Becky McCall

BARCELONA – It is a long held and substantiated belief that osteoarthritis is a biomechanical disease, but evidence is accumulating to support an inflammatory cause. As testament to the strength of both possible causes of the disease, the vote after the World Congress on Osteoarthritis debate, titled "Is OA a mechanical disease or an inflammatory disease?" resulted in a swing from approximately 70/30 in favor of a biomechanical explanation, to 50/50.

Dr. David T. Felson, professor of medicine and public health, and principal investigator of the NIH-funded Boston University Multipurpose Arthritis and Musculoskeletal Diseases Center, argued in favor of OA as a disease of mechanics.

In opposition, Dr. Francis Berenbaum, head of the department of rheumatology, Saint-Antoine Hospital, Paris, advanced his case for OA as an inflammatory disease.

Dr. Felson went first, noting that "OA is caused by increased physical forces across a local area of a joint. This is either from abnormal anatomy leading to increased stress with normal load, or excess overall load such as with obesity, or a combination of the two."

The animal models of OA almost all have relied on joint injury and major injury to knees such as meniscal tears, which would support a biomechanical origin for OA. "But diseases are often [the result of] the interplay between different causes," he conceded.

Meniscal tears account for 40%-50% of knee OA, Dr. Felson said, adding: "Multiple studies show surgery to remove tears increases focal stress on the cartilage and causes a high rate of subsequent OA."

Dr. Felson’s argument for abnormal stress as being the cause of OA was further supported when he pointed out that congenital dysplasia increases focal load and markedly increases risk of hip OA at a young age. He also listed various occupations and related sites of OA: for example, cotton workers’ fingers; farmers’ hips and knees; and miners’ knees and spines.

The second major tenet of Dr. Felson’s talk centered on the fact that once OA had developed, pathomechanics overwhelmed all other factors. He described the vicious cycle of joint damage caused by a misaligned knee. "Increased focal stress across one area causes cartilage debris and bone damage." Dr. Felson noted that the inflammation seen in OA is caused by absorption of debris by the synovium, which precipitated more cartilage damage and worsened misalignment.

Dr. Felson supported his point about the role of misalignment worsening OA with data from the Multicenter Osteoarthritis Study (MOST) (Ann. Rheum. Dis. 2012 May 1 [doi: 10.1136/annrheumdis-2011-201070]), which found that 82% of knees with OA had misalignment. Furthermore, he said, "I would contend to you that the genetics of OA is probably predominantly related to abnormally shaped joints. Only 5% of OA is associated with systemic genetics."

Finally, conceding that inflammation was a feature of OA but not a primary cause, Dr. Felson explained its role in the disease. "Inflammation in OA is mostly a consequence of pathomechanics, that is meniscal tears and [anterior cruciate ligament] tears that lead to cytokine release in the synovium and induces joint damage."

If the injury was severe or there were multiple injuries then there was no requirement for inflammatory cytokine release because OA could occur without it, Dr. Felson concluded.

During his presentation, Dr. Berenbaum quoted some renowned names in the field of OA research, and linked them to papers on inflammatory causes of OA. He joked that in light of these papers, his job was nearly done; however he then began to build his expert case for OA as an inflammatory disease.

Approaching the first pillar of his argument from a clinical standpoint, Dr. Berenbaum described the existence of flares in OA that sometimes resembled other inflammatory arthritis. "There’s pain at night, morning stiffness, and swelling."

Focusing on both the macroscopic and histological levels, Dr. Berenbaum added that OA showed evidence of synovitis, featuring different levels of inflammation. "It is a patchy synovitis rather than pannus as in [rheumatoid arthritis], but the degree of inflammation has been shown to be correlated to prognosis, which is more severe when a high degree of synovitis is present," he commented.

This synovitis has been well characterized using MRI and ultrasound, according to Dr. Berenbaum. He addressed the evidence on a tissue and cellular level, by saying that inflammatory and immunologic cells have been seen in the OA synovium. "T-cells, B-cells, and macrophages, which play a role in cartilage degradation, have been shown in a murine experimental model. If macrophages are removed from the synovium in collagenase-induced OA, the cartilage is protected from degradation," explained Dr. Berenbaum.

Inflammatory mediators play critical roles in the three most characterized phenotypes, that is, in posttrauma OA, metabolic OA and aging, he continued.

All joint tissue including subchondral bone cells, synovial cells, and chondrocytes were able to produce inflammatory cytokines, according to Dr. Berenbaum. "Moreover, nonphysiologic mechanical stress applied on cartilage or subchondral bone induces the release of inflammatory mediators by chondrocytes, or osteoblasts and osteocytes via mechanoreceptors present at the surface of these cells."

"So mechanical stress is a cytokine," he stated.

Findings from experimental models of posttrauma OA provide "...evidence that complement pathways and innate immunity are involved in the OA process."

Adipokines or cytokines produced by the adipose tissue may play a role in OA, he suggested. Hand OA is twice as common in obese patients as in those of normal weight, meaning that systemic mediators may act on joints in obesity, Dr. Berenbaum said.

Courtesy Dr. Francis Berenbaum

To reinforce his point that inflammatory causes rather than mechanical were to blame, Dr. Berenbaum quipped, "I don’t see many obese patients walking on their hands."

