional movements. Tackling people’s fear of movement will also be a priority. “I think it’s very important that we promote, if not implement, physical activity guidelines.”
Education is also going to be an important part of any secondary prevention program for PTOA, ensuring that people have realistic expectations about re-injury and their risk of developing osteoarthritis and the importance of remaining physically active. Balancing physical activity against their likelihood of flare-ups and learning how to avoid re-injury if at all possible. Weight control and diet will also be a component to include.
One final component is how clinicians work with patients to minimize their risk of PTOA. “We need to co-manage these patients,” Dr. Whittaker said. “We need to have difficult conversations with them and really balance giving them a picture of reality without over medicalizing the situation.”
Dr. Whitaker stated that she had no financial relationships or commercial interests to disclose.
SOURCE: Whittaker J, et al. Osteoarthritis Cartilage 2018:26(1):S7-8. Abstract I-22.
, Jackie Whittaker, PT, PhD, said at the World Congress of Osteoarthritis.
“We all know that the burden of this disease is enormous and it’s expanding at an alarming rate,” she said at the congress, sponsored by the Osteoarthritis Research Society International.
“The only way that we have at this moment to try to reduce the burden of this disease is to shift our approach to management upstream and focus on prevention,” said Dr. Whittaker, who is an associate professor and research director at the University of Alberta, Edmonton, Canada.
According to the World Health Organization, OA is expected to become the fourth leading cause of disability worldwide by 2020. Furthermore, there will be a projected rise in prevalence from 12% to 25% in North America by 2030.
Dr. Whittaker suggested that it was time to try to identify those at risk of developing OA, such as after a joint injury, and ran through some suggestions on how posttraumatic OA (PTOA) might be preventable.
Secondary prevention of posttraumatic osteoarthritis
The prevention of PTOA can be split into primary, secondary and tertiary prevention, with primary prevention trying to prevent injuries from occurring in the first place.
“Strategies aimed at identifying and slowing down the onset of symptomatic osteoarthritis in preclinical populations would be referred to as secondary prevention,” Dr. Whittaker explained, adding that tertiary prevention would then be strategies aimed at improving function and reducing disability in those who already have symptomatic PTOA.
While there are programs that address primary and tertiary prevention – such as Footy First, an exercise training program adopted by the Australian Football League to reduce the risk of common leg injuries and the Good Life with osteoArthritis in Denmark (GLA:D®) education and supervised exercise program for those with symptomatic OA – there is more of a gap for secondary prevention.
Some of the first steps to developing a secondary prevention model would be to determine the extent of PTOA after joint injury and then identify risk factors or causal mechanisms. Then, prevention strategies could be developed and tested before implementation and effectiveness studies are performed.
Performing the necessary prospective cohort studies, however, is when things get challenging – PTOA can take 10–15 years to manifest and studies would potentially need to run for long periods of time, which comes at a cost. Other challenges are that there is no commonly agree definition. PTOA is multifactorial, and because people may be in their 20s, there could be other contributing factors to the disease course.
Identifying modifiable risk factors
There are a “fair number” of prospective and retrospective studies that have been done to try to identify patients at risk for OA after joint injury. Several have looked at unmodifiable risk factors, such as age and sex, and the type of injury. Others have looked at potentially modifiable factors such as the treatment approach and avoiding re-injury, joint mechanics and strength, body composition and aerobic fitness and behavioral characteristics such as physical activity and return to sport.
Data from the Alberta Youth PrE-OA Study, an ongoing longitudinal cohort study, have shown that structural changes consistent with OA are not unique to tears in the anterior cruciate ligament or to meniscal tears, which are known to up the risk of PTOA. Furthermore, the odds of having MRI-defined OA 3–10 years after a knee injury varies by the injury history, type, and surgery.
Other findings from the Alberta Youth PrE-OA Study data have shown that previously injured subjects have a 30% risk for re-injury, with weaker knee extensors and flexors and poorer dynamic balance than uninjured study participants. The results have also shown that there is reduced physical activity and avoidance in those who have been injured.
Who is the population at risk?
“Although the supporting evidence and the level of evidence for some of the risk factors is not as thorough as we would like it, there are some common themes across the literature, that are consistent to what we see in clinical practice, and what we know from primary and tertiary prevention,” Dr. Whittaker said. “Based upon that, we can start to hypothesize who’s at greatest risk of developing posttraumatic osteoarthritis and what we might start doing about it right now.”
Dr. Whittaker proposed the following risk factors could be used to “build a profile” of someone at risk of PTOA:
- Having sustained an anterior cruciate ligament (ACL) tear with or without a damaged meniscus
- Elevated body mass index (BMI) or adiposity, and low grade systemic inflammation
- Weak knee muscles, and poor dynamic balance
- Reduced or disengaged from physical activity
- Insufficient rehabilitation, pain or stiffness, or fear of movement
There is also an argument for nutrition being involved, Dr. Whittaker said, with levels of micronutrients such as vitamins D and K and calcium playing an integral role in bone health.
What could secondary prevention look like?
“So, with this risk profile, what can be done?” Dr. Whittaker asked rhetorically. Exercise therapy is key, and increasing the muscle strength of the knee and lower extremity are an important component of this strategy. Strength alone may not be enough, so exercise programs will need to increase the neuromuscular control of functional movements. Tackling people’s fear of movement will also be a priority. “I think it’s very important that we promote, if not implement, physical activity guidelines.”
Education is also going to be an important part of any secondary prevention program for PTOA, ensuring that people have realistic expectations about re-injury and their risk of developing osteoarthritis and the importance of remaining physically active. Balancing physical activity against their likelihood of flare-ups and learning how to avoid re-injury if at all possible. Weight control and diet will also be a component to include.
One final component is how clinicians work with patients to minimize their risk of PTOA. “We need to co-manage these patients,” Dr. Whittaker said. “We need to have difficult conversations with them and really balance giving them a picture of reality without over medicalizing the situation.”
Dr. Whitaker stated that she had no financial relationships or commercial interests to disclose.
SOURCE: Whittaker J, et al. Osteoarthritis Cartilage 2018:26(1):S7-8. Abstract I-22.
, Jackie Whittaker, PT, PhD, said at the World Congress of Osteoarthritis.
“We all know that the burden of this disease is enormous and it’s expanding at an alarming rate,” she said at the congress, sponsored by the Osteoarthritis Research Society International.
“The only way that we have at this moment to try to reduce the burden of this disease is to shift our approach to management upstream and focus on prevention,” said Dr. Whittaker, who is an associate professor and research director at the University of Alberta, Edmonton, Canada.
According to the World Health Organization, OA is expected to become the fourth leading cause of disability worldwide by 2020. Furthermore, there will be a projected rise in prevalence from 12% to 25% in North America by 2030.
Dr. Whittaker suggested that it was time to try to identify those at risk of developing OA, such as after a joint injury, and ran through some suggestions on how posttraumatic OA (PTOA) might be preventable.
Secondary prevention of posttraumatic osteoarthritis
The prevention of PTOA can be split into primary, secondary and tertiary prevention, with primary prevention trying to prevent injuries from occurring in the first place.
“Strategies aimed at identifying and slowing down the onset of symptomatic osteoarthritis in preclinical populations would be referred to as secondary prevention,” Dr. Whittaker explained, adding that tertiary prevention would then be strategies aimed at improving function and reducing disability in those who already have symptomatic PTOA.
While there are programs that address primary and tertiary prevention – such as Footy First, an exercise training program adopted by the Australian Football League to reduce the risk of common leg injuries and the Good Life with osteoArthritis in Denmark (GLA:D®) education and supervised exercise program for those with symptomatic OA – there is more of a gap for secondary prevention.
Some of the first steps to developing a secondary prevention model would be to determine the extent of PTOA after joint injury and then identify risk factors or causal mechanisms. Then, prevention strategies could be developed and tested before implementation and effectiveness studies are performed.
Performing the necessary prospective cohort studies, however, is when things get challenging – PTOA can take 10–15 years to manifest and studies would potentially need to run for long periods of time, which comes at a cost. Other challenges are that there is no commonly agree definition. PTOA is multifactorial, and because people may be in their 20s, there could be other contributing factors to the disease course.
Identifying modifiable risk factors
There are a “fair number” of prospective and retrospective studies that have been done to try to identify patients at risk for OA after joint injury. Several have looked at unmodifiable risk factors, such as age and sex, and the type of injury. Others have looked at potentially modifiable factors such as the treatment approach and avoiding re-injury, joint mechanics and strength, body composition and aerobic fitness and behavioral characteristics such as physical activity and return to sport.
Data from the Alberta Youth PrE-OA Study, an ongoing longitudinal cohort study, have shown that structural changes consistent with OA are not unique to tears in the anterior cruciate ligament or to meniscal tears, which are known to up the risk of PTOA. Furthermore, the odds of having MRI-defined OA 3–10 years after a knee injury varies by the injury history, type, and surgery.
Other findings from the Alberta Youth PrE-OA Study data have shown that previously injured subjects have a 30% risk for re-injury, with weaker knee extensors and flexors and poorer dynamic balance than uninjured study participants. The results have also shown that there is reduced physical activity and avoidance in those who have been injured.
Who is the population at risk?
“Although the supporting evidence and the level of evidence for some of the risk factors is not as thorough as we would like it, there are some common themes across the literature, that are consistent to what we see in clinical practice, and what we know from primary and tertiary prevention,” Dr. Whittaker said. “Based upon that, we can start to hypothesize who’s at greatest risk of developing posttraumatic osteoarthritis and what we might start doing about it right now.”
Dr. Whittaker proposed the following risk factors could be used to “build a profile” of someone at risk of PTOA:
- Having sustained an anterior cruciate ligament (ACL) tear with or without a damaged meniscus
- Elevated body mass index (BMI) or adiposity, and low grade systemic inflammation
- Weak knee muscles, and poor dynamic balance
- Reduced or disengaged from physical activity
- Insufficient rehabilitation, pain or stiffness, or fear of movement
There is also an argument for nutrition being involved, Dr. Whittaker said, with levels of micronutrients such as vitamins D and K and calcium playing an integral role in bone health.
What could secondary prevention look like?
“So, with this risk profile, what can be done?” Dr. Whittaker asked rhetorically. Exercise therapy is key, and increasing the muscle strength of the knee and lower extremity are an important component of this strategy. Strength alone may not be enough, so exercise programs will need to increase the neuromuscular control of functional movements. Tackling people’s fear of movement will also be a priority. “I think it’s very important that we promote, if not implement, physical activity guidelines.”
Education is also going to be an important part of any secondary prevention program for PTOA, ensuring that people have realistic expectations about re-injury and their risk of developing osteoarthritis and the importance of remaining physically active. Balancing physical activity against their likelihood of flare-ups and learning how to avoid re-injury if at all possible. Weight control and diet will also be a component to include.
One final component is how clinicians work with patients to minimize their risk of PTOA. “We need to co-manage these patients,” Dr. Whittaker said. “We need to have difficult conversations with them and really balance giving them a picture of reality without over medicalizing the situation.”
Dr. Whitaker stated that she had no financial relationships or commercial interests to disclose.
SOURCE: Whittaker J, et al. Osteoarthritis Cartilage 2018:26(1):S7-8. Abstract I-22.
REPORTING FROM OARSI 2018
Prior knee injury osteoarthritis ‘distinct subgroup’
LIVERPOOL, ENGLAND – according to data from the Good Life with osteoArthritis in Denmark (GLA:D®) Registry.
Clear differences in the clinical presentation can be observed between patients with knee OA who have and have not had a previous knee injury, researcher Paetur Mikal Holm reported at the World Congress on Osteoarthritis.
“These differences include being younger, being a male, having a lower BMI [body mass index], and being more physically active; also, we see reduced quality of life, longer symptom duration, and widespread pain” said Mr. Holm, a PhD fellow in the department of sports science and clinical biomechanics, musculoskeletal function, and physiotherapy at the University of Southern Denmark in Odense. “The last two characteristics in particular – widespread pain and symptom duration – may have an important impact on treatment,” he added. 
“People with a prior knee injury have a 25% higher probability of having widespread pain compared to people without a prior knee injury,” Mr. Holm and his associates said in their abstract. This could mean that specialized interventions are needed to address pain in these individuals, especially when there is a long duration of symptoms.
Disease characteristics and trajectories in knee osteoarthritis are highly variable, Mr. Holm observed, and there are multiple phenotypes already reported. Posttraumatic knee OA is one of these phenotypes, but, until now, their clinical characteristics were poorly understood.
A cross-sectional study was performed using baseline data on 5,477 individuals enrolled in the GLA:D® Registry, 91% of whom had radiographic knee OA. These patients were divided into two groups based on whether they did (n = 2,440) or did not (n = 3,037) self-report a prior knee injury. This is one of the limitations of the study, Mr. Holm acknowledged. There was no specific investigation of what the prior knee injury actually was.
However, results clearly showed a significant (P less than .05) difference between the two groups. For example, the mean age of those with a prior knee injury was 64 years, whereas those without were about 65 years old (odds ratio, 0.99; 95% confidence interval, 0.98-0.99). About 29% of those with a previous knee injury were men, versus roughly 25% of those without (OR, 1.28; 95% CI, 1.12-1.46). Widespread pain was present in about 45% and 38%, respectively, for those with and without a prior knee injury (OR, 1.25; 95% CI, 1.11-1.40), and the mean duration of symptoms was 60 versus 35 months (OR, 1.05; 95% CI, 1.04-1.06). Those who reported exercising 2-4 days a week had an OR of 1.30 (95% CI, 1.05-1.59).
“Being a clinician, to me it is a worry to see that these people are young and have had symptoms for a long time,” coauthor Ewa M. Roos, PT, PhD, said at the congress, which was sponsored by the Osteoarthritis Research Society International.
“Here is a group of people that we don’t necessarily think about as athletes, these are people with osteoarthritis. They are seen in primary care, but maybe we don’t think about them as osteoarthritis patients at a younger age, but this is a group that we need to be very careful to recognize,” added Dr. Roos, also of University of Southern Denmark. She cochaired the session where the findings were presented.
The GLA:D® Registry is funded by various sources including the Danish Rheumatism Association, Naestved-Slagelse-Ringsted Hospitals, Region Zealand, and the Danish Physiotherapy Association. Dr. Holm had no conflicts of interest.
SOURCE: Holm PM et al. Osteoarthr Cartil. 2018:26(1):S56.OARSI 2018 Abstract 84.
LIVERPOOL, ENGLAND – according to data from the Good Life with osteoArthritis in Denmark (GLA:D®) Registry.
Clear differences in the clinical presentation can be observed between patients with knee OA who have and have not had a previous knee injury, researcher Paetur Mikal Holm reported at the World Congress on Osteoarthritis.
“These differences include being younger, being a male, having a lower BMI [body mass index], and being more physically active; also, we see reduced quality of life, longer symptom duration, and widespread pain” said Mr. Holm, a PhD fellow in the department of sports science and clinical biomechanics, musculoskeletal function, and physiotherapy at the University of Southern Denmark in Odense. “The last two characteristics in particular – widespread pain and symptom duration – may have an important impact on treatment,” he added.