Dr. Berenbaum then drew further rationale for his case by describing the features and functions of a particular type of chondrocyte. "The secretory phenotype of a chondrocyte is a well known characteristic of chondrocyte senescence and leads to overexpression of several inflammatory mediators by these cells."

"This means that when exposed to the same level of stress as a younger cell, aging cells produce more cytokines," he explained.

Finally, Dr. Berenbaum described findings supporting the likelihood that there is a systemic effect of low-grade inflammation induced by OA. He discussed a recent paper showing that in a murine model of Alzheimer’s, disease could be accelerated by the presence of OA in multiple joints through the release of the inflammatory mediator interleukin-6 in the blood.

He added that support for this hypothesis was found in publications of studies showing an increase in cytokine production in the blood of patients with OA.

In conclusion, he agreed that in the case of trauma, inflammation was secondary, "but other phenotypes exist which provide signals that inflammation can actually drive OA," he said.

Audience member Dr. Marc Hochberg, professor of medicine, epidemiology, and preventive medicine, and head of the division of rheumatology and clinical immunology, University of Maryland, Baltimore, asked the presenters if their beliefs about biomechanical and inflammatory drivers explained the sex differences seen in OA.

Dr. Felson replied: "I think women’s joints are anatomically smaller and we haven’t seen much study on size of joint relative to size of person and whether stress is greater in relatively smaller joints. But certainly women are weaker than men and weakness is predisposing to disease. They also have greater dynamic laxity in their joints than men which might predispose them to more mechanical injury than men."

An audience member from Copenhagen highlighted the conundrum of treating OA with pain relief when pain relief actually led to increased mechanical loading. "This is one of the reasons why finding treatments in OA has been so difficult," answered Dr. Felson. "If we treat successfully by diminishing pain we face the increased risk of more loading and then more damage and acceleration of the OA. This might be the explanation for the tanezumab story, in that pain is beautifully ablated only to have some patients go on to have rapid joint destruction."

He added that he thought this was an argument in favor of biomechanical therapies that aimed to address the underlying etiology. "This would enable loading that is healthier to the joint and to promote more levels of activity."

The congress was sponsored by Osteoarthritis Research Society International.

BARCELONA – It is a long held and substantiated belief that osteoarthritis is a biomechanical disease, but evidence is accumulating to support an inflammatory cause. As testament to the strength of both possible causes of the disease, the vote after the World Congress on Osteoarthritis debate, titled "Is OA a mechanical disease or an inflammatory disease?" resulted in a swing from approximately 70/30 in favor of a biomechanical explanation, to 50/50.

Dr. David T. Felson, professor of medicine and public health, and principal investigator of the NIH-funded Boston University Multipurpose Arthritis and Musculoskeletal Diseases Center, argued in favor of OA as a disease of mechanics.

In opposition, Dr. Francis Berenbaum, head of the department of rheumatology, Saint-Antoine Hospital, Paris, advanced his case for OA as an inflammatory disease.

Dr. Felson went first, noting that "OA is caused by increased physical forces across a local area of a joint. This is either from abnormal anatomy leading to increased stress with normal load, or excess overall load such as with obesity, or a combination of the two."

The animal models of OA almost all have relied on joint injury and major injury to knees such as meniscal tears, which would support a biomechanical origin for OA. "But diseases are often [the result of] the interplay between different causes," he conceded.

Meniscal tears account for 40%-50% of knee OA, Dr. Felson said, adding: "Multiple studies show surgery to remove tears increases focal stress on the cartilage and causes a high rate of subsequent OA."

Dr. Felson’s argument for abnormal stress as being the cause of OA was further supported when he pointed out that congenital dysplasia increases focal load and markedly increases risk of hip OA at a young age. He also listed various occupations and related sites of OA: for example, cotton workers’ fingers; farmers’ hips and knees; and miners’ knees and spines.

The second major tenet of Dr. Felson’s talk centered on the fact that once OA had developed, pathomechanics overwhelmed all other factors. He described the vicious cycle of joint damage caused by a misaligned knee. "Increased focal stress across one area causes cartilage debris and bone damage." Dr. Felson noted that the inflammation seen in OA is caused by absorption of debris by the synovium, which precipitated more cartilage damage and worsened misalignment.

Dr. Felson supported his point about the role of misalignment worsening OA with data from the Multicenter Osteoarthritis Study (MOST) (Ann. Rheum. Dis. 2012 May 1 [doi: 10.1136/annrheumdis-2011-201070]), which found that 82% of knees with OA had misalignment. Furthermore, he said, "I would contend to you that the genetics of OA is probably predominantly related to abnormally shaped joints. Only 5% of OA is associated with systemic genetics."

Finally, conceding that inflammation was a feature of OA but not a primary cause, Dr. Felson explained its role in the disease. "Inflammation in OA is mostly a consequence of pathomechanics, that is meniscal tears and [anterior cruciate ligament] tears that lead to cytokine release in the synovium and induces joint damage."

If the injury was severe or there were multiple injuries then there was no requirement for inflammatory cytokine release because OA could occur without it, Dr. Felson concluded.

During his presentation, Dr. Berenbaum quoted some renowned names in the field of OA research, and linked them to papers on inflammatory causes of OA. He joked that in light of these papers, his job was nearly done; however he then began to build his expert case for OA as an inflammatory disease.

Approaching the first pillar of his argument from a clinical standpoint, Dr. Berenbaum described the existence of flares in OA that sometimes resembled other inflammatory arthritis. "There’s pain at night, morning stiffness, and swelling."

Focusing on both the macroscopic and histological levels, Dr. Berenbaum added that OA showed evidence of synovitis, featuring different levels of inflammation. "It is a patchy synovitis rather than pannus as in [rheumatoid arthritis], but the degree of inflammation has been shown to be correlated to prognosis, which is more severe when a high degree of synovitis is present," he commented.

This synovitis has been well characterized using MRI and ultrasound, according to Dr. Berenbaum. He addressed the evidence on a tissue and cellular level, by saying that inflammatory and immunologic cells have been seen in the OA synovium. "T-cells, B-cells, and macrophages, which play a role in cartilage degradation, have been shown in a murine experimental model. If macrophages are removed from the synovium in collagenase-induced OA, the cartilage is protected from degradation," explained Dr. Berenbaum.

Inflammatory mediators play critical roles in the three most characterized phenotypes, that is, in posttrauma OA, metabolic OA and aging, he continued.

All joint tissue including subchondral bone cells, synovial cells, and chondrocytes were able to produce inflammatory cytokines, according to Dr. Berenbaum. "Moreover, nonphysiologic mechanical stress applied on cartilage or subchondral bone induces the release of inflammatory mediators by chondrocytes, or osteoblasts and osteocytes via mechanoreceptors present at the surface of these cells."

"So mechanical stress is a cytokine," he stated.

Findings from experimental models of posttrauma OA provide "...evidence that complement pathways and innate immunity are involved in the OA process."

Adipokines or cytokines produced by the adipose tissue may play a role in OA, he suggested. Hand OA is twice as common in obese patients as in those of normal weight, meaning that systemic mediators may act on joints in obesity, Dr. Berenbaum said.

Courtesy Dr. Francis Berenbaum

To reinforce his point that inflammatory causes rather than mechanical were to blame, Dr. Berenbaum quipped, "I don’t see many obese patients walking on their hands."

Dr. Berenbaum then drew further rationale for his case by describing the features and functions of a particular type of chondrocyte. "The secretory phenotype of a chondrocyte is a well known characteristic of chondrocyte senescence and leads to overexpression of several inflammatory mediators by these cells."

"This means that when exposed to the same level of stress as a younger cell, aging cells produce more cytokines," he explained.

Finally, Dr. Berenbaum described findings supporting the likelihood that there is a systemic effect of low-grade inflammation induced by OA. He discussed a recent paper showing that in a murine model of Alzheimer’s, disease could be accelerated by the presence of OA in multiple joints through the release of the inflammatory mediator interleukin-6 in the blood.

He added that support for this hypothesis was found in publications of studies showing an increase in cytokine production in the blood of patients with OA.

In conclusion, he agreed that in the case of trauma, inflammation was secondary, "but other phenotypes exist which provide signals that inflammation can actually drive OA," he said.

Audience member Dr. Marc Hochberg, professor of medicine, epidemiology, and preventive medicine, and head of the division of rheumatology and clinical immunology, University of Maryland, Baltimore, asked the presenters if their beliefs about biomechanical and inflammatory drivers explained the sex differences seen in OA.

Dr. Felson replied: "I think women’s joints are anatomically smaller and we haven’t seen much study on size of joint relative to size of person and whether stress is greater in relatively smaller joints. But certainly women are weaker than men and weakness is predisposing to disease. They also have greater dynamic laxity in their joints than men which might predispose them to more mechanical injury than men."

An audience member from Copenhagen highlighted the conundrum of treating OA with pain relief when pain relief actually led to increased mechanical loading. "This is one of the reasons why finding treatments in OA has been so difficult," answered Dr. Felson. "If we treat successfully by diminishing pain we face the increased risk of more loading and then more damage and acceleration of the OA. This might be the explanation for the tanezumab story, in that pain is beautifully ablated only to have some patients go on to have rapid joint destruction."

He added that he thought this was an argument in favor of biomechanical therapies that aimed to address the underlying etiology. "This would enable loading that is healthier to the joint and to promote more levels of activity."

The congress was sponsored by Osteoarthritis Research Society International.

BARCELONA – It is a long held and substantiated belief that osteoarthritis is a biomechanical disease, but evidence is accumulating to support an inflammatory cause. As testament to the strength of both possible causes of the disease, the vote after the World Congress on Osteoarthritis debate, titled "Is OA a mechanical disease or an inflammatory disease?" resulted in a swing from approximately 70/30 in favor of a biomechanical explanation, to 50/50.

Dr. David T. Felson, professor of medicine and public health, and principal investigator of the NIH-funded Boston University Multipurpose Arthritis and Musculoskeletal Diseases Center, argued in favor of OA as a disease of mechanics.

In opposition, Dr. Francis Berenbaum, head of the department of rheumatology, Saint-Antoine Hospital, Paris, advanced his case for OA as an inflammatory disease.

Dr. Felson went first, noting that "OA is caused by increased physical forces across a local area of a joint. This is either from abnormal anatomy leading to increased stress with normal load, or excess overall load such as with obesity, or a combination of the two."