“People with a prior knee injury have a 25% higher probability of having widespread pain compared to people without a prior knee injury,” Mr. Holm and his associates said in their abstract. This could mean that specialized interventions are needed to address pain in these individuals, especially when there is a long duration of symptoms.
Disease characteristics and trajectories in knee osteoarthritis are highly variable, Mr. Holm observed, and there are multiple phenotypes already reported. Posttraumatic knee OA is one of these phenotypes, but, until now, their clinical characteristics were poorly understood.
A cross-sectional study was performed using baseline data on 5,477 individuals enrolled in the GLA:D® Registry, 91% of whom had radiographic knee OA. These patients were divided into two groups based on whether they did (n = 2,440) or did not (n = 3,037) self-report a prior knee injury. This is one of the limitations of the study, Mr. Holm acknowledged. There was no specific investigation of what the prior knee injury actually was.
However, results clearly showed a significant (P less than .05) difference between the two groups. For example, the mean age of those with a prior knee injury was 64 years, whereas those without were about 65 years old (odds ratio, 0.99; 95% confidence interval, 0.98-0.99). About 29% of those with a previous knee injury were men, versus roughly 25% of those without (OR, 1.28; 95% CI, 1.12-1.46). Widespread pain was present in about 45% and 38%, respectively, for those with and without a prior knee injury (OR, 1.25; 95% CI, 1.11-1.40), and the mean duration of symptoms was 60 versus 35 months (OR, 1.05; 95% CI, 1.04-1.06). Those who reported exercising 2-4 days a week had an OR of 1.30 (95% CI, 1.05-1.59).
“Being a clinician, to me it is a worry to see that these people are young and have had symptoms for a long time,” coauthor Ewa M. Roos, PT, PhD, said at the congress, which was sponsored by the Osteoarthritis Research Society International.
“Here is a group of people that we don’t necessarily think about as athletes, these are people with osteoarthritis. They are seen in primary care, but maybe we don’t think about them as osteoarthritis patients at a younger age, but this is a group that we need to be very careful to recognize,” added Dr. Roos, also of University of Southern Denmark. She cochaired the session where the findings were presented.
The GLA:D® Registry is funded by various sources including the Danish Rheumatism Association, Naestved-Slagelse-Ringsted Hospitals, Region Zealand, and the Danish Physiotherapy Association. Dr. Holm had no conflicts of interest.
SOURCE: Holm PM et al. Osteoarthr Cartil. 2018:26(1):S56.OARSI 2018 Abstract 84.
LIVERPOOL, ENGLAND – according to data from the Good Life with osteoArthritis in Denmark (GLA:D®) Registry.
Clear differences in the clinical presentation can be observed between patients with knee OA who have and have not had a previous knee injury, researcher Paetur Mikal Holm reported at the World Congress on Osteoarthritis.
“These differences include being younger, being a male, having a lower BMI [body mass index], and being more physically active; also, we see reduced quality of life, longer symptom duration, and widespread pain” said Mr. Holm, a PhD fellow in the department of sports science and clinical biomechanics, musculoskeletal function, and physiotherapy at the University of Southern Denmark in Odense. “The last two characteristics in particular – widespread pain and symptom duration – may have an important impact on treatment,” he added.
“People with a prior knee injury have a 25% higher probability of having widespread pain compared to people without a prior knee injury,” Mr. Holm and his associates said in their abstract. This could mean that specialized interventions are needed to address pain in these individuals, especially when there is a long duration of symptoms.
Disease characteristics and trajectories in knee osteoarthritis are highly variable, Mr. Holm observed, and there are multiple phenotypes already reported. Posttraumatic knee OA is one of these phenotypes, but, until now, their clinical characteristics were poorly understood.
A cross-sectional study was performed using baseline data on 5,477 individuals enrolled in the GLA:D® Registry, 91% of whom had radiographic knee OA. These patients were divided into two groups based on whether they did (n = 2,440) or did not (n = 3,037) self-report a prior knee injury. This is one of the limitations of the study, Mr. Holm acknowledged. There was no specific investigation of what the prior knee injury actually was.
However, results clearly showed a significant (P less than .05) difference between the two groups. For example, the mean age of those with a prior knee injury was 64 years, whereas those without were about 65 years old (odds ratio, 0.99; 95% confidence interval, 0.98-0.99). About 29% of those with a previous knee injury were men, versus roughly 25% of those without (OR, 1.28; 95% CI, 1.12-1.46). Widespread pain was present in about 45% and 38%, respectively, for those with and without a prior knee injury (OR, 1.25; 95% CI, 1.11-1.40), and the mean duration of symptoms was 60 versus 35 months (OR, 1.05; 95% CI, 1.04-1.06). Those who reported exercising 2-4 days a week had an OR of 1.30 (95% CI, 1.05-1.59).
“Being a clinician, to me it is a worry to see that these people are young and have had symptoms for a long time,” coauthor Ewa M. Roos, PT, PhD, said at the congress, which was sponsored by the Osteoarthritis Research Society International.
“Here is a group of people that we don’t necessarily think about as athletes, these are people with osteoarthritis. They are seen in primary care, but maybe we don’t think about them as osteoarthritis patients at a younger age, but this is a group that we need to be very careful to recognize,” added Dr. Roos, also of University of Southern Denmark. She cochaired the session where the findings were presented.
The GLA:D® Registry is funded by various sources including the Danish Rheumatism Association, Naestved-Slagelse-Ringsted Hospitals, Region Zealand, and the Danish Physiotherapy Association. Dr. Holm had no conflicts of interest.
SOURCE: Holm PM et al. Osteoarthr Cartil. 2018:26(1):S56.OARSI 2018 Abstract 84.
REPORTING FROM OARSI 2018
Key clinical point: People with posttraumatic knee osteoarthritis are a distinct subgroup of patients that might be underrecognized.
Major finding: Widespread pain was present in about 45% and 38%, respectively, of those with and without a prior knee injury (OR, 1.25, 95% CI, 1.11-1.40).
Study details: Cross-sectional study of 5,477 patients enrolled in the Good Life with osteoArthritis in Denmark (GLA:D®) Registry.
Disclosures: The GLA:D® Registry is funded by various sources including the Danish Rheumatism Association, Naestved-Slagelse-Ringsted Hospitals, Region Zealand, and the Danish Physiotherapy Association. The presenting author, Dr. Paetur Mikal Holm, had no conflicts of interest.
Source: Holm PM et al. Osteoarthr Cartil. 2018:26(1):S56. Abstract 84.
Disease burden higher in osteoarthritis than rheumatoid arthritis
LIVERPOOL, ENGLAND – Osteoarthritis is associated with a “considerably higher disease burden” than rheumatoid arthritis 6 months after initial presentation, according to one expert’s analysis at the World Congress on Osteoarthritis.
This may partly be because of the improved treatments now available for rheumatoid arthritis, whereas there remain few treatments, and no disease-modifying therapy as yet, for osteoarthritis, Theodore Pincus, MD, suggested at the congress sponsored by the Osteoarthritis Research Society International.
“The ‘conventional’ wisdom is that ‘osteoarthritis is the most common type of arthritis,’ and ‘rheumatoid arthritis is recognized as the most crippling or disabling type of arthritis,’ ” he said, citing text from a health website and a report of the World Health Organization.
“We all know there is a lot of information on the Internet that may not be as accurate as we would like,” he observed. “We characterize this as ‘eminence-based medicine,’ ” Dr. Pincus joked, “which is defined as making the same mistakes with increasing confidence over an impressive number of years!” The alternative is, of course, evidence-based medicine, which is “the best approach,” requiring data from both clinical observations and clinical trials.
Even seemingly credible sources of health information can relay incorrect, or out-of-date, messages, such as RA being associated with worse functional status than OA. Recent observational data (RMD Open. 2017;3[1]:e000391), suggest that actually the reverse may be true, and that the disease burden seen with OA in routine care is as great as, if not greater than, RA.
Indeed, patients with OA who completed the Multi-Dimensional Health Assessment Questionnaire (MDHAQ)/Routine Assessment of Patient Index Data (RAPID3) at diagnosis at four different sites were found to have similar or worse scores for physical function, pain, and patient global assessment when compared with RA.
The MDHAQ/RAPID3 is a simple assessment tool that consists of two pages and asks patients to rate items such as their physical function in activities of daily living and levels of pain in the past week. It also asks about levels of anxiety, depression, and quality of sleep, and it includes a self-reported joint count and a patient global assessment. Scores on RAPID3 range from 0 to 30, and comprise three 0-10 scores for physical function, pain, and patient global assessment subscales in which higher scores indicate greater disease burden.
“Using this tool, we’ve been able to obtain data on patients with OA and RA for at least 30 years,” Dr. Pincus said.
One of the issues with comparing the burden of the two diseases, he noted, is that there are few places that have used the same assessment tool.
Dr. Pincus and his associates at Rush University have also shown that the disease burden in OA remains high 6 months after first visit, while greater improvement is seen in RA over this period (Osteoarthritis Cartilage. 2018;26[1]:S260. Abstract 491).
In a study of 151 patients with OA and 202 with RA, they found the composite RAPID3 scores were equally high in patients with OA and RA at their first visit (16.0 vs. 15.5, respectively) but higher in OA patients at the 6-month reassessment (14.3 vs. 11.9; P less than .004).
“We can now say that at presentation, OA and RA are similar in MDHAQ/RAPID3 scores, which were adjusted for age and BMI,” Dr. Pincus said. “Both the OA and RA patients improved, but considerably greater improvement in RA versus OA resulted in significantly poorer status for OA versus RA at 6 months.”
However, that’s not to say that OA is a worse disease than RA in every patient, Dr. Pincus was keen to point out. “Some patients with each disease have mild, moderate, or severe disease,” he stated. RA is used as benchmark for a severe disease, so these data highlight that “OA is a severe disease as well.”
This sentiment was the focus of a 2016 white paper produced by OARSI and submitted to the Food and Drug Administration, which states the case for the need to take OA more seriously and for regulatory restrictions to be removed to enable new treatments to be developed.
The prevalence of OA is at least 10-20 times higher than RA, and it’s likely that a large percentage of OA patients never get to see a rheumatologist, Dr. Pincus said. Yet the resources that go into managing RA are far greater if one excludes joint replacement.
Dr. Pincus noted that RA was not always regarded as a severe disease: 30 years ago the textbooks were stating that it had a good prognosis in the majority of cases and that patients could, by and large, use conservative regimens to manage their disease. However, real-world evidence showed that RA was associated with severe declines in function, high levels of work disability, and increased mortality, Dr. Pincus observed.
“Is osteoarthritis in 2018 where rheumatoid arthritis was in 1988, 30 years ago?” he asked rhetorically.
“The risk of long-term mortality in RA, OA, and most rheumatic disease is similar to, or greater than, hypertension, diabetes, as well as many cardiovascular and neoplastic diseases,” Dr. Pincus continued. Whereas mechanisms exist to try to log all cancer cases and compile data on the number of deaths, a rheumatic disease often is not listed anywhere on the death certificate, even as contributing to mortality, as rheumatic diseases generally are not the acute cause of death.
Functional disability and socioeconomic status are more important predictors of work disability and mortality than “any biomarker or imaging data, except x-ray.” Perhaps, Dr. Pincus said, these could also be important indicators of poor prognosis in OA and all chronic diseases?
“Physical function is a big deal,” he said. Data from a study looking at adults over the age of 50 years in the general Finnish population showed 5-year survival was significantly reduced by poorer functional capacity and less frequent physical exercise, at levels higher than smoking. Perhaps, the musculoskeletal system is more important than the other organs of the body for maintaining health, Dr. Pincus suggested.
Assessing functional status with tools such as the MDHAQ/RAPID3 is “really useful” in daily practice, Dr. Pincus said. He concluded with the words of Rudolph Virchow, who observed more than 100 years ago, that “the improvement of medicine would eventually prolong human life, but improvement of social conditions could achieve this result now and more rapidly and successfully.”
Dr. Pincus is the president of Medical History Services, which receives royalties and license fees from copyright and trademark of MDHAQ, RAPID3, or both, all of which are used to support further development of quantitative clinical measurement by both patients and physicians. He holds stock in the company and has received research funding from the company. Dr. Pincus also disclosed having a consulting agreement with Lilly.
SOURCE: Pincus T et al. Osteoarthritis Cartilage. 2018:26(1):S4. Abstract I-11.
*This story was updated 5/24/2018.
LIVERPOOL, ENGLAND – Osteoarthritis is associated with a “considerably higher disease burden” than rheumatoid arthritis 6 months after initial presentation, according to one expert’s analysis at the World Congress on Osteoarthritis.
This may partly be because of the improved treatments now available for rheumatoid arthritis, whereas there remain few treatments, and no disease-modifying therapy as yet, for osteoarthritis, Theodore Pincus, MD, suggested at the congress sponsored by the Osteoarthritis Research Society International.
“The ‘conventional’ wisdom is that ‘osteoarthritis is the most common type of arthritis,’ and ‘rheumatoid arthritis is recognized as the most crippling or disabling type of arthritis,’ ” he said, citing text from a health website and a report of the World Health Organization.
“We all know there is a lot of information on the Internet that may not be as accurate as we would like,” he observed. “We characterize this as ‘eminence-based medicine,’ ” Dr. Pincus joked, “which is defined as making the same mistakes with increasing confidence over an impressive number of years!” The alternative is, of course, evidence-based medicine, which is “the best approach,” requiring data from both clinical observations and clinical trials.
Even seemingly credible sources of health information can relay incorrect, or out-of-date, messages, such as RA being associated with worse functional status than OA. Recent observational data (RMD Open. 2017;3[1]:e000391), suggest that actually the reverse may be true, and that the disease burden seen with OA in routine care is as great as, if not greater than, RA.
Indeed, patients with OA who completed the Multi-Dimensional Health Assessment Questionnaire (MDHAQ)/Routine Assessment of Patient Index Data (RAPID3) at diagnosis at four different sites were found to have similar or worse scores for physical function, pain, and patient global assessment when compared with RA.
The MDHAQ/RAPID3 is a simple assessment tool that consists of two pages and asks patients to rate items such as their physical function in activities of daily living and levels of pain in the past week. It also asks about levels of anxiety, depression, and quality of sleep, and it includes a self-reported joint count and a patient global assessment. Scores on RAPID3 range from 0 to 30, and comprise three 0-10 scores for physical function, pain, and patient global assessment subscales in which higher scores indicate greater disease burden.
“Using this tool, we’ve been able to obtain data on patients with OA and RA for at least 30 years,” Dr. Pincus said.
One of the issues with comparing the burden of the two diseases, he noted, is that there are few places that have used the same assessment tool.
Dr. Pincus and his associates at Rush University have also shown that the disease burden in OA remains high 6 months after first visit, while greater improvement is seen in RA over this period (Osteoarthritis Cartilage. 2018;26[1]:S260. Abstract 491).
In a study of 151 patients with OA and 202 with RA, they found the composite RAPID3 scores were equally high in patients with OA and RA at their first visit (16.0 vs. 15.5, respectively) but higher in OA patients at the 6-month reassessment (14.3 vs. 11.9; P less than .004).
“We can now say that at presentation, OA and RA are similar in MDHAQ/RAPID3 scores, which were adjusted for age and BMI,” Dr. Pincus said. “Both the OA and RA patients improved, but considerably greater improvement in RA versus OA resulted in significantly poorer status for OA versus RA at 6 months.”
However, that’s not to say that OA is a worse disease than RA in every patient, Dr. Pincus was keen to point out. “Some patients with each disease have mild, moderate, or severe disease,” he stated. RA is used as benchmark for a severe disease, so these data highlight that “OA is a severe disease as well.”
This sentiment was the focus of a 2016 white paper produced by OARSI and submitted to the Food and Drug Administration, which states the case for the need to take OA more seriously and for regulatory restrictions to be removed to enable new treatments to be developed.
The prevalence of OA is at least 10-20 times higher than RA, and it’s likely that a large percentage of OA patients never get to see a rheumatologist, Dr. Pincus said. Yet the resources that go into managing RA are far greater if one excludes joint replacement.
Dr. Pincus noted that RA was not always regarded as a severe disease: 30 years ago the textbooks were stating that it had a good prognosis in the majority of cases and that patients could, by and large, use conservative regimens to manage their disease. However, real-world evidence showed that RA was associated with severe declines in function, high levels of work disability, and increased mortality, Dr. Pincus observed.
“Is osteoarthritis in 2018 where rheumatoid arthritis was in 1988, 30 years ago?” he asked rhetorically.
“The risk of long-term mortality in RA, OA, and most rheumatic disease is similar to, or greater than, hypertension, diabetes, as well as many cardiovascular and neoplastic diseases,” Dr. Pincus continued. Whereas mechanisms exist to try to log all cancer cases and compile data on the number of deaths, a rheumatic disease often is not listed anywhere on the death certificate, even as contributing to mortality, as rheumatic diseases generally are not the acute cause of death.
Functional disability and socioeconomic status are more important predictors of work disability and mortality than “any biomarker or imaging data, except x-ray.” Perhaps, Dr. Pincus said, these could also be important indicators of poor prognosis in OA and all chronic diseases?
“Physical function is a big deal,” he said. Data from a study looking at adults over the age of 50 years in the general Finnish population showed 5-year survival was significantly reduced by poorer functional capacity and less frequent physical exercise, at levels higher than smoking. Perhaps, the musculoskeletal system is more important than the other organs of the body for maintaining health, Dr. Pincus suggested.
Assessing functional status with tools such as the MDHAQ/RAPID3 is “really useful” in daily practice, Dr. Pincus said. He concluded with the words of Rudolph Virchow, who observed more than 100 years ago, that “the improvement of medicine would eventually prolong human life, but improvement of social conditions could achieve this result now and more rapidly and successfully.”
Dr. Pincus is the president of Medical History Services, which receives royalties and license fees from copyright and trademark of MDHAQ, RAPID3, or both, all of which are used to support further development of quantitative clinical measurement by both patients and physicians. He holds stock in the company and has received research funding from the company. Dr. Pincus also disclosed having a consulting agreement with Lilly.
SOURCE: Pincus T et al. Osteoarthritis Cartilage. 2018:26(1):S4. Abstract I-11.
*This story was updated 5/24/2018.
LIVERPOOL, ENGLAND – Osteoarthritis is associated with a “considerably higher disease burden” than rheumatoid arthritis 6 months after initial presentation, according to one expert’s analysis at the World Congress on Osteoarthritis.
This may partly be because of the improved treatments now available for rheumatoid arthritis, whereas there remain few treatments, and no disease-modifying therapy as yet, for osteoarthritis, Theodore Pincus, MD, suggested at the congress sponsored by the Osteoarthritis Research Society International.
“The ‘conventional’ wisdom is that ‘osteoarthritis is the most common type of arthritis,’ and ‘rheumatoid arthritis is recognized as the most crippling or disabling type of arthritis,’ ” he said, citing text from a health website and a report of the World Health Organization.
“We all know there is a lot of information on the Internet that may not be as accurate as we would like,” he observed. “We characterize this as ‘eminence-based medicine,’ ” Dr. Pincus joked, “which is defined as making the same mistakes with increasing confidence over an impressive number of years!” The alternative is, of course, evidence-based medicine, which is “the best approach,” requiring data from both clinical observations and clinical trials.
Even seemingly credible sources of health information can relay incorrect, or out-of-date, messages, such as RA being associated with worse functional status than OA. Recent observational data (RMD Open. 2017;3[1]:e000391), suggest that actually the reverse may be true, and that the disease burden seen with OA in routine care is as great as, if not greater than, RA.
Indeed, patients with OA who completed the Multi-Dimensional Health Assessment Questionnaire (MDHAQ)/Routine Assessment of Patient Index Data (RAPID3) at diagnosis at four different sites were found to have similar or worse scores for physical function, pain, and patient global assessment when compared with RA.
The MDHAQ/RAPID3 is a simple assessment tool that consists of two pages and asks patients to rate items such as their physical function in activities of daily living and levels of pain in the past week. It also asks about levels of anxiety, depression, and quality of sleep, and it includes a self-reported joint count and a patient global assessment. Scores on RAPID3 range from 0 to 30, and comprise three 0-10 scores for physical function, pain, and patient global assessment subscales in which higher scores indicate greater disease burden.
“Using this tool, we’ve been able to obtain data on patients with OA and RA for at least 30 years,” Dr. Pincus said.
One of the issues with comparing the burden of the two diseases, he noted, is that there are few places that have used the same assessment tool.
Dr. Pincus and his associates at Rush University have also shown that the disease burden in OA remains high 6 months after first visit, while greater improvement is seen in RA over this period (Osteoarthritis Cartilage. 2018;26[1]:S260. Abstract 491).
In a study of 151 patients with OA and 202 with RA, they found the composite RAPID3 scores were equally high in patients with OA and RA at their first visit (16.0 vs. 15.5, respectively) but higher in OA patients at the 6-month reassessment (14.3 vs. 11.9; P less than .004).
“We can now say that at presentation, OA and RA are similar in MDHAQ/RAPID3 scores, which were adjusted for age and BMI,” Dr. Pincus said. “Both the OA and RA patients improved, but considerably greater improvement in RA versus OA resulted in significantly poorer status for OA versus RA at 6 months.”
However, that’s not to say that OA is a worse disease than RA in every patient, Dr. Pincus was keen to point out. “Some patients with each disease have mild, moderate, or severe disease,” he stated. RA is used as benchmark for a severe disease, so these data highlight that “OA is a severe disease as well.”
This sentiment was the focus of a 2016 white paper produced by OARSI and submitted to the Food and Drug Administration, which states the case for the need to take OA more seriously and for regulatory restrictions to be removed to enable new treatments to be developed.
The prevalence of OA is at least 10-20 times higher than RA, and it’s likely that a large percentage of OA patients never get to see a rheumatologist, Dr. Pincus said. Yet the resources that go into managing RA are far greater if one excludes joint replacement.
Dr. Pincus noted that RA was not always regarded as a severe disease: 30 years ago the textbooks were stating that it had a good prognosis in the majority of cases and that patients could, by and large, use conservative regimens to manage their disease. However, real-world evidence showed that RA was associated with severe declines in function, high levels of work disability, and increased mortality, Dr. Pincus observed.
“Is osteoarthritis in 2018 where rheumatoid arthritis was in 1988, 30 years ago?” he asked rhetorically.
“The risk of long-term mortality in RA, OA, and most rheumatic disease is similar to, or greater than, hypertension, diabetes, as well as many cardiovascular and neoplastic diseases,” Dr. Pincus continued. Whereas mechanisms exist to try to log all cancer cases and compile data on the number of deaths, a rheumatic disease often is not listed anywhere on the death certificate, even as contributing to mortality, as rheumatic diseases generally are not the acute cause of death.
Functional disability and socioeconomic status are more important predictors of work disability and mortality than “any biomarker or imaging data, except x-ray.” Perhaps, Dr. Pincus said, these could also be important indicators of poor prognosis in OA and all chronic diseases?
“Physical function is a big deal,” he said. Data from a study looking at adults over the age of 50 years in the general Finnish population showed 5-year survival was significantly reduced by poorer functional capacity and less frequent physical exercise, at levels higher than smoking. Perhaps, the musculoskeletal system is more important than the other organs of the body for maintaining health, Dr. Pincus suggested.
Assessing functional status with tools such as the MDHAQ/RAPID3 is “really useful” in daily practice, Dr. Pincus said. He concluded with the words of Rudolph Virchow, who observed more than 100 years ago, that “the improvement of medicine would eventually prolong human life, but improvement of social conditions could achieve this result now and more rapidly and successfully.”
Dr. Pincus is the president of Medical History Services, which receives royalties and license fees from copyright and trademark of MDHAQ, RAPID3, or both, all of which are used to support further development of quantitative clinical measurement by both patients and physicians. He holds stock in the company and has received research funding from the company. Dr. Pincus also disclosed having a consulting agreement with Lilly.
SOURCE: Pincus T et al. Osteoarthritis Cartilage. 2018:26(1):S4. Abstract I-11.
*This story was updated 5/24/2018.
REPORTING FROM OARSI 2018
New device could noninvasively detect osteoarthritis using sound and motion
LIVERPOOL, ENGLAND – The measurement of acoustic emissions and kinetic instability of the knee could become a promising noninvasive way to detect osteoarthritis (OA), according to a recent study.
Researchers at the University of Oulu (Finland) have developed a prototype device that allows multimodal assessment of the sound and motion of the knee.
“The OA diagnostic chain has many problems, some modalities are very expensive, and some have a low sensitivity as well,” said study investigator Aleksei Tiulpin, MSc, at the World Congress on Osteoarthritis, referring to magnetic resonance imaging, x-ray imaging, and symptomatic assessment, respectively.
The investigational device that the research team has developed is worn like a brace around the knee and has microphones embedded within it to capture sound coming from the right and left sides of the knee. The device also uses two accelerometers, one placed on the thigh and one on the lower limb to measure movement simultaneously.
“We developed all the software and all the hardware ourselves for this project,” Mr. Tiulpin noted at the congress, sponsored by the Osteoarthritis Research Society International. “The acoustic and kinematic information was measured simultaneously.”
To see whether the prototype device was able to aid the diagnosis of OA, Mr. Tiulpin and his associates recruited 66 women aged 44-67 years old, roughly half of whom (51.5%) had radiographically confirmed knee OA of Kellgren-Lawrence grade 2 or higher.
The participants were asked to perform three exercise tests while wearing the device. First, they had to stand from a sitting position 10 times. Second, they were asked to extend the leg from the knee while sitting down (flexion-extension) 10 times. Third, and finally, they were asked to perform a one leg stand on the right leg twice.
For the acoustic data analysis, data from the standing phase of the sit-to-stand test and the extension phase of the flexion-extension tests were used. Mr. Tuilpin explained that the acoustic signals underwent processing to segment and filter them into candidate locations. The average sound patterns seen in the candidate locations were then analyzed, then a consistency analysis was undertaken. With this approach, inconsistent patterns of knee crepitation could be captured, Mr. Tiulpin explained.
Kinematic signals received from the movement sensors were used to determine the degree of knee instability. Higher signal magnitudes could potentially indicate stability problems, which can be quantified using signal power, Mr. Tiulpin’s slides stated.
A variety of statistical calculations were made to see how well the device might predict OA changes, and a model combining body mass index and age had an area under the curve of 84%, which suggested that it might be possible to improve OA detection with the addition of the device versus BMI and age alone.
“Our results indicated highly promising applications of the method,” Mr. Tiulpin suggested.
These findings are “very interesting,” commented one of the moderators of the session, Erwin van Spil, MD, of University Medical Center Utrecht (The Netherlands) as he opened up the floor to questions.
“I’ve had this question for years … what causes the clicks?” one delegate asked Mr. Tiulpin during discussion. He responded that it could be down to many things, one of which is cartilage components grinding against each other.
Dr. Spil, who was not involved in the study, commented in an interview that using acoustics in the detection of knee OA was still quite a novel concept. “It’s noninvasive, which is quite unique in our general approach, and it might enable an early diagnosis of OA, which is what we are aiming for.”
Although the study did have control subjects, it’s not clear at this point whether very early OA was being assessed, Dr. Spil suggested. “We did not have the opportunity to ask about the OA characteristics. I think they had radiographic OA, but we don’t know the grade and we were not informed about the clinical situation, so we don’t know if anyone had pain, for example.”
Mr. Tiulpin did not have any conflicts of interest to disclose.
SOURCE: Tiulpin A et al. Osteoarthritis Cartilage 2018;26(1):S40–S41.
LIVERPOOL, ENGLAND – The measurement of acoustic emissions and kinetic instability of the knee could become a promising noninvasive way to detect osteoarthritis (OA), according to a recent study.
Researchers at the University of Oulu (Finland) have developed a prototype device that allows multimodal assessment of the sound and motion of the knee.
“The OA diagnostic chain has many problems, some modalities are very expensive, and some have a low sensitivity as well,” said study investigator Aleksei Tiulpin, MSc, at the World Congress on Osteoarthritis, referring to magnetic resonance imaging, x-ray imaging, and symptomatic assessment, respectively.
The investigational device that the research team has developed is worn like a brace around the knee and has microphones embedded within it to capture sound coming from the right and left sides of the knee. The device also uses two accelerometers, one placed on the thigh and one on the lower limb to measure movement simultaneously.
“We developed all the software and all the hardware ourselves for this project,” Mr. Tiulpin noted at the congress, sponsored by the Osteoarthritis Research Society International. “The acoustic and kinematic information was measured simultaneously.”
To see whether the prototype device was able to aid the diagnosis of OA, Mr. Tiulpin and his associates recruited 66 women aged 44-67 years old, roughly half of whom (51.5%) had radiographically confirmed knee OA of Kellgren-Lawrence grade 2 or higher.
The participants were asked to perform three exercise tests while wearing the device. First, they had to stand from a sitting position 10 times. Second, they were asked to extend the leg from the knee while sitting down (flexion-extension) 10 times. Third, and finally, they were asked to perform a one leg stand on the right leg twice.
For the acoustic data analysis, data from the standing phase of the sit-to-stand test and the extension phase of the flexion-extension tests were used. Mr. Tuilpin explained that the acoustic signals underwent processing to segment and filter them into candidate locations. The average sound patterns seen in the candidate locations were then analyzed, then a consistency analysis was undertaken. With this approach, inconsistent patterns of knee crepitation could be captured, Mr. Tiulpin explained.