The animal models of OA almost all have relied on joint injury and major injury to knees such as meniscal tears, which would support a biomechanical origin for OA. "But diseases are often [the result of] the interplay between different causes," he conceded.

Meniscal tears account for 40%-50% of knee OA, Dr. Felson said, adding: "Multiple studies show surgery to remove tears increases focal stress on the cartilage and causes a high rate of subsequent OA."

Dr. Felson’s argument for abnormal stress as being the cause of OA was further supported when he pointed out that congenital dysplasia increases focal load and markedly increases risk of hip OA at a young age. He also listed various occupations and related sites of OA: for example, cotton workers’ fingers; farmers’ hips and knees; and miners’ knees and spines.

The second major tenet of Dr. Felson’s talk centered on the fact that once OA had developed, pathomechanics overwhelmed all other factors. He described the vicious cycle of joint damage caused by a misaligned knee. "Increased focal stress across one area causes cartilage debris and bone damage." Dr. Felson noted that the inflammation seen in OA is caused by absorption of debris by the synovium, which precipitated more cartilage damage and worsened misalignment.

Dr. Felson supported his point about the role of misalignment worsening OA with data from the Multicenter Osteoarthritis Study (MOST) (Ann. Rheum. Dis. 2012 May 1 [doi: 10.1136/annrheumdis-2011-201070]), which found that 82% of knees with OA had misalignment. Furthermore, he said, "I would contend to you that the genetics of OA is probably predominantly related to abnormally shaped joints. Only 5% of OA is associated with systemic genetics."

Finally, conceding that inflammation was a feature of OA but not a primary cause, Dr. Felson explained its role in the disease. "Inflammation in OA is mostly a consequence of pathomechanics, that is meniscal tears and [anterior cruciate ligament] tears that lead to cytokine release in the synovium and induces joint damage."

If the injury was severe or there were multiple injuries then there was no requirement for inflammatory cytokine release because OA could occur without it, Dr. Felson concluded.

During his presentation, Dr. Berenbaum quoted some renowned names in the field of OA research, and linked them to papers on inflammatory causes of OA. He joked that in light of these papers, his job was nearly done; however he then began to build his expert case for OA as an inflammatory disease.

Approaching the first pillar of his argument from a clinical standpoint, Dr. Berenbaum described the existence of flares in OA that sometimes resembled other inflammatory arthritis. "There’s pain at night, morning stiffness, and swelling."

Focusing on both the macroscopic and histological levels, Dr. Berenbaum added that OA showed evidence of synovitis, featuring different levels of inflammation. "It is a patchy synovitis rather than pannus as in [rheumatoid arthritis], but the degree of inflammation has been shown to be correlated to prognosis, which is more severe when a high degree of synovitis is present," he commented.

This synovitis has been well characterized using MRI and ultrasound, according to Dr. Berenbaum. He addressed the evidence on a tissue and cellular level, by saying that inflammatory and immunologic cells have been seen in the OA synovium. "T-cells, B-cells, and macrophages, which play a role in cartilage degradation, have been shown in a murine experimental model. If macrophages are removed from the synovium in collagenase-induced OA, the cartilage is protected from degradation," explained Dr. Berenbaum.

Inflammatory mediators play critical roles in the three most characterized phenotypes, that is, in posttrauma OA, metabolic OA and aging, he continued.

All joint tissue including subchondral bone cells, synovial cells, and chondrocytes were able to produce inflammatory cytokines, according to Dr. Berenbaum. "Moreover, nonphysiologic mechanical stress applied on cartilage or subchondral bone induces the release of inflammatory mediators by chondrocytes, or osteoblasts and osteocytes via mechanoreceptors present at the surface of these cells."

"So mechanical stress is a cytokine," he stated.

Findings from experimental models of posttrauma OA provide "...evidence that complement pathways and innate immunity are involved in the OA process."

Adipokines or cytokines produced by the adipose tissue may play a role in OA, he suggested. Hand OA is twice as common in obese patients as in those of normal weight, meaning that systemic mediators may act on joints in obesity, Dr. Berenbaum said.

Courtesy Dr. Francis Berenbaum

To reinforce his point that inflammatory causes rather than mechanical were to blame, Dr. Berenbaum quipped, "I don’t see many obese patients walking on their hands."

Dr. Berenbaum then drew further rationale for his case by describing the features and functions of a particular type of chondrocyte. "The secretory phenotype of a chondrocyte is a well known characteristic of chondrocyte senescence and leads to overexpression of several inflammatory mediators by these cells."

"This means that when exposed to the same level of stress as a younger cell, aging cells produce more cytokines," he explained.

Finally, Dr. Berenbaum described findings supporting the likelihood that there is a systemic effect of low-grade inflammation induced by OA. He discussed a recent paper showing that in a murine model of Alzheimer’s, disease could be accelerated by the presence of OA in multiple joints through the release of the inflammatory mediator interleukin-6 in the blood.

He added that support for this hypothesis was found in publications of studies showing an increase in cytokine production in the blood of patients with OA.

In conclusion, he agreed that in the case of trauma, inflammation was secondary, "but other phenotypes exist which provide signals that inflammation can actually drive OA," he said.

Audience member Dr. Marc Hochberg, professor of medicine, epidemiology, and preventive medicine, and head of the division of rheumatology and clinical immunology, University of Maryland, Baltimore, asked the presenters if their beliefs about biomechanical and inflammatory drivers explained the sex differences seen in OA.