Kinematic signals received from the movement sensors were used to determine the degree of knee instability. Higher signal magnitudes could potentially indicate stability problems, which can be quantified using signal power, Mr. Tiulpin’s slides stated.
A variety of statistical calculations were made to see how well the device might predict OA changes, and a model combining body mass index and age had an area under the curve of 84%, which suggested that it might be possible to improve OA detection with the addition of the device versus BMI and age alone.
“Our results indicated highly promising applications of the method,” Mr. Tiulpin suggested.
These findings are “very interesting,” commented one of the moderators of the session, Erwin van Spil, MD, of University Medical Center Utrecht (The Netherlands) as he opened up the floor to questions.
“I’ve had this question for years … what causes the clicks?” one delegate asked Mr. Tiulpin during discussion. He responded that it could be down to many things, one of which is cartilage components grinding against each other.
Dr. Spil, who was not involved in the study, commented in an interview that using acoustics in the detection of knee OA was still quite a novel concept. “It’s noninvasive, which is quite unique in our general approach, and it might enable an early diagnosis of OA, which is what we are aiming for.”
Although the study did have control subjects, it’s not clear at this point whether very early OA was being assessed, Dr. Spil suggested. “We did not have the opportunity to ask about the OA characteristics. I think they had radiographic OA, but we don’t know the grade and we were not informed about the clinical situation, so we don’t know if anyone had pain, for example.”
Mr. Tiulpin did not have any conflicts of interest to disclose.
SOURCE: Tiulpin A et al. Osteoarthritis Cartilage 2018;26(1):S40–S41.
LIVERPOOL, ENGLAND – The measurement of acoustic emissions and kinetic instability of the knee could become a promising noninvasive way to detect osteoarthritis (OA), according to a recent study.
Researchers at the University of Oulu (Finland) have developed a prototype device that allows multimodal assessment of the sound and motion of the knee.
“The OA diagnostic chain has many problems, some modalities are very expensive, and some have a low sensitivity as well,” said study investigator Aleksei Tiulpin, MSc, at the World Congress on Osteoarthritis, referring to magnetic resonance imaging, x-ray imaging, and symptomatic assessment, respectively.
The investigational device that the research team has developed is worn like a brace around the knee and has microphones embedded within it to capture sound coming from the right and left sides of the knee. The device also uses two accelerometers, one placed on the thigh and one on the lower limb to measure movement simultaneously.
“We developed all the software and all the hardware ourselves for this project,” Mr. Tiulpin noted at the congress, sponsored by the Osteoarthritis Research Society International. “The acoustic and kinematic information was measured simultaneously.”
To see whether the prototype device was able to aid the diagnosis of OA, Mr. Tiulpin and his associates recruited 66 women aged 44-67 years old, roughly half of whom (51.5%) had radiographically confirmed knee OA of Kellgren-Lawrence grade 2 or higher.
The participants were asked to perform three exercise tests while wearing the device. First, they had to stand from a sitting position 10 times. Second, they were asked to extend the leg from the knee while sitting down (flexion-extension) 10 times. Third, and finally, they were asked to perform a one leg stand on the right leg twice.
For the acoustic data analysis, data from the standing phase of the sit-to-stand test and the extension phase of the flexion-extension tests were used. Mr. Tuilpin explained that the acoustic signals underwent processing to segment and filter them into candidate locations. The average sound patterns seen in the candidate locations were then analyzed, then a consistency analysis was undertaken. With this approach, inconsistent patterns of knee crepitation could be captured, Mr. Tiulpin explained.
Kinematic signals received from the movement sensors were used to determine the degree of knee instability. Higher signal magnitudes could potentially indicate stability problems, which can be quantified using signal power, Mr. Tiulpin’s slides stated.
A variety of statistical calculations were made to see how well the device might predict OA changes, and a model combining body mass index and age had an area under the curve of 84%, which suggested that it might be possible to improve OA detection with the addition of the device versus BMI and age alone.
“Our results indicated highly promising applications of the method,” Mr. Tiulpin suggested.
These findings are “very interesting,” commented one of the moderators of the session, Erwin van Spil, MD, of University Medical Center Utrecht (The Netherlands) as he opened up the floor to questions.
“I’ve had this question for years … what causes the clicks?” one delegate asked Mr. Tiulpin during discussion. He responded that it could be down to many things, one of which is cartilage components grinding against each other.
Dr. Spil, who was not involved in the study, commented in an interview that using acoustics in the detection of knee OA was still quite a novel concept. “It’s noninvasive, which is quite unique in our general approach, and it might enable an early diagnosis of OA, which is what we are aiming for.”
Although the study did have control subjects, it’s not clear at this point whether very early OA was being assessed, Dr. Spil suggested. “We did not have the opportunity to ask about the OA characteristics. I think they had radiographic OA, but we don’t know the grade and we were not informed about the clinical situation, so we don’t know if anyone had pain, for example.”
Mr. Tiulpin did not have any conflicts of interest to disclose.
SOURCE: Tiulpin A et al. Osteoarthritis Cartilage 2018;26(1):S40–S41.
REPORTING FROM OARSI 2018
Key clinical point: A prototype device showed a promising application as a noninvasive method to detect osteoarthritis.
Major finding: In a model that combined it with BMI and age, the device had an area under the curve of 84%, which suggested that this device might be able to improve OA detection.
Study details: Single-center study of 66 women aged 44-67 years old; 51.5% had radiographically confirmed OA of Kellgren-Lawrence grade 2 or higher.
Disclosures: Mr. Tiulpin did not have any conflicts of interest to disclose.
Source: Tiulpin A et al. Osteoarthritis Cartilage. 2018;26(1):S40–S41.
Cannabidiol gel for osteoarthritis knee pain gives lukewarm results
LIVERPOOL, ENGLAND – There was no significant reduction in pain from knee osteoarthritis (OA) with the use of investigational cannabidiol (CBD) gel ZYN002 in a phase 2a trial presented at the World Congress on Osteoarthritis.
The mean reductions in baseline knee pain scores from study entry to a 12-week assessment were –2.4 for placebo and –2.6 (P = .5) and –2.8 (P = .25), respectively, for a 250-mg and a 500-mg formulation of the gel.
While there was a trend for benefit, it was “neither statistically or clinically significant,” reported David Hunter, MBBS, PhD.
However, he observed that a significantly (P = .016) greater number of patients who received the 250-mg dose (52.7%) were “composite responders,” compared with patients who received placebo (34.1%). A composite response was defined as at least a 30% reduction in pain, and a 20% decrease in WOMAC physical function subscale score at the last observation.
Although the percentage of composite responders was also higher than placebo with the 500-mg dose, the difference wasn’t significant (45.1% vs. 34.1%; P = .0169).
Post-hoc analyses also suggested that perhaps some patients may benefit more than others, reported Dr. Hunter, professor of medicine at the University of Sydney and the Royal North Shore Hospital, Sydney.
For example, patients with baseline pain scores or 7 or more had greater mean reduction in pain at 12 weeks with both doses of the gel combined than placebo at week 4 (–2.2 vs. –1.6; P = .029), although the difference was not significant at week 8 (–3.0 vs. –2.2; P = .05) or 12 (–3.3 vs. –2.5; P = .086).
Women also exhibited a greater placebo response than did men, and “patients with less variability in baseline pain scores may have had greater separation between placebo and the treatment,” Dr. Hunter said. Indeed, 50%-52% of patients with less than 33% variation in baseline scores had a composite response to the gel, versus 27% for the placebo arm.
Evidence from preclinical models suggest that cannabinoids have antinociceptive and antihyperalgesic effects, Dr. Hunter explained at the congress, sponsored by the Osteoarthritis Research Society International. CBD has also been shown to have broad anti-inflammatory effects, and it may even promote osteoclast cell function and decrease bone resorption.
ZYN002 is a synthetic CBD formulated for transdermal delivery using a patented method to enhance its permeation through the skin. According to the manufacturer, Zynerba, it was developed for neuropsychiatric disorders, including fragile X syndrome, adult refractory epilepsy, and developmental and epileptic encephalopathies.
The primary aim of the phase 2 trial reported by Dr. Hunter was to assess ZYN002’s efficacy in managing osteoarthritis knee pain. Secondary objectives were to assess the gel’s safety and tolerability.
The STOP 1 (Synthetic Transdermal Cannabidiol for the Treatment of Knee Pain Due to Osteoarthritis) trial was a double-blind, placebo-controlled trial. For inclusion in the study, patients had to be between age 40 and 75 years and have had knee pain for at least 12 months because of primary OA, based on clinical and x-ray data as per American College of Rheumatology criteria. Anyone with a history of fibromyalgia or epilepsy was excluded.
A total of 320 patients with painful knee OA, with a mean age of 62 years, were randomized and underwent a 1-week washout period in which all their analgesic medications being used for osteoarthritis knee pain, except acetaminophen, were stopped. That was followed by a 7- to 10-day period when baseline daily worst pain levels were captured using a 0-10 numeric rating scale. Patients then underwent 12 weeks of treatment with either a high (500 mg) or a low (250 mg) dose of the gel, or placebo, given in twice-daily doses.
Just over a third (34%) of patients in the placebo arm discontinued the study, compared with 22% and 24% of those in the high- and low-dose gel arms. The main reason for discontinuation was withdrawn consent because of lack of efficacy in the placebo arm, with 8%, 8%, and 4% of patients, respectively, discontinuing because of adverse effects.
“Treatment-emergent adverse effects were roughly equally distributed across the three groups,” Dr. Hunter reported. The adverse events of more interest, he noted, were application site dryness, reaction, or pain. There was “a slight predisposition” to each of these in the 250-mg gel arm (5%, 3%, and 3% of patients affected) versus the 500-mg gel (3%, 0%, and 0%) and placebo (1%, 1%, 0%) arms.
SOURCE: Hunter D et al. Osteoarthritis Cartilage 2018:26(1):S26. Abstract 30.
LIVERPOOL, ENGLAND – There was no significant reduction in pain from knee osteoarthritis (OA) with the use of investigational cannabidiol (CBD) gel ZYN002 in a phase 2a trial presented at the World Congress on Osteoarthritis.
The mean reductions in baseline knee pain scores from study entry to a 12-week assessment were –2.4 for placebo and –2.6 (P = .5) and –2.8 (P = .25), respectively, for a 250-mg and a 500-mg formulation of the gel.
While there was a trend for benefit, it was “neither statistically or clinically significant,” reported David Hunter, MBBS, PhD.
However, he observed that a significantly (P = .016) greater number of patients who received the 250-mg dose (52.7%) were “composite responders,” compared with patients who received placebo (34.1%). A composite response was defined as at least a 30% reduction in pain, and a 20% decrease in WOMAC physical function subscale score at the last observation.
Although the percentage of composite responders was also higher than placebo with the 500-mg dose, the difference wasn’t significant (45.1% vs. 34.1%; P = .0169).
Post-hoc analyses also suggested that perhaps some patients may benefit more than others, reported Dr. Hunter, professor of medicine at the University of Sydney and the Royal North Shore Hospital, Sydney.
For example, patients with baseline pain scores or 7 or more had greater mean reduction in pain at 12 weeks with both doses of the gel combined than placebo at week 4 (–2.2 vs. –1.6; P = .029), although the difference was not significant at week 8 (–3.0 vs. –2.2; P = .05) or 12 (–3.3 vs. –2.5; P = .086).
Women also exhibited a greater placebo response than did men, and “patients with less variability in baseline pain scores may have had greater separation between placebo and the treatment,” Dr. Hunter said. Indeed, 50%-52% of patients with less than 33% variation in baseline scores had a composite response to the gel, versus 27% for the placebo arm.
Evidence from preclinical models suggest that cannabinoids have antinociceptive and antihyperalgesic effects, Dr. Hunter explained at the congress, sponsored by the Osteoarthritis Research Society International. CBD has also been shown to have broad anti-inflammatory effects, and it may even promote osteoclast cell function and decrease bone resorption.
ZYN002 is a synthetic CBD formulated for transdermal delivery using a patented method to enhance its permeation through the skin. According to the manufacturer, Zynerba, it was developed for neuropsychiatric disorders, including fragile X syndrome, adult refractory epilepsy, and developmental and epileptic encephalopathies.
The primary aim of the phase 2 trial reported by Dr. Hunter was to assess ZYN002’s efficacy in managing osteoarthritis knee pain. Secondary objectives were to assess the gel’s safety and tolerability.
The STOP 1 (Synthetic Transdermal Cannabidiol for the Treatment of Knee Pain Due to Osteoarthritis) trial was a double-blind, placebo-controlled trial. For inclusion in the study, patients had to be between age 40 and 75 years and have had knee pain for at least 12 months because of primary OA, based on clinical and x-ray data as per American College of Rheumatology criteria. Anyone with a history of fibromyalgia or epilepsy was excluded.
A total of 320 patients with painful knee OA, with a mean age of 62 years, were randomized and underwent a 1-week washout period in which all their analgesic medications being used for osteoarthritis knee pain, except acetaminophen, were stopped. That was followed by a 7- to 10-day period when baseline daily worst pain levels were captured using a 0-10 numeric rating scale. Patients then underwent 12 weeks of treatment with either a high (500 mg) or a low (250 mg) dose of the gel, or placebo, given in twice-daily doses.
Just over a third (34%) of patients in the placebo arm discontinued the study, compared with 22% and 24% of those in the high- and low-dose gel arms. The main reason for discontinuation was withdrawn consent because of lack of efficacy in the placebo arm, with 8%, 8%, and 4% of patients, respectively, discontinuing because of adverse effects.
“Treatment-emergent adverse effects were roughly equally distributed across the three groups,” Dr. Hunter reported. The adverse events of more interest, he noted, were application site dryness, reaction, or pain. There was “a slight predisposition” to each of these in the 250-mg gel arm (5%, 3%, and 3% of patients affected) versus the 500-mg gel (3%, 0%, and 0%) and placebo (1%, 1%, 0%) arms.
SOURCE: Hunter D et al. Osteoarthritis Cartilage 2018:26(1):S26. Abstract 30.
LIVERPOOL, ENGLAND – There was no significant reduction in pain from knee osteoarthritis (OA) with the use of investigational cannabidiol (CBD) gel ZYN002 in a phase 2a trial presented at the World Congress on Osteoarthritis.
The mean reductions in baseline knee pain scores from study entry to a 12-week assessment were –2.4 for placebo and –2.6 (P = .5) and –2.8 (P = .25), respectively, for a 250-mg and a 500-mg formulation of the gel.
While there was a trend for benefit, it was “neither statistically or clinically significant,” reported David Hunter, MBBS, PhD.
However, he observed that a significantly (P = .016) greater number of patients who received the 250-mg dose (52.7%) were “composite responders,” compared with patients who received placebo (34.1%). A composite response was defined as at least a 30% reduction in pain, and a 20% decrease in WOMAC physical function subscale score at the last observation.
Although the percentage of composite responders was also higher than placebo with the 500-mg dose, the difference wasn’t significant (45.1% vs. 34.1%; P = .0169).
Post-hoc analyses also suggested that perhaps some patients may benefit more than others, reported Dr. Hunter, professor of medicine at the University of Sydney and the Royal North Shore Hospital, Sydney.
For example, patients with baseline pain scores or 7 or more had greater mean reduction in pain at 12 weeks with both doses of the gel combined than placebo at week 4 (–2.2 vs. –1.6; P = .029), although the difference was not significant at week 8 (–3.0 vs. –2.2; P = .05) or 12 (–3.3 vs. –2.5; P = .086).
Women also exhibited a greater placebo response than did men, and “patients with less variability in baseline pain scores may have had greater separation between placebo and the treatment,” Dr. Hunter said. Indeed, 50%-52% of patients with less than 33% variation in baseline scores had a composite response to the gel, versus 27% for the placebo arm.
Evidence from preclinical models suggest that cannabinoids have antinociceptive and antihyperalgesic effects, Dr. Hunter explained at the congress, sponsored by the Osteoarthritis Research Society International. CBD has also been shown to have broad anti-inflammatory effects, and it may even promote osteoclast cell function and decrease bone resorption.
ZYN002 is a synthetic CBD formulated for transdermal delivery using a patented method to enhance its permeation through the skin. According to the manufacturer, Zynerba, it was developed for neuropsychiatric disorders, including fragile X syndrome, adult refractory epilepsy, and developmental and epileptic encephalopathies.
The primary aim of the phase 2 trial reported by Dr. Hunter was to assess ZYN002’s efficacy in managing osteoarthritis knee pain. Secondary objectives were to assess the gel’s safety and tolerability.
The STOP 1 (Synthetic Transdermal Cannabidiol for the Treatment of Knee Pain Due to Osteoarthritis) trial was a double-blind, placebo-controlled trial. For inclusion in the study, patients had to be between age 40 and 75 years and have had knee pain for at least 12 months because of primary OA, based on clinical and x-ray data as per American College of Rheumatology criteria. Anyone with a history of fibromyalgia or epilepsy was excluded.
A total of 320 patients with painful knee OA, with a mean age of 62 years, were randomized and underwent a 1-week washout period in which all their analgesic medications being used for osteoarthritis knee pain, except acetaminophen, were stopped. That was followed by a 7- to 10-day period when baseline daily worst pain levels were captured using a 0-10 numeric rating scale. Patients then underwent 12 weeks of treatment with either a high (500 mg) or a low (250 mg) dose of the gel, or placebo, given in twice-daily doses.
Just over a third (34%) of patients in the placebo arm discontinued the study, compared with 22% and 24% of those in the high- and low-dose gel arms. The main reason for discontinuation was withdrawn consent because of lack of efficacy in the placebo arm, with 8%, 8%, and 4% of patients, respectively, discontinuing because of adverse effects.
“Treatment-emergent adverse effects were roughly equally distributed across the three groups,” Dr. Hunter reported. The adverse events of more interest, he noted, were application site dryness, reaction, or pain. There was “a slight predisposition” to each of these in the 250-mg gel arm (5%, 3%, and 3% of patients affected) versus the 500-mg gel (3%, 0%, and 0%) and placebo (1%, 1%, 0%) arms.
SOURCE: Hunter D et al. Osteoarthritis Cartilage 2018:26(1):S26. Abstract 30.
REPORTING FROM OARSI 2018
Key clinical point:
Major finding: Mean knee pain scores at 12 weeks fell by –2.4 for placebo, and –2.6 (P = .5) and –2.8 (P = .25) for a 250-mg and a 500-mg formulation of the gel.
Study details: A 12-week, randomized, double-blind, placebo-controlled, phase 2, multidose study involving 320 patients with osteoarthritis knee pain for at least 12 months.
Disclosures: Dr. Hunter has consulted for Flexion, Merck Serono, TissueGene, and Zynerba, and has received royalties from DJO for a patellofemoral brace.
Source: Hunter D et al. Osteoarthritis Cartilage 2018:26(1):S26. Abstract 30.
Surgery may be best option for hip impingement syndrome
LIVERPOOL, ENGLAND – Hip arthroscopic surgery produced better long-term results than did personalized hip physiotherapy for femoroacetabular impingement syndrome in a randomized trial conduced across multiple U.K. centers.
At 12 months, respective International Hip Outcome Tool-33 (iHOT-33) scores were 58.8 and 49.7, a difference of 9.1 points before and 6.8 points after adjustment for potential confounding factors (P = .0093).
“This trial shows that hip arthroscopic surgery and personalized hip therapy both improved hip-related quality of life for patients with FAI [femoroacetabular impingement] syndrome, but that the surgery did indeed produce a greater improvement at our primary time point of 12 months,” she added. Dr. Foster is professor of musculoskeletal health in primary care at Keele University, Newcastle-under-Lyme, England, one of the 23 centers involved in the FASHIoN study in England, Wales, and Scotland.
“FAI is a very common cause of hip and groin pain in young adults, and it’s associated with the development of hip osteoarthritis,” Dr. Foster noted.
There are three types of FAI – pincer, cam, and combined. The pincer type of FAI is where there is “prominence or overcoverage of the rim of the acetabulum,” and the cam type is where there is a “bony prominence of the femoral head-neck junction,” she explained at the meeting sponsored by the Osteoarthritis Research Society International.
The link to OA comes when the femur and acetabulum prematurely connect, usually during activity, causing damage to the labrum and articular cartilage in the long term. Thus, treating FAI is important, not just for relieving patient’s pain and joint stiffness.
Hip arthroscopic surgery has become an established way of treating FAI syndrome – more than 2,400 operations were performed in 2013 in the United Kingdom alone, Dr. Foster observed. The aim of surgery is to try to reshape the hip joint to prevent impingement, and resect, repair, or reconstruct any intra-articular damage that may be present.
“Physiotherapy aims to improve hip muscle control and strength, and to correct the abnormal movement patterns that we see in these patients,” Dr. Foster said. “Through that, we hope to prevent the premature contact that occurs in FAI syndrome and thereby improve symptoms, allowing patients to return to activities and prevent recurrence.”
Working with physiotherapists, physicians, and surgeons, Dr. Foster and her associates have previously developed a “best conservative care” intervention that they call personalized hip therapy (PHT), which involves the delivery and supervision of an individualized exercise program by experienced physiotherapists over a 3- to 6-month period, and which patients repeat at home (PM R. 2013 May;5[5]:418-26).
The aim of the UK FASHIoN trial was to compare the clinical and cost-effectiveness of hip arthroscopy and PHT for FAI syndrome, as there was no robust clinical trial evidence to demonstrate a benefit of one over the other.
A total of 351 adults with hip and groin pain were randomized to either arthroscopic surgery (n = 173) or PHT (n = 178). The mean age of participants was 35 years, with no significant differences between the two treatment groups in terms of baseline demographics or type or duration of hip impingement.
While surgery was better in terms of patient outcomes, the study didn’t demonstrate its cost-effectiveness within the first 12 months, Dr. Foster observed. Cost-effectiveness, together with various other quality-of-life measurements, was a secondary endpoint of the study.
“Longer-term outcomes are required to establish whether improvement is sustained, and whether surgery is cost-effective at the longer time points for our health service,” she said.
Responding to a question about whether any of the patients in the study had radiographic evidence of osteoarthritis, Dr. Foster said that such patients had been excluded from the study.
“One of the hopes of the trial’s team is that, with the long-term follow-up, we might be able to get data at 5 and 10 years on things like hip osteoarthritis in these patients,” she said.
The study was funded by the National Institute for Health Research. Dr. Foster had no financial relationships or commercial interests to disclose.
SOURCE: Griffin DR et al. Osteoarthritis Cartilage. 2018:26(1):S24-25. Abstract 28
LIVERPOOL, ENGLAND – Hip arthroscopic surgery produced better long-term results than did personalized hip physiotherapy for femoroacetabular impingement syndrome in a randomized trial conduced across multiple U.K. centers.
At 12 months, respective International Hip Outcome Tool-33 (iHOT-33) scores were 58.8 and 49.7, a difference of 9.1 points before and 6.8 points after adjustment for potential confounding factors (P = .0093).
“This trial shows that hip arthroscopic surgery and personalized hip therapy both improved hip-related quality of life for patients with FAI [femoroacetabular impingement] syndrome, but that the surgery did indeed produce a greater improvement at our primary time point of 12 months,” she added. Dr. Foster is professor of musculoskeletal health in primary care at Keele University, Newcastle-under-Lyme, England, one of the 23 centers involved in the FASHIoN study in England, Wales, and Scotland.
“FAI is a very common cause of hip and groin pain in young adults, and it’s associated with the development of hip osteoarthritis,” Dr. Foster noted.
There are three types of FAI – pincer, cam, and combined. The pincer type of FAI is where there is “prominence or overcoverage of the rim of the acetabulum,” and the cam type is where there is a “bony prominence of the femoral head-neck junction,” she explained at the meeting sponsored by the Osteoarthritis Research Society International.
The link to OA comes when the femur and acetabulum prematurely connect, usually during activity, causing damage to the labrum and articular cartilage in the long term. Thus, treating FAI is important, not just for relieving patient’s pain and joint stiffness.
Hip arthroscopic surgery has become an established way of treating FAI syndrome – more than 2,400 operations were performed in 2013 in the United Kingdom alone, Dr. Foster observed. The aim of surgery is to try to reshape the hip joint to prevent impingement, and resect, repair, or reconstruct any intra-articular damage that may be present.
“Physiotherapy aims to improve hip muscle control and strength, and to correct the abnormal movement patterns that we see in these patients,” Dr. Foster said. “Through that, we hope to prevent the premature contact that occurs in FAI syndrome and thereby improve symptoms, allowing patients to return to activities and prevent recurrence.”
Working with physiotherapists, physicians, and surgeons, Dr. Foster and her associates have previously developed a “best conservative care” intervention that they call personalized hip therapy (PHT), which involves the delivery and supervision of an individualized exercise program by experienced physiotherapists over a 3- to 6-month period, and which patients repeat at home (PM R. 2013 May;5[5]:418-26).
The aim of the UK FASHIoN trial was to compare the clinical and cost-effectiveness of hip arthroscopy and PHT for FAI syndrome, as there was no robust clinical trial evidence to demonstrate a benefit of one over the other.
A total of 351 adults with hip and groin pain were randomized to either arthroscopic surgery (n = 173) or PHT (n = 178). The mean age of participants was 35 years, with no significant differences between the two treatment groups in terms of baseline demographics or type or duration of hip impingement.
While surgery was better in terms of patient outcomes, the study didn’t demonstrate its cost-effectiveness within the first 12 months, Dr. Foster observed. Cost-effectiveness, together with various other quality-of-life measurements, was a secondary endpoint of the study.
“Longer-term outcomes are required to establish whether improvement is sustained, and whether surgery is cost-effective at the longer time points for our health service,” she said.
Responding to a question about whether any of the patients in the study had radiographic evidence of osteoarthritis, Dr. Foster said that such patients had been excluded from the study.
“One of the hopes of the trial’s team is that, with the long-term follow-up, we might be able to get data at 5 and 10 years on things like hip osteoarthritis in these patients,” she said.
The study was funded by the National Institute for Health Research. Dr. Foster had no financial relationships or commercial interests to disclose.
SOURCE: Griffin DR et al. Osteoarthritis Cartilage. 2018:26(1):S24-25. Abstract 28
LIVERPOOL, ENGLAND – Hip arthroscopic surgery produced better long-term results than did personalized hip physiotherapy for femoroacetabular impingement syndrome in a randomized trial conduced across multiple U.K. centers.
At 12 months, respective International Hip Outcome Tool-33 (iHOT-33) scores were 58.8 and 49.7, a difference of 9.1 points before and 6.8 points after adjustment for potential confounding factors (P = .0093).
“This trial shows that hip arthroscopic surgery and personalized hip therapy both improved hip-related quality of life for patients with FAI [femoroacetabular impingement] syndrome, but that the surgery did indeed produce a greater improvement at our primary time point of 12 months,” she added. Dr. Foster is professor of musculoskeletal health in primary care at Keele University, Newcastle-under-Lyme, England, one of the 23 centers involved in the FASHIoN study in England, Wales, and Scotland.
“FAI is a very common cause of hip and groin pain in young adults, and it’s associated with the development of hip osteoarthritis,” Dr. Foster noted.
There are three types of FAI – pincer, cam, and combined. The pincer type of FAI is where there is “prominence or overcoverage of the rim of the acetabulum,” and the cam type is where there is a “bony prominence of the femoral head-neck junction,” she explained at the meeting sponsored by the Osteoarthritis Research Society International.
The link to OA comes when the femur and acetabulum prematurely connect, usually during activity, causing damage to the labrum and articular cartilage in the long term. Thus, treating FAI is important, not just for relieving patient’s pain and joint stiffness.
Hip arthroscopic surgery has become an established way of treating FAI syndrome – more than 2,400 operations were performed in 2013 in the United Kingdom alone, Dr. Foster observed. The aim of surgery is to try to reshape the hip joint to prevent impingement, and resect, repair, or reconstruct any intra-articular damage that may be present.
“Physiotherapy aims to improve hip muscle control and strength, and to correct the abnormal movement patterns that we see in these patients,” Dr. Foster said. “Through that, we hope to prevent the premature contact that occurs in FAI syndrome and thereby improve symptoms, allowing patients to return to activities and prevent recurrence.”
Working with physiotherapists, physicians, and surgeons, Dr. Foster and her associates have previously developed a “best conservative care” intervention that they call personalized hip therapy (PHT), which involves the delivery and supervision of an individualized exercise program by experienced physiotherapists over a 3- to 6-month period, and which patients repeat at home (PM R. 2013 May;5[5]:418-26).
The aim of the UK FASHIoN trial was to compare the clinical and cost-effectiveness of hip arthroscopy and PHT for FAI syndrome, as there was no robust clinical trial evidence to demonstrate a benefit of one over the other.
A total of 351 adults with hip and groin pain were randomized to either arthroscopic surgery (n = 173) or PHT (n = 178). The mean age of participants was 35 years, with no significant differences between the two treatment groups in terms of baseline demographics or type or duration of hip impingement.
While surgery was better in terms of patient outcomes, the study didn’t demonstrate its cost-effectiveness within the first 12 months, Dr. Foster observed. Cost-effectiveness, together with various other quality-of-life measurements, was a secondary endpoint of the study.
“Longer-term outcomes are required to establish whether improvement is sustained, and whether surgery is cost-effective at the longer time points for our health service,” she said.
Responding to a question about whether any of the patients in the study had radiographic evidence of osteoarthritis, Dr. Foster said that such patients had been excluded from the study.
“One of the hopes of the trial’s team is that, with the long-term follow-up, we might be able to get data at 5 and 10 years on things like hip osteoarthritis in these patients,” she said.