Dr. Felson replied: "I think women’s joints are anatomically smaller and we haven’t seen much study on size of joint relative to size of person and whether stress is greater in relatively smaller joints. But certainly women are weaker than men and weakness is predisposing to disease. They also have greater dynamic laxity in their joints than men which might predispose them to more mechanical injury than men."

An audience member from Copenhagen highlighted the conundrum of treating OA with pain relief when pain relief actually led to increased mechanical loading. "This is one of the reasons why finding treatments in OA has been so difficult," answered Dr. Felson. "If we treat successfully by diminishing pain we face the increased risk of more loading and then more damage and acceleration of the OA. This might be the explanation for the tanezumab story, in that pain is beautifully ablated only to have some patients go on to have rapid joint destruction."

He added that he thought this was an argument in favor of biomechanical therapies that aimed to address the underlying etiology. "This would enable loading that is healthier to the joint and to promote more levels of activity."

The congress was sponsored by Osteoarthritis Research Society International.

BARCELONA – People with knee and hip osteoarthritis tend to overstate their walking disability, but timed walking tests provide an accurate assessment of their lameness, according to a new study.

Dr. Luke Brunton, orthopedic surgeon and researcher at the musculoskeletal research unit at the University of Bristol (England), and his colleagues wanted to find out whether patient self-reports of walking could be used to accurately represent their walking ability. "We found a very poor correlation between self-reports and objective tests," said Dr. Brunton at the World Congress on Osteoarthritis.

He added that "the observers found that patients were performing much more easily than they reported. There was a much better correlation between the observers’ reports and the tests than the patient’s self-reported walking ability."

According to Dr. Brunton, walking impairment in patients with hip and knee OA was particularly important because it was part of the reason for patients’ reduced life span, is linked to social isolation, and has been associated with dementia.

"Questions on walking are very often used to assess function, quality of life, and disability in people with OA. People are commonly asked to self-report on either walking restrictions or distance limitations, however, simply asking patients may not give the whole picture," said Dr. Brunton.

The researchers looked at the correlations between self-reported walking ability and functional tests, and observers’ assessments and the same functional tests of walking ability.

Data from a large U.K. community based cohort study known as the South West and Avon Survey of Health (SASH) cohort were used including demographic and disease-related data.

Self-assessment questions were taken from the commonly used Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Lequesne assessment. WOMAC asked, ‘What degree of difficulty have you experienced walking on flat ground in the last week due to your hips or knees?’ while Lequesne asked, "What is the maximum distance you can walk with pain?"

The study involved 806 participants with a mean age of 68 years and body mass index of 28.6 kg/m². They were asked to carry out a timed 6-meter walking test and a "get up and go" test. The latter test times how long patients take to stand up from a sitting position, walk 3 meters, turn around, and sit down again.

In particular, research observers looked at whether patients had any difficulties walking and how far they said they could walk. They correlated these findings with the 6-meter walk and the "get-up and go" test results, and compared this to the correlation between patient self-reports and the same objective tests.

"We tell the observers it doesn’t matter how long the person is taking. The important thing is how easy it is for the patient to complete the test or not," explained Dr. Brunton.

A stronger association was found between observer evaluation of walking ability and the timed walk (ANOVA r2 = 0.58; P less than .001) and "get up and go" tests (ANOVA r2= 0.56; P less than .001), than patient self-reports (SF-36; ANOVA r2 = 0.23; P less than .001 and Lequesne ANOVA r2 = 0.27; P less than .001) with the objective tests. ANOVA r2 is a measure of the statistical correlation between the two variables

"It is notable that the observers were watching the patients actually carry out a test whereas patients were asked generally how well they walked," he continued, admitting it was a very different scenario being assessed. "But if you are only asking patients one question on walking you are assuming that their self-assessment and their functional test should be very similar. We have showed this isn’t the case."

The data showed most people did the test with similar times how they rated their own walking ability.

"You can’t just take a questionnaire but you may need to undertake a functional assessment too. Most clinicians would assess patients themselves rather than relying solely on questionnaires. For research, I think we also need a combination of the two methods," he said.

Dr. Brunton has reported no relevant financial disclosures. The meeting was sponsored by the Osteoarthritis Research Society International.

BARCELONA – People with knee and hip osteoarthritis tend to overstate their walking disability, but timed walking tests provide an accurate assessment of their lameness, according to a new study.

Dr. Luke Brunton, orthopedic surgeon and researcher at the musculoskeletal research unit at the University of Bristol (England), and his colleagues wanted to find out whether patient self-reports of walking could be used to accurately represent their walking ability. "We found a very poor correlation between self-reports and objective tests," said Dr. Brunton at the World Congress on Osteoarthritis.

He added that "the observers found that patients were performing much more easily than they reported. There was a much better correlation between the observers’ reports and the tests than the patient’s self-reported walking ability."

According to Dr. Brunton, walking impairment in patients with hip and knee OA was particularly important because it was part of the reason for patients’ reduced life span, is linked to social isolation, and has been associated with dementia.

"Questions on walking are very often used to assess function, quality of life, and disability in people with OA. People are commonly asked to self-report on either walking restrictions or distance limitations, however, simply asking patients may not give the whole picture," said Dr. Brunton.