The study was funded by the National Institute for Health Research. Dr. Foster had no financial relationships or commercial interests to disclose.
SOURCE: Griffin DR et al. Osteoarthritis Cartilage. 2018:26(1):S24-25. Abstract 28
REPORTING FROM OARSI 2018
Key clinical point: Hip arthroscopy produced better results at 12 months than did the best conservative care.
Major finding: iHOT-33 scores at 12 months were 58.3 for surgery and 49.7 for personalized hip therapy (P = .0093)
Study details: Multicenter, randomized controlled UK FASHIoN trial of 351 adults with hip and groin pain.
Disclosures: The study was funded by the National Institute for Health Research. Dr. Foster had nothing to disclose.
Source: Griffin DR et al. Osteoarthritis Cartilage. 2018:26(1):S24-25. Abstract 28.
Sprifermin moves FORWARD with sustained effects in osteoarthritis
LIVERPOOL, ENGLAND – At 3 years of follow-up, the cartilage-building effects of sprifermin appear to be sustained, according to further data to be released from the phase 2 FORWARD trial.
The difference from placebo in mean cartilage thickness at the tibiofemoral joint (TFJ) at 3 years was 0.05 mm for a 100-mcg dose of sprifermin given every 6 months (P less than .0001), 0.02 mm for a 100-mcg dose given every 12 months (P = .193), 0.01 mm for a 50-mcg dose given every 6 months (P = .530), and –0.02 mm for a 50-mcg dose given every 12 months (P = .160).
“These data, 18 months after the last active injection, extend the results which we previously presented and assessed at 6 months after the last injection,” study investigator Marc Hochberg, MD, said at the World Congress on Osteoarthritis.
The prior 2-year findings, which were reported at the annual meeting of the American College of Rheumatology in November 2017, showed statistically significant dose-dependent structural modification in TFJ cartilage. Furthermore, the increase in cartilage thickness was seen in both medial and lateral compartments of the TFJ, and in the central medial subregion of the TFJ.
Sprifermin is one of several drugs currently being investigated as a potential disease-modifying osteoarthritis drug, none of which are currently licensed for use. It is a novel human recombinant version of fibroblast growth factor 18 that has been shown to increase chondrocyte proliferation that results in overall extracellular matrix production and subsequent hyaline-line cartilage formation.
The study comprised 549 patients with symptomatic radiographic primary femorotibial knee OA who were aged 40-85 years. For inclusion, patients had to have Kellgren-Lawrence Grade 2 or 3, with a medial minimum joint space width of 2.5 mm or more. In addition, patients had to have a history of OA pain for at least 6 months and either symptoms requiring pain medication or a pain score of 4-9 on the 10-point question 1 of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).
Dr. Hochberg, professor of medicine, epidemiology, and public health and head of the division of rheumatology and clinical immunology at the University of Maryland, Baltimore, noted that the current analysis at 3 years’ follow up had been prespecified and that the plan was to continue follow-up out to 5 years.
There was a statistically significant treatment effect and dose response effect seen in TFJ cartilage thickness.
“Although cartilage thickness declined in all treatment groups between years 2 and 3, the difference in cartilage thickness observed in year 2 with sprifermin at the highest dose [100 mcg every 6 months] versus placebo persisted through year 3,” Dr. Hochberg said at the congress, which was sponsored by the Osteoarthritis Research Society International.
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As for secondary endpoints of thickness in the medial and lateral tibiofemoral cartilage, “there are significant differences between the higher-dose sprifermin group and the placebo group,” he said.
“Based on imaging, sprifermin appears to be effective at modifying structural changes in articular cartilage in a dose-dependent manner in patients with knee osteoarthritis, with an acceptable safety profile.”
Dr. Hochberg added that there was “marked symptomatic improvement” as shown by changes in WOMAC scores in all treatment groups including placebo. The improvement in total WOMAC scores by approximately 50% in all treatment groups by the second year was continued to the third year.
Adverse effects occurred with a similar frequency in the active treatment groups and the placebo group. They were also of a similar nature. The most commonly reported side effects involved the musculoskeletal system or were connective tissue disorders (e.g. arthralgia). Importantly, there was no difference in the frequency, severity, or nature of serious adverse events, treatment-related adverse events, or discontinuation due to adverse events with active versus placebo therapy, Dr. Hochberg said.
The percentages of patients completing the study to the second and third years were a respective 87.8% and 81.6% in the sprifermin groups and 80.6% and 75.9% in the placebo group.
Merck KGaA and EMD Serono Research Institute funded the study. Dr. Hochberg has received consulting fees from EMD Serono and multiple other companies developing treatments for OA.
SOURCE: Hochberg M et al. Osteoarthritis Cartilage. 2018:26(1):S26-27. Abstract 32
LIVERPOOL, ENGLAND – At 3 years of follow-up, the cartilage-building effects of sprifermin appear to be sustained, according to further data to be released from the phase 2 FORWARD trial.
The difference from placebo in mean cartilage thickness at the tibiofemoral joint (TFJ) at 3 years was 0.05 mm for a 100-mcg dose of sprifermin given every 6 months (P less than .0001), 0.02 mm for a 100-mcg dose given every 12 months (P = .193), 0.01 mm for a 50-mcg dose given every 6 months (P = .530), and –0.02 mm for a 50-mcg dose given every 12 months (P = .160).
“These data, 18 months after the last active injection, extend the results which we previously presented and assessed at 6 months after the last injection,” study investigator Marc Hochberg, MD, said at the World Congress on Osteoarthritis.
The prior 2-year findings, which were reported at the annual meeting of the American College of Rheumatology in November 2017, showed statistically significant dose-dependent structural modification in TFJ cartilage. Furthermore, the increase in cartilage thickness was seen in both medial and lateral compartments of the TFJ, and in the central medial subregion of the TFJ.
Sprifermin is one of several drugs currently being investigated as a potential disease-modifying osteoarthritis drug, none of which are currently licensed for use. It is a novel human recombinant version of fibroblast growth factor 18 that has been shown to increase chondrocyte proliferation that results in overall extracellular matrix production and subsequent hyaline-line cartilage formation.
The study comprised 549 patients with symptomatic radiographic primary femorotibial knee OA who were aged 40-85 years. For inclusion, patients had to have Kellgren-Lawrence Grade 2 or 3, with a medial minimum joint space width of 2.5 mm or more. In addition, patients had to have a history of OA pain for at least 6 months and either symptoms requiring pain medication or a pain score of 4-9 on the 10-point question 1 of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).
Dr. Hochberg, professor of medicine, epidemiology, and public health and head of the division of rheumatology and clinical immunology at the University of Maryland, Baltimore, noted that the current analysis at 3 years’ follow up had been prespecified and that the plan was to continue follow-up out to 5 years.
There was a statistically significant treatment effect and dose response effect seen in TFJ cartilage thickness.
“Although cartilage thickness declined in all treatment groups between years 2 and 3, the difference in cartilage thickness observed in year 2 with sprifermin at the highest dose [100 mcg every 6 months] versus placebo persisted through year 3,” Dr. Hochberg said at the congress, which was sponsored by the Osteoarthritis Research Society International.
As for secondary endpoints of thickness in the medial and lateral tibiofemoral cartilage, “there are significant differences between the higher-dose sprifermin group and the placebo group,” he said.
“Based on imaging, sprifermin appears to be effective at modifying structural changes in articular cartilage in a dose-dependent manner in patients with knee osteoarthritis, with an acceptable safety profile.”
Dr. Hochberg added that there was “marked symptomatic improvement” as shown by changes in WOMAC scores in all treatment groups including placebo. The improvement in total WOMAC scores by approximately 50% in all treatment groups by the second year was continued to the third year.
Adverse effects occurred with a similar frequency in the active treatment groups and the placebo group. They were also of a similar nature. The most commonly reported side effects involved the musculoskeletal system or were connective tissue disorders (e.g. arthralgia). Importantly, there was no difference in the frequency, severity, or nature of serious adverse events, treatment-related adverse events, or discontinuation due to adverse events with active versus placebo therapy, Dr. Hochberg said.
The percentages of patients completing the study to the second and third years were a respective 87.8% and 81.6% in the sprifermin groups and 80.6% and 75.9% in the placebo group.
Merck KGaA and EMD Serono Research Institute funded the study. Dr. Hochberg has received consulting fees from EMD Serono and multiple other companies developing treatments for OA.
SOURCE: Hochberg M et al. Osteoarthritis Cartilage. 2018:26(1):S26-27. Abstract 32
LIVERPOOL, ENGLAND – At 3 years of follow-up, the cartilage-building effects of sprifermin appear to be sustained, according to further data to be released from the phase 2 FORWARD trial.
The difference from placebo in mean cartilage thickness at the tibiofemoral joint (TFJ) at 3 years was 0.05 mm for a 100-mcg dose of sprifermin given every 6 months (P less than .0001), 0.02 mm for a 100-mcg dose given every 12 months (P = .193), 0.01 mm for a 50-mcg dose given every 6 months (P = .530), and –0.02 mm for a 50-mcg dose given every 12 months (P = .160).
“These data, 18 months after the last active injection, extend the results which we previously presented and assessed at 6 months after the last injection,” study investigator Marc Hochberg, MD, said at the World Congress on Osteoarthritis.
The prior 2-year findings, which were reported at the annual meeting of the American College of Rheumatology in November 2017, showed statistically significant dose-dependent structural modification in TFJ cartilage. Furthermore, the increase in cartilage thickness was seen in both medial and lateral compartments of the TFJ, and in the central medial subregion of the TFJ.
Sprifermin is one of several drugs currently being investigated as a potential disease-modifying osteoarthritis drug, none of which are currently licensed for use. It is a novel human recombinant version of fibroblast growth factor 18 that has been shown to increase chondrocyte proliferation that results in overall extracellular matrix production and subsequent hyaline-line cartilage formation.
The study comprised 549 patients with symptomatic radiographic primary femorotibial knee OA who were aged 40-85 years. For inclusion, patients had to have Kellgren-Lawrence Grade 2 or 3, with a medial minimum joint space width of 2.5 mm or more. In addition, patients had to have a history of OA pain for at least 6 months and either symptoms requiring pain medication or a pain score of 4-9 on the 10-point question 1 of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).
Dr. Hochberg, professor of medicine, epidemiology, and public health and head of the division of rheumatology and clinical immunology at the University of Maryland, Baltimore, noted that the current analysis at 3 years’ follow up had been prespecified and that the plan was to continue follow-up out to 5 years.
There was a statistically significant treatment effect and dose response effect seen in TFJ cartilage thickness.
“Although cartilage thickness declined in all treatment groups between years 2 and 3, the difference in cartilage thickness observed in year 2 with sprifermin at the highest dose [100 mcg every 6 months] versus placebo persisted through year 3,” Dr. Hochberg said at the congress, which was sponsored by the Osteoarthritis Research Society International.
As for secondary endpoints of thickness in the medial and lateral tibiofemoral cartilage, “there are significant differences between the higher-dose sprifermin group and the placebo group,” he said.
“Based on imaging, sprifermin appears to be effective at modifying structural changes in articular cartilage in a dose-dependent manner in patients with knee osteoarthritis, with an acceptable safety profile.”
Dr. Hochberg added that there was “marked symptomatic improvement” as shown by changes in WOMAC scores in all treatment groups including placebo. The improvement in total WOMAC scores by approximately 50% in all treatment groups by the second year was continued to the third year.
Adverse effects occurred with a similar frequency in the active treatment groups and the placebo group. They were also of a similar nature. The most commonly reported side effects involved the musculoskeletal system or were connective tissue disorders (e.g. arthralgia). Importantly, there was no difference in the frequency, severity, or nature of serious adverse events, treatment-related adverse events, or discontinuation due to adverse events with active versus placebo therapy, Dr. Hochberg said.
The percentages of patients completing the study to the second and third years were a respective 87.8% and 81.6% in the sprifermin groups and 80.6% and 75.9% in the placebo group.
Merck KGaA and EMD Serono Research Institute funded the study. Dr. Hochberg has received consulting fees from EMD Serono and multiple other companies developing treatments for OA.
SOURCE: Hochberg M et al. Osteoarthritis Cartilage. 2018:26(1):S26-27. Abstract 32
REPORTING FROM OARSI 2018
Key clinical point:
Major finding: The difference from placebo in mean cartilage thickness at the tibiofemoral joint at 3 years was 0.05 mm for the 100-mcg dose of sprifermin given every 6 months (P less than .0001).
Study details: Phase 2 study of 549 patients with knee osteoarthritis treated with one of four intra-articular doses of sprifermin or placebo.
Disclosures: Merck KGaA and EMD Serono Research Institute funded the study. Dr. Hochberg has received consulting fees from EMD Serono and multiple other companies developing treatments for OA.
Source: Hochberg M et al. Osteoarthritis Cartilage. 2018:26(1):S26-27. Abstract 32.
‘Bright future’ for growth factor therapy in osteoarthritis
LIVERPOOL, ENGLAND – (OA), according to David Hunter, MBBS, PhD.
Dr. Hunter, who is the Florance and Cope Chair of Rheumatology and professor of medicine at the University of Sydney and the Royal North Shore Hospital, Sydney, Australia, outlined some of the recent research with these agents in OA.
In 2013, a U.S. study (Arthritis Care Res. 2013;65[5]:703-11) showed that the 2007-2008 incidence of symptomatic knee OA was highest between the ages of 54 and 64 years, with the estimated median age at diagnosis of 55.8 years. Patients were substantially younger than were those who had been diagnosed at a median age of 68.5 years more than a decade earlier in 1991-1992.
“So, we’re developing [OA] at a much earlier age, but we’re obviously living longer and living with that morbidity for a substantial period of time,” Dr. Hunter said at the World Congress on Osteoarthritis, sponsored by the Osteoarthritis Research Society International.
“It’s within that context that we really need to think about both the individual and societal burden of osteoarthritis, and why we’re developing agents such as growth factors to help retard symptoms related to disease,” continued Dr. Hunter, chair of the Institute of Bone and Joint Research, deputy dean of the Northern Clinical School, and consultant rheumatologist at North Sydney Orthopaedic and Sports Medicine Centre, Sydney.
OA is characterized by articular cartilage damage, low-grade synovial inflammation, and hypertrophic bone changes that lead to pain and functional deterioration (Expert Opin Emerg Drugs. 2015;20[3]:361-78). Attempts to modify the disease process have thus focused on these three areas, aiming to regulate cartilage catabolism and anabolism, control inflammation, and remodel subchondral bone (Rheumatology [Oxford]. 2018;57[suppl. 4]:iv108-iv123).
Growth factors fall under the category of regulating cartilage catabolism and anabolism, playing a “significant role in musculoskeletal tissues’ homeostasis and repair,” Dr. Hunter explained. “They influence chemotaxis, differentiation, proliferation, and synthetic activity of cartilage and bone cells, and can regulate physiological remodeling and cartilage healing.”
Examples of growth factors of interest in OA include transforming growth factor-beta superfamily and bone morphogenic proteins 2 and 7, fibroblast growth factors 2 and 18, and insulin-like growth factor-1.
Two currently unproven and somewhat controversial ways of regulating cartilage catabolism and anabolism is the use of mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP). Neither are ready for widespread use, Dr. Hunter observed, and more data on these approaches still need to be gathered.
The rationale behind the use of MSCs is that all joint tissues contain these cells, and they can potentially differentiate into cartilage, bone, or other tissues. There are changes in the quantity, phenotype, and differentiation potential of these cells in patients with OA, however, leading researchers to see if intra-articular injection of MSCs could be a possible therapeutic strategy. MSCs can be isolated from a number of different tissues and differentiate into multiple cells types. Animal model data suggest that their transplantation into an affected joint can stimulate articular repair.
“From a clinical perspective, there have been a vast array of clinical trials looking at different types of MSCs and different types of administration,” Dr. Hunter noted. Pooled data suggest that stem cell therapy does help to improve pain and function. However, the quality of trials has been called into question, with a positive publication bias suggested. There’s no clear evidence of any structural benefits, Dr. Hunter stated. “There’s a lot of stem cells being used for clinical purposes without the evidence to support their efficacy,” he cautioned. “We need much better regulation.”
There are several PRP agents, which deliver growth factors, cytokines, adhesive proteins, and other plasma proteins, such as clotting factors. It’s unknown how PRP therapy works in OA, whether it is just pain relieving or could affect the progression of joint damage. So far, studies have been done only in knee OA, so data in other joints need to be obtained.
“Whilst they have great potential, the literature on the use of PRP is conflicting,” Dr. Hunter said. “There are a lot of positive trials out there, but their quality in general is quite low.”
Better data are perhaps available for the recombinant human fibroblast growth factor–18 sprifermin, with recent 3-year data from an ongoing 5-year randomized, placebo-controlled, phase 2 study showing increased total cartilage thickness in the tibiofemoral joint relative to placebo. “There does appear to be a structure benefit,” Dr. Hunter said of sprifermin’s effects in the study versus intra-articular saline.
Although improvement in total Western Ontario and McMaster Universities Osteoarthritis Index scores were seen in the patients with knee OA, there was no real differentiation by dose or by placebo. The rationale for having a longer trial follow-up – the last dose of sprifermin was given at 18 months – is to see if there is a later effect.
In the later stages of development is Invossa TissueGene-C; this is drug that consists of patients’ normal and genetically-modified chondrocyte cells that express transforming growth factor-beta 1. Phase 2 findings have shown that it can improve pain and function scores in patients with moderate to advanced knee OA (BMC Musculoskelet Disord. 2017;18[1]:461). Based on those findings, two phase 3 trials are currently underway, with some further findings presented elsewhere at the OARSI meeting.
Even though there is still no disease-modifying osteoarthritis drug currently licensed for use, “I’m really positive about all of what we’ve learned, particularly with the application to future trials and ongoing trials in this space,” Dr. Hunter observed.
“Future strategies should differentiate between those agents aiming to reduce pain, and those targeting structural evolution, incorporating a combination of anabolic and anti-catabolic therapies,” Dr. Hunter suggested. One of the challenges, however, is to address the placebo effect, which can be exaggerated by the context of administration or surgery.
Furthermore, he proposed that new treatments should “fit into the natural progression of OA” by focusing on early disease where changes might still be reversible. “We’re getting more nuanced about where to intervene,” Dr. Hunter said.
Emerging treatments should also take the location of the disease and its heterogenic nature into account.
Dr. Hunter has consulted for Zynerba, TLC, Kolon TissueGene, and Merck Serono, and he disclosed receiving royalties from DJO for a patellofemoral brace patent.
SOURCE: Lohmander S et al. Osteoarthritis Cartilage. 2018:26(1):S6. Abstract I-18
LIVERPOOL, ENGLAND – (OA), according to David Hunter, MBBS, PhD.
Dr. Hunter, who is the Florance and Cope Chair of Rheumatology and professor of medicine at the University of Sydney and the Royal North Shore Hospital, Sydney, Australia, outlined some of the recent research with these agents in OA.
In 2013, a U.S. study (Arthritis Care Res. 2013;65[5]:703-11) showed that the 2007-2008 incidence of symptomatic knee OA was highest between the ages of 54 and 64 years, with the estimated median age at diagnosis of 55.8 years. Patients were substantially younger than were those who had been diagnosed at a median age of 68.5 years more than a decade earlier in 1991-1992.
“So, we’re developing [OA] at a much earlier age, but we’re obviously living longer and living with that morbidity for a substantial period of time,” Dr. Hunter said at the World Congress on Osteoarthritis, sponsored by the Osteoarthritis Research Society International.
“It’s within that context that we really need to think about both the individual and societal burden of osteoarthritis, and why we’re developing agents such as growth factors to help retard symptoms related to disease,” continued Dr. Hunter, chair of the Institute of Bone and Joint Research, deputy dean of the Northern Clinical School, and consultant rheumatologist at North Sydney Orthopaedic and Sports Medicine Centre, Sydney.
OA is characterized by articular cartilage damage, low-grade synovial inflammation, and hypertrophic bone changes that lead to pain and functional deterioration (Expert Opin Emerg Drugs. 2015;20[3]:361-78). Attempts to modify the disease process have thus focused on these three areas, aiming to regulate cartilage catabolism and anabolism, control inflammation, and remodel subchondral bone (Rheumatology [Oxford]. 2018;57[suppl. 4]:iv108-iv123).
Growth factors fall under the category of regulating cartilage catabolism and anabolism, playing a “significant role in musculoskeletal tissues’ homeostasis and repair,” Dr. Hunter explained. “They influence chemotaxis, differentiation, proliferation, and synthetic activity of cartilage and bone cells, and can regulate physiological remodeling and cartilage healing.”
Examples of growth factors of interest in OA include transforming growth factor-beta superfamily and bone morphogenic proteins 2 and 7, fibroblast growth factors 2 and 18, and insulin-like growth factor-1.
Two currently unproven and somewhat controversial ways of regulating cartilage catabolism and anabolism is the use of mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP). Neither are ready for widespread use, Dr. Hunter observed, and more data on these approaches still need to be gathered.
The rationale behind the use of MSCs is that all joint tissues contain these cells, and they can potentially differentiate into cartilage, bone, or other tissues. There are changes in the quantity, phenotype, and differentiation potential of these cells in patients with OA, however, leading researchers to see if intra-articular injection of MSCs could be a possible therapeutic strategy. MSCs can be isolated from a number of different tissues and differentiate into multiple cells types. Animal model data suggest that their transplantation into an affected joint can stimulate articular repair.
“From a clinical perspective, there have been a vast array of clinical trials looking at different types of MSCs and different types of administration,” Dr. Hunter noted. Pooled data suggest that stem cell therapy does help to improve pain and function. However, the quality of trials has been called into question, with a positive publication bias suggested. There’s no clear evidence of any structural benefits, Dr. Hunter stated. “There’s a lot of stem cells being used for clinical purposes without the evidence to support their efficacy,” he cautioned. “We need much better regulation.”
There are several PRP agents, which deliver growth factors, cytokines, adhesive proteins, and other plasma proteins, such as clotting factors. It’s unknown how PRP therapy works in OA, whether it is just pain relieving or could affect the progression of joint damage. So far, studies have been done only in knee OA, so data in other joints need to be obtained.
“Whilst they have great potential, the literature on the use of PRP is conflicting,” Dr. Hunter said. “There are a lot of positive trials out there, but their quality in general is quite low.”
Better data are perhaps available for the recombinant human fibroblast growth factor–18 sprifermin, with recent 3-year data from an ongoing 5-year randomized, placebo-controlled, phase 2 study showing increased total cartilage thickness in the tibiofemoral joint relative to placebo. “There does appear to be a structure benefit,” Dr. Hunter said of sprifermin’s effects in the study versus intra-articular saline.
Although improvement in total Western Ontario and McMaster Universities Osteoarthritis Index scores were seen in the patients with knee OA, there was no real differentiation by dose or by placebo. The rationale for having a longer trial follow-up – the last dose of sprifermin was given at 18 months – is to see if there is a later effect.
In the later stages of development is Invossa TissueGene-C; this is drug that consists of patients’ normal and genetically-modified chondrocyte cells that express transforming growth factor-beta 1. Phase 2 findings have shown that it can improve pain and function scores in patients with moderate to advanced knee OA (BMC Musculoskelet Disord. 2017;18[1]:461). Based on those findings, two phase 3 trials are currently underway, with some further findings presented elsewhere at the OARSI meeting.
Even though there is still no disease-modifying osteoarthritis drug currently licensed for use, “I’m really positive about all of what we’ve learned, particularly with the application to future trials and ongoing trials in this space,” Dr. Hunter observed.
“Future strategies should differentiate between those agents aiming to reduce pain, and those targeting structural evolution, incorporating a combination of anabolic and anti-catabolic therapies,” Dr. Hunter suggested. One of the challenges, however, is to address the placebo effect, which can be exaggerated by the context of administration or surgery.
Furthermore, he proposed that new treatments should “fit into the natural progression of OA” by focusing on early disease where changes might still be reversible. “We’re getting more nuanced about where to intervene,” Dr. Hunter said.
Emerging treatments should also take the location of the disease and its heterogenic nature into account.
Dr. Hunter has consulted for Zynerba, TLC, Kolon TissueGene, and Merck Serono, and he disclosed receiving royalties from DJO for a patellofemoral brace patent.
SOURCE: Lohmander S et al. Osteoarthritis Cartilage. 2018:26(1):S6. Abstract I-18
LIVERPOOL, ENGLAND – (OA), according to David Hunter, MBBS, PhD.
Dr. Hunter, who is the Florance and Cope Chair of Rheumatology and professor of medicine at the University of Sydney and the Royal North Shore Hospital, Sydney, Australia, outlined some of the recent research with these agents in OA.
In 2013, a U.S. study (Arthritis Care Res. 2013;65[5]:703-11) showed that the 2007-2008 incidence of symptomatic knee OA was highest between the ages of 54 and 64 years, with the estimated median age at diagnosis of 55.8 years. Patients were substantially younger than were those who had been diagnosed at a median age of 68.5 years more than a decade earlier in 1991-1992.
“So, we’re developing [OA] at a much earlier age, but we’re obviously living longer and living with that morbidity for a substantial period of time,” Dr. Hunter said at the World Congress on Osteoarthritis, sponsored by the Osteoarthritis Research Society International.
“It’s within that context that we really need to think about both the individual and societal burden of osteoarthritis, and why we’re developing agents such as growth factors to help retard symptoms related to disease,” continued Dr. Hunter, chair of the Institute of Bone and Joint Research, deputy dean of the Northern Clinical School, and consultant rheumatologist at North Sydney Orthopaedic and Sports Medicine Centre, Sydney.
OA is characterized by articular cartilage damage, low-grade synovial inflammation, and hypertrophic bone changes that lead to pain and functional deterioration (Expert Opin Emerg Drugs. 2015;20[3]:361-78). Attempts to modify the disease process have thus focused on these three areas, aiming to regulate cartilage catabolism and anabolism, control inflammation, and remodel subchondral bone (Rheumatology [Oxford]. 2018;57[suppl. 4]:iv108-iv123).
Growth factors fall under the category of regulating cartilage catabolism and anabolism, playing a “significant role in musculoskeletal tissues’ homeostasis and repair,” Dr. Hunter explained. “They influence chemotaxis, differentiation, proliferation, and synthetic activity of cartilage and bone cells, and can regulate physiological remodeling and cartilage healing.”
Examples of growth factors of interest in OA include transforming growth factor-beta superfamily and bone morphogenic proteins 2 and 7, fibroblast growth factors 2 and 18, and insulin-like growth factor-1.
Two currently unproven and somewhat controversial ways of regulating cartilage catabolism and anabolism is the use of mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP). Neither are ready for widespread use, Dr. Hunter observed, and more data on these approaches still need to be gathered.
The rationale behind the use of MSCs is that all joint tissues contain these cells, and they can potentially differentiate into cartilage, bone, or other tissues. There are changes in the quantity, phenotype, and differentiation potential of these cells in patients with OA, however, leading researchers to see if intra-articular injection of MSCs could be a possible therapeutic strategy. MSCs can be isolated from a number of different tissues and differentiate into multiple cells types. Animal model data suggest that their transplantation into an affected joint can stimulate articular repair.
“From a clinical perspective, there have been a vast array of clinical trials looking at different types of MSCs and different types of administration,” Dr. Hunter noted. Pooled data suggest that stem cell therapy does help to improve pain and function. However, the quality of trials has been called into question, with a positive publication bias suggested. There’s no clear evidence of any structural benefits, Dr. Hunter stated. “There’s a lot of stem cells being used for clinical purposes without the evidence to support their efficacy,” he cautioned. “We need much better regulation.”
There are several PRP agents, which deliver growth factors, cytokines, adhesive proteins, and other plasma proteins, such as clotting factors. It’s unknown how PRP therapy works in OA, whether it is just pain relieving or could affect the progression of joint damage. So far, studies have been done only in knee OA, so data in other joints need to be obtained.
“Whilst they have great potential, the literature on the use of PRP is conflicting,” Dr. Hunter said. “There are a lot of positive trials out there, but their quality in general is quite low.”
Better data are perhaps available for the recombinant human fibroblast growth factor–18 sprifermin, with recent 3-year data from an ongoing 5-year randomized, placebo-controlled, phase 2 study showing increased total cartilage thickness in the tibiofemoral joint relative to placebo. “There does appear to be a structure benefit,” Dr. Hunter said of sprifermin’s effects in the study versus intra-articular saline.
Although improvement in total Western Ontario and McMaster Universities Osteoarthritis Index scores were seen in the patients with knee OA, there was no real differentiation by dose or by placebo. The rationale for having a longer trial follow-up – the last dose of sprifermin was given at 18 months – is to see if there is a later effect.
In the later stages of development is Invossa TissueGene-C; this is drug that consists of patients’ normal and genetically-modified chondrocyte cells that express transforming growth factor-beta 1. Phase 2 findings have shown that it can improve pain and function scores in patients with moderate to advanced knee OA (BMC Musculoskelet Disord. 2017;18[1]:461). Based on those findings, two phase 3 trials are currently underway, with some further findings presented elsewhere at the OARSI meeting.
Even though there is still no disease-modifying osteoarthritis drug currently licensed for use, “I’m really positive about all of what we’ve learned, particularly with the application to future trials and ongoing trials in this space,” Dr. Hunter observed.
“Future strategies should differentiate between those agents aiming to reduce pain, and those targeting structural evolution, incorporating a combination of anabolic and anti-catabolic therapies,” Dr. Hunter suggested. One of the challenges, however, is to address the placebo effect, which can be exaggerated by the context of administration or surgery.
Furthermore, he proposed that new treatments should “fit into the natural progression of OA” by focusing on early disease where changes might still be reversible. “We’re getting more nuanced about where to intervene,” Dr. Hunter said.