The researchers looked at the correlations between self-reported walking ability and functional tests, and observers’ assessments and the same functional tests of walking ability.

Data from a large U.K. community based cohort study known as the South West and Avon Survey of Health (SASH) cohort were used including demographic and disease-related data.

Self-assessment questions were taken from the commonly used Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Lequesne assessment. WOMAC asked, ‘What degree of difficulty have you experienced walking on flat ground in the last week due to your hips or knees?’ while Lequesne asked, "What is the maximum distance you can walk with pain?"

The study involved 806 participants with a mean age of 68 years and body mass index of 28.6 kg/m². They were asked to carry out a timed 6-meter walking test and a "get up and go" test. The latter test times how long patients take to stand up from a sitting position, walk 3 meters, turn around, and sit down again.

In particular, research observers looked at whether patients had any difficulties walking and how far they said they could walk. They correlated these findings with the 6-meter walk and the "get-up and go" test results, and compared this to the correlation between patient self-reports and the same objective tests.

"We tell the observers it doesn’t matter how long the person is taking. The important thing is how easy it is for the patient to complete the test or not," explained Dr. Brunton.

A stronger association was found between observer evaluation of walking ability and the timed walk (ANOVA r2 = 0.58; P less than .001) and "get up and go" tests (ANOVA r2= 0.56; P less than .001), than patient self-reports (SF-36; ANOVA r2 = 0.23; P less than .001 and Lequesne ANOVA r2 = 0.27; P less than .001) with the objective tests. ANOVA r2 is a measure of the statistical correlation between the two variables

"It is notable that the observers were watching the patients actually carry out a test whereas patients were asked generally how well they walked," he continued, admitting it was a very different scenario being assessed. "But if you are only asking patients one question on walking you are assuming that their self-assessment and their functional test should be very similar. We have showed this isn’t the case."

The data showed most people did the test with similar times how they rated their own walking ability.

"You can’t just take a questionnaire but you may need to undertake a functional assessment too. Most clinicians would assess patients themselves rather than relying solely on questionnaires. For research, I think we also need a combination of the two methods," he said.

Dr. Brunton has reported no relevant financial disclosures. The meeting was sponsored by the Osteoarthritis Research Society International.

BARCELONA – People with knee and hip osteoarthritis tend to overstate their walking disability, but timed walking tests provide an accurate assessment of their lameness, according to a new study.

Dr. Luke Brunton, orthopedic surgeon and researcher at the musculoskeletal research unit at the University of Bristol (England), and his colleagues wanted to find out whether patient self-reports of walking could be used to accurately represent their walking ability. "We found a very poor correlation between self-reports and objective tests," said Dr. Brunton at the World Congress on Osteoarthritis.

He added that "the observers found that patients were performing much more easily than they reported. There was a much better correlation between the observers’ reports and the tests than the patient’s self-reported walking ability."

According to Dr. Brunton, walking impairment in patients with hip and knee OA was particularly important because it was part of the reason for patients’ reduced life span, is linked to social isolation, and has been associated with dementia.

"Questions on walking are very often used to assess function, quality of life, and disability in people with OA. People are commonly asked to self-report on either walking restrictions or distance limitations, however, simply asking patients may not give the whole picture," said Dr. Brunton.

The researchers looked at the correlations between self-reported walking ability and functional tests, and observers’ assessments and the same functional tests of walking ability.

Data from a large U.K. community based cohort study known as the South West and Avon Survey of Health (SASH) cohort were used including demographic and disease-related data.

Self-assessment questions were taken from the commonly used Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Lequesne assessment. WOMAC asked, ‘What degree of difficulty have you experienced walking on flat ground in the last week due to your hips or knees?’ while Lequesne asked, "What is the maximum distance you can walk with pain?"

The study involved 806 participants with a mean age of 68 years and body mass index of 28.6 kg/m². They were asked to carry out a timed 6-meter walking test and a "get up and go" test. The latter test times how long patients take to stand up from a sitting position, walk 3 meters, turn around, and sit down again.

In particular, research observers looked at whether patients had any difficulties walking and how far they said they could walk. They correlated these findings with the 6-meter walk and the "get-up and go" test results, and compared this to the correlation between patient self-reports and the same objective tests.

"We tell the observers it doesn’t matter how long the person is taking. The important thing is how easy it is for the patient to complete the test or not," explained Dr. Brunton.

A stronger association was found between observer evaluation of walking ability and the timed walk (ANOVA r2 = 0.58; P less than .001) and "get up and go" tests (ANOVA r2= 0.56; P less than .001), than patient self-reports (SF-36; ANOVA r2 = 0.23; P less than .001 and Lequesne ANOVA r2 = 0.27; P less than .001) with the objective tests. ANOVA r2 is a measure of the statistical correlation between the two variables

"It is notable that the observers were watching the patients actually carry out a test whereas patients were asked generally how well they walked," he continued, admitting it was a very different scenario being assessed. "But if you are only asking patients one question on walking you are assuming that their self-assessment and their functional test should be very similar. We have showed this isn’t the case."

The data showed most people did the test with similar times how they rated their own walking ability.

"You can’t just take a questionnaire but you may need to undertake a functional assessment too. Most clinicians would assess patients themselves rather than relying solely on questionnaires. For research, I think we also need a combination of the two methods," he said.