Emerging treatments should also take the location of the disease and its heterogenic nature into account.
Dr. Hunter has consulted for Zynerba, TLC, Kolon TissueGene, and Merck Serono, and he disclosed receiving royalties from DJO for a patellofemoral brace patent.
SOURCE: Lohmander S et al. Osteoarthritis Cartilage. 2018:26(1):S6. Abstract I-18
EXPERT ANALYSIS FROM OARSI 2018
TissueGene-C effects on knee OA seen at 3 years
LIVERPOOL, ENGLAND – TissueGene-C continues to show promise as a potential disease-modifying osteoarthritis drug, according to the long-term follow-up data of a phase 3 trial.
Within 2-3 years of receiving a single injection of the novel cell-gene therapy, patients with moderate knee OA were still experiencing significant improvement in the coprimary endpoints of knee symptoms, function, sports activity, and knee pain versus baseline values.
Differences in International Knee Documentation Committee (IKDC) scores from baseline to 2 and 3 years were a respective 15.3 and 14.8 points (both P less than .05 vs. baseline). Pain, assessed on a visual analog scale, was also significantly improved from baseline to 2 and 3 years (score changes –23.5 and –23.3; P less than .05 vs. baseline).
There were also significant improvements in the secondary endpoint of pain, stiffness, and physical function measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), with changes in scores of –19.8 and –17.4 versus baseline at 2 and 3 years, respectively (both P less than .05 vs. baseline).
“INVOISSA-K [TissueGene-C] is the first-in-class cell and gene therapy for the treatment of knee OA,” Dr. Lee reminded delegates at the congress, which is sponsored by the Osteoarthritis Research Society International. The novel treatment was made by collecting chondrocytes from a subject with polydactyl hands and then culturing these to create two subpopulations of cells, one with allogenic chondrocytes and the other with genetically modified chondrocytes that overexpress transforming growth factor-beta1. These subpopulations are then mixed in the ratio of 3:1 and delivered in a single intra-articular injection.
Dr. Lee, who is the president and chief executive officer of Kolon TissueGene, Rockville, Md., reported new findings of a phase 3 trial conducted exclusively in Korea at 12 study centers, the results of which were first presented at OARSI 2016.
At that time only the 12-month primary endpoint data were available, which showed that TissueGene-C improved IKDC scores from baseline by a significantly greater amount than a saline placebo, with changes in scores of 15.1 and 5 points, respectively, versus baseline values. Improvements in IKDC scores were seen as early as 3 months but only became significantly better than placebo at 6 months.
Similarly, visual analog scale pain scores had improved from baseline as early as 3 months but were only significantly different from placebo at 6 months (–23.4 change from baseline for TissueGene-C vs. –14.6 for placebo) and out to 12 months (–24.5 vs. –10.3). WOMAC scores with TissueGene-C were only significantly different from placebo at 12 months (–13.5 vs. –6.2 from baseline, respectively).
The 12-month OMERACT-OARSI responder rate was 84% for TissueGene-C and 45% for placebo. The most common adverse events seen with TissueGene-C were related to the injection site, with peripheral edema (9%), arthralgia (8%), joint swelling (6%), and injection-site pain (5%) reported.
A total of 163 patients were recruited into the study, all had Kellgren-Lawrence grade 3 knee OA, which was also graded as 3 or 4 on the International Cartilage Regeneration & Joint Preservation Society scale. Major lesions had be 6 cm2 or smaller. Active treatment was given to 78 patients, and 81 received placebo. The primary assessment period was at 12 months, but patients continued to be followed out to 5 years.
At OARSI 2018, Dr. Lee presented the findings of 12-month structural modification analyses for the first time. These showed that while the osteophyte score on MRI was not significantly different from baseline in the active-treatment arm, there was a significantly increased osteophyte score and total cartilage defect in the placebo-treated patients versus baseline values.
Subchondral bone changes at 12 months showed a trend for less bone area change with TissueGene-C than placebo and a trend for increased cartilage thickness. Greater reductions in serum CTX-1 and urine CTX-II were seen with active treatment than placebo, relative to screening values.
X-ray evaluation of joint-space narrowing showed that nonprogression was more likely in patients treated with TissueGene-C than with placebo (77% vs. 57%), although this was not significant. In addition, fewer patients treated with TissueGene-C than placebo who needed a total knee replacement at 2 years (0% and 7.5%) and at 3 years (2% and 14%).
TissueGene-C “has great potential” for being the first disease-modifying osteoarthritis drug to get to market, Dr. Lee suggested.
The clinical development program for TissueGene-C is further advanced in Korea than in the United States, where a phase 3 trial is about to start recruitment soon.
“We started our clinical trials in 2005 in Korea and in the U.S. simultaneously,” Dr. Lee said, noting that a biologics license application submitted in Korea in 2016 had been accepted by the Ministry of Food and Drug Safety on July 12, 2017, while only phase 1 and 2 trials have been completed in the United States
The study was funded by Kolon Life Science and TissueGene. Dr. Lee is an employee of TissueGene.
SOURCE: Lee B et al. Osteoarthritis Cartilage. 2018 Apr;26(1):S43-4.
LIVERPOOL, ENGLAND – TissueGene-C continues to show promise as a potential disease-modifying osteoarthritis drug, according to the long-term follow-up data of a phase 3 trial.
Within 2-3 years of receiving a single injection of the novel cell-gene therapy, patients with moderate knee OA were still experiencing significant improvement in the coprimary endpoints of knee symptoms, function, sports activity, and knee pain versus baseline values.
Differences in International Knee Documentation Committee (IKDC) scores from baseline to 2 and 3 years were a respective 15.3 and 14.8 points (both P less than .05 vs. baseline). Pain, assessed on a visual analog scale, was also significantly improved from baseline to 2 and 3 years (score changes –23.5 and –23.3; P less than .05 vs. baseline).
There were also significant improvements in the secondary endpoint of pain, stiffness, and physical function measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), with changes in scores of –19.8 and –17.4 versus baseline at 2 and 3 years, respectively (both P less than .05 vs. baseline).
“INVOISSA-K [TissueGene-C] is the first-in-class cell and gene therapy for the treatment of knee OA,” Dr. Lee reminded delegates at the congress, which is sponsored by the Osteoarthritis Research Society International. The novel treatment was made by collecting chondrocytes from a subject with polydactyl hands and then culturing these to create two subpopulations of cells, one with allogenic chondrocytes and the other with genetically modified chondrocytes that overexpress transforming growth factor-beta1. These subpopulations are then mixed in the ratio of 3:1 and delivered in a single intra-articular injection.
Dr. Lee, who is the president and chief executive officer of Kolon TissueGene, Rockville, Md., reported new findings of a phase 3 trial conducted exclusively in Korea at 12 study centers, the results of which were first presented at OARSI 2016.
At that time only the 12-month primary endpoint data were available, which showed that TissueGene-C improved IKDC scores from baseline by a significantly greater amount than a saline placebo, with changes in scores of 15.1 and 5 points, respectively, versus baseline values. Improvements in IKDC scores were seen as early as 3 months but only became significantly better than placebo at 6 months.
Similarly, visual analog scale pain scores had improved from baseline as early as 3 months but were only significantly different from placebo at 6 months (–23.4 change from baseline for TissueGene-C vs. –14.6 for placebo) and out to 12 months (–24.5 vs. –10.3). WOMAC scores with TissueGene-C were only significantly different from placebo at 12 months (–13.5 vs. –6.2 from baseline, respectively).
The 12-month OMERACT-OARSI responder rate was 84% for TissueGene-C and 45% for placebo. The most common adverse events seen with TissueGene-C were related to the injection site, with peripheral edema (9%), arthralgia (8%), joint swelling (6%), and injection-site pain (5%) reported.
A total of 163 patients were recruited into the study, all had Kellgren-Lawrence grade 3 knee OA, which was also graded as 3 or 4 on the International Cartilage Regeneration & Joint Preservation Society scale. Major lesions had be 6 cm2 or smaller. Active treatment was given to 78 patients, and 81 received placebo. The primary assessment period was at 12 months, but patients continued to be followed out to 5 years.
At OARSI 2018, Dr. Lee presented the findings of 12-month structural modification analyses for the first time. These showed that while the osteophyte score on MRI was not significantly different from baseline in the active-treatment arm, there was a significantly increased osteophyte score and total cartilage defect in the placebo-treated patients versus baseline values.
Subchondral bone changes at 12 months showed a trend for less bone area change with TissueGene-C than placebo and a trend for increased cartilage thickness. Greater reductions in serum CTX-1 and urine CTX-II were seen with active treatment than placebo, relative to screening values.
X-ray evaluation of joint-space narrowing showed that nonprogression was more likely in patients treated with TissueGene-C than with placebo (77% vs. 57%), although this was not significant. In addition, fewer patients treated with TissueGene-C than placebo who needed a total knee replacement at 2 years (0% and 7.5%) and at 3 years (2% and 14%).
TissueGene-C “has great potential” for being the first disease-modifying osteoarthritis drug to get to market, Dr. Lee suggested.
The clinical development program for TissueGene-C is further advanced in Korea than in the United States, where a phase 3 trial is about to start recruitment soon.
“We started our clinical trials in 2005 in Korea and in the U.S. simultaneously,” Dr. Lee said, noting that a biologics license application submitted in Korea in 2016 had been accepted by the Ministry of Food and Drug Safety on July 12, 2017, while only phase 1 and 2 trials have been completed in the United States
The study was funded by Kolon Life Science and TissueGene. Dr. Lee is an employee of TissueGene.
SOURCE: Lee B et al. Osteoarthritis Cartilage. 2018 Apr;26(1):S43-4.
LIVERPOOL, ENGLAND – TissueGene-C continues to show promise as a potential disease-modifying osteoarthritis drug, according to the long-term follow-up data of a phase 3 trial.
Within 2-3 years of receiving a single injection of the novel cell-gene therapy, patients with moderate knee OA were still experiencing significant improvement in the coprimary endpoints of knee symptoms, function, sports activity, and knee pain versus baseline values.
Differences in International Knee Documentation Committee (IKDC) scores from baseline to 2 and 3 years were a respective 15.3 and 14.8 points (both P less than .05 vs. baseline). Pain, assessed on a visual analog scale, was also significantly improved from baseline to 2 and 3 years (score changes –23.5 and –23.3; P less than .05 vs. baseline).
There were also significant improvements in the secondary endpoint of pain, stiffness, and physical function measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), with changes in scores of –19.8 and –17.4 versus baseline at 2 and 3 years, respectively (both P less than .05 vs. baseline).
“INVOISSA-K [TissueGene-C] is the first-in-class cell and gene therapy for the treatment of knee OA,” Dr. Lee reminded delegates at the congress, which is sponsored by the Osteoarthritis Research Society International. The novel treatment was made by collecting chondrocytes from a subject with polydactyl hands and then culturing these to create two subpopulations of cells, one with allogenic chondrocytes and the other with genetically modified chondrocytes that overexpress transforming growth factor-beta1. These subpopulations are then mixed in the ratio of 3:1 and delivered in a single intra-articular injection.
Dr. Lee, who is the president and chief executive officer of Kolon TissueGene, Rockville, Md., reported new findings of a phase 3 trial conducted exclusively in Korea at 12 study centers, the results of which were first presented at OARSI 2016.
At that time only the 12-month primary endpoint data were available, which showed that TissueGene-C improved IKDC scores from baseline by a significantly greater amount than a saline placebo, with changes in scores of 15.1 and 5 points, respectively, versus baseline values. Improvements in IKDC scores were seen as early as 3 months but only became significantly better than placebo at 6 months.
Similarly, visual analog scale pain scores had improved from baseline as early as 3 months but were only significantly different from placebo at 6 months (–23.4 change from baseline for TissueGene-C vs. –14.6 for placebo) and out to 12 months (–24.5 vs. –10.3). WOMAC scores with TissueGene-C were only significantly different from placebo at 12 months (–13.5 vs. –6.2 from baseline, respectively).
The 12-month OMERACT-OARSI responder rate was 84% for TissueGene-C and 45% for placebo. The most common adverse events seen with TissueGene-C were related to the injection site, with peripheral edema (9%), arthralgia (8%), joint swelling (6%), and injection-site pain (5%) reported.
A total of 163 patients were recruited into the study, all had Kellgren-Lawrence grade 3 knee OA, which was also graded as 3 or 4 on the International Cartilage Regeneration & Joint Preservation Society scale. Major lesions had be 6 cm2 or smaller. Active treatment was given to 78 patients, and 81 received placebo. The primary assessment period was at 12 months, but patients continued to be followed out to 5 years.
At OARSI 2018, Dr. Lee presented the findings of 12-month structural modification analyses for the first time. These showed that while the osteophyte score on MRI was not significantly different from baseline in the active-treatment arm, there was a significantly increased osteophyte score and total cartilage defect in the placebo-treated patients versus baseline values.
Subchondral bone changes at 12 months showed a trend for less bone area change with TissueGene-C than placebo and a trend for increased cartilage thickness. Greater reductions in serum CTX-1 and urine CTX-II were seen with active treatment than placebo, relative to screening values.
X-ray evaluation of joint-space narrowing showed that nonprogression was more likely in patients treated with TissueGene-C than with placebo (77% vs. 57%), although this was not significant. In addition, fewer patients treated with TissueGene-C than placebo who needed a total knee replacement at 2 years (0% and 7.5%) and at 3 years (2% and 14%).
TissueGene-C “has great potential” for being the first disease-modifying osteoarthritis drug to get to market, Dr. Lee suggested.
The clinical development program for TissueGene-C is further advanced in Korea than in the United States, where a phase 3 trial is about to start recruitment soon.
“We started our clinical trials in 2005 in Korea and in the U.S. simultaneously,” Dr. Lee said, noting that a biologics license application submitted in Korea in 2016 had been accepted by the Ministry of Food and Drug Safety on July 12, 2017, while only phase 1 and 2 trials have been completed in the United States
The study was funded by Kolon Life Science and TissueGene. Dr. Lee is an employee of TissueGene.
SOURCE: Lee B et al. Osteoarthritis Cartilage. 2018 Apr;26(1):S43-4.
REPORTING FROM OARSI 2018
Key clinical point: A single intra-articular injection of TissueGene C produced significant and long-term relief of knee osteoarthritis.
Major finding: Changes in baseline International Knee Documentation Committee and visual analog scale pain scores from baseline to 2 and 3 years were 15.3 and 14.8 points (P less than .05), and –23.5 and –23.3 (P less than .05), respectively.
Study details: A multicenter, phase 3, randomized, double-blind, placebo-controlled trial of 163 patients with knee osteoarthritis.
Disclosures: The study was funded by Kolon Life Science and TissueGene. Dr. Lee is an employee of TissueGene.
Source: Lee B et al. Osteoarthritis Cartilage. 2018 Apr;26(1):S43-4.