Dr. Brunton has reported no relevant financial disclosures. The meeting was sponsored by the Osteoarthritis Research Society International.

BARCELONA – Dramatic weight loss favorably alters mechanical and inflammatory mechanisms that are part of the osteoarthritis disease pathway, according to 18-month findings from a prospective, single-line randomized controlled trial.

Weight loss appears to reduce knee joint compressive loads and the inflammatory markers interleukin-6 (IL-6) and leptin, explained Stephen P. Messier, Ph.D., at the World Congress on Osteoarthritis.

Exercise also plays a role, he stressed. In fact, "the pain data suggest the combination of diet and exercise is the best," because weight loss offsets the slight increase in joint loads and inflammation that is seen with exercise only. The combination packs a one-two punch: Weight loss impacts the mechanisms of OA, while the combination of diet and exercise impacts the clinical aspects of OA.

Dr. Messier, director of the J.B. Snow Biomechanics Laboratory at Wake Forest University, Winston-Salem, N.C., and his colleagues have been looking at the effects of different types of exercise for 20 years. The culmination of this work has resulted in exercise becoming the standard of care in knee OA. "We no longer expect people with knee OA to sit around and do nothing because it hurts. It actually hurts more if they don’t do anything and less if they do," he said

But because many people with OA are obese, Dr. Messier and his colleagues were spurred to investigate the effects of a combination of exercise and weight loss.

They initially carried out investigations with the aim of a 5% weight-loss target, and found clinically significant differences in the patients who followed the diet and exercise program.

But Dr. Messier also found that the 5% weight loss was insufficient to make an impact on the mechanical and physiological pathways. "So we decided to double the weight-loss target to 10%, and we’ve found it has made a difference."

Dr. Messier pointed out that he chose an 18-month over a 6-month program because he wanted this to be a change in lifestyle and something the participants do for the rest of their lives.

Dr. Messier presented primary results from the Intensive Diet and Exercise for Arthritis (IDEA) trial, which involved 454 overweight and obese (body mass index, 27-40.5 kg/m²) adults over age 55 with tibiofemoral OA (Kellgren-Lawrence grade of 2-3). Participants were randomly assigned to three groups: intensive dietary restriction (minimum 1,200 calories for men and 1,100 calories for women), intensive dietary restriction and exercise, or exercise only. More than 85% of participants in each group adhered to their regimen for the full 18-month period.

Exercise involved low- to moderate-intensity walking and resistance training for 3 days per week at 1 hour per day. High-speed motion analysis and musculoskeletal modeling were used to assess biomechanics during exercise and to calculate knee joint loads. Fasting serum concentrations of inflammatory biomarkers also were measured. Results from the three groups were compared at baseline, and at 6 and 18 months combined.

The investigators also conducted a gait analysis with six cameras and a force platform. Participants walked across the platform, and "from this we can determine the loads on the joints," Dr. Messier explained.

Mean weight loss over the 18 months was highest in the diet and exercise group at 11%. For participants on diet alone the loss was 10%, and for exercise alone, 2%.

At the American College of Rheumatology (ACR) meeting in November 2011, the researchers had reported that all three groups reduced pain over the 18 months, with the diet and exercise group reducing pain by approximately 50%. At the study’s end, 4 of 10 (38%) participants in the diet and exercise group reported little or no pain, with pain scores of 0 or 1 on a scale of 0-20, compared with about 2 of 10 for the diet-only and exercise-only groups.

"If you can tell someone you can cut their pain in half without taking drugs, that’s good," he noted.

Walking speed changed in those on the diet and exercise program, showing an increase from 1.20 m/second to 1.34 m/second. Those on diet alone changed from 1.18 meters/second to 1.30 m/second.

Measures of interleukin-6 (IL-6), the primary outcome, decreased significantly in the diet-alone group, with a mean change of –0.43 pg/mL; in the diet and exercise group, the mean change was –0.36 pg/mL; and in the exercise-alone group, it was +0.04 pg/mL (P = .005). Leptin levels also were affected, with changes of –13, –14, and –3 ng/mL in the groups, respectively.

The primary mechanical outcome, knee compressive force, decreased by 174 newtons/step (39.1 pounds/step) in the diet-only group, and by 51 newtons/step (11.5 pounds/step) in the exercise and diet group. Knee compressive force increased by 154 newtons/step (34.6 pounds/step) in the exercise-only group.

The decreases in both mechanical load and inflammation are posited to be the two factors that result in the reduction in pain.

"We spend so much on knee replacements, if we just took some of that money and invested it in prevention it would prevent some of these operations. That’s where I’m going with my research. I want to know how I can relate this to the real world," Dr. Messier said.

Dr. Marcia U. Rezende from the department of orthopedics and trauma at the University of São Paulo (Brazil) General Hospital, said she would make one alteration to the intervention: "Since these patients had knee pain, why not think about cycling rather than walking? It has less force and slower motion, and it is the sort of aerobic exercise that might not increase inflammatory reaction as the walking did. So you would have the aerobic part, the strengthening program, and it would be as effective."

The congress was sponsored by Osteoarthritis Research Society International. The IDEA study was funded by the Department of Health and Human Services, the National Institutes of Health, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Messier reported having no relevant conflicts of interest.

BARCELONA – Dramatic weight loss favorably alters mechanical and inflammatory mechanisms that are part of the osteoarthritis disease pathway, according to 18-month findings from a prospective, single-line randomized controlled trial.

Weight loss appears to reduce knee joint compressive loads and the inflammatory markers interleukin-6 (IL-6) and leptin, explained Stephen P. Messier, Ph.D., at the World Congress on Osteoarthritis.

Exercise also plays a role, he stressed. In fact, "the pain data suggest the combination of diet and exercise is the best," because weight loss offsets the slight increase in joint loads and inflammation that is seen with exercise only. The combination packs a one-two punch: Weight loss impacts the mechanisms of OA, while the combination of diet and exercise impacts the clinical aspects of OA.

Dr. Messier, director of the J.B. Snow Biomechanics Laboratory at Wake Forest University, Winston-Salem, N.C., and his colleagues have been looking at the effects of different types of exercise for 20 years. The culmination of this work has resulted in exercise becoming the standard of care in knee OA. "We no longer expect people with knee OA to sit around and do nothing because it hurts. It actually hurts more if they don’t do anything and less if they do," he said

But because many people with OA are obese, Dr. Messier and his colleagues were spurred to investigate the effects of a combination of exercise and weight loss.

They initially carried out investigations with the aim of a 5% weight-loss target, and found clinically significant differences in the patients who followed the diet and exercise program.

But Dr. Messier also found that the 5% weight loss was insufficient to make an impact on the mechanical and physiological pathways. "So we decided to double the weight-loss target to 10%, and we’ve found it has made a difference."

Dr. Messier pointed out that he chose an 18-month over a 6-month program because he wanted this to be a change in lifestyle and something the participants do for the rest of their lives.

Dr. Messier presented primary results from the Intensive Diet and Exercise for Arthritis (IDEA) trial, which involved 454 overweight and obese (body mass index, 27-40.5 kg/m²) adults over age 55 with tibiofemoral OA (Kellgren-Lawrence grade of 2-3). Participants were randomly assigned to three groups: intensive dietary restriction (minimum 1,200 calories for men and 1,100 calories for women), intensive dietary restriction and exercise, or exercise only. More than 85% of participants in each group adhered to their regimen for the full 18-month period.

Exercise involved low- to moderate-intensity walking and resistance training for 3 days per week at 1 hour per day. High-speed motion analysis and musculoskeletal modeling were used to assess biomechanics during exercise and to calculate knee joint loads. Fasting serum concentrations of inflammatory biomarkers also were measured. Results from the three groups were compared at baseline, and at 6 and 18 months combined.

The investigators also conducted a gait analysis with six cameras and a force platform. Participants walked across the platform, and "from this we can determine the loads on the joints," Dr. Messier explained.

Mean weight loss over the 18 months was highest in the diet and exercise group at 11%. For participants on diet alone the loss was 10%, and for exercise alone, 2%.

At the American College of Rheumatology (ACR) meeting in November 2011, the researchers had reported that all three groups reduced pain over the 18 months, with the diet and exercise group reducing pain by approximately 50%. At the study’s end, 4 of 10 (38%) participants in the diet and exercise group reported little or no pain, with pain scores of 0 or 1 on a scale of 0-20, compared with about 2 of 10 for the diet-only and exercise-only groups.

"If you can tell someone you can cut their pain in half without taking drugs, that’s good," he noted.

Walking speed changed in those on the diet and exercise program, showing an increase from 1.20 m/second to 1.34 m/second. Those on diet alone changed from 1.18 meters/second to 1.30 m/second.

Measures of interleukin-6 (IL-6), the primary outcome, decreased significantly in the diet-alone group, with a mean change of –0.43 pg/mL; in the diet and exercise group, the mean change was –0.36 pg/mL; and in the exercise-alone group, it was +0.04 pg/mL (P = .005). Leptin levels also were affected, with changes of –13, –14, and –3 ng/mL in the groups, respectively.

The primary mechanical outcome, knee compressive force, decreased by 174 newtons/step (39.1 pounds/step) in the diet-only group, and by 51 newtons/step (11.5 pounds/step) in the exercise and diet group. Knee compressive force increased by 154 newtons/step (34.6 pounds/step) in the exercise-only group.

The decreases in both mechanical load and inflammation are posited to be the two factors that result in the reduction in pain.

"We spend so much on knee replacements, if we just took some of that money and invested it in prevention it would prevent some of these operations. That’s where I’m going with my research. I want to know how I can relate this to the real world," Dr. Messier said.

Dr. Marcia U. Rezende from the department of orthopedics and trauma at the University of São Paulo (Brazil) General Hospital, said she would make one alteration to the intervention: "Since these patients had knee pain, why not think about cycling rather than walking? It has less force and slower motion, and it is the sort of aerobic exercise that might not increase inflammatory reaction as the walking did. So you would have the aerobic part, the strengthening program, and it would be as effective."

The congress was sponsored by Osteoarthritis Research Society International. The IDEA study was funded by the Department of Health and Human Services, the National Institutes of Health, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Messier reported having no relevant conflicts of interest.

BARCELONA – Dramatic weight loss favorably alters mechanical and inflammatory mechanisms that are part of the osteoarthritis disease pathway, according to 18-month findings from a prospective, single-line randomized controlled trial.

Weight loss appears to reduce knee joint compressive loads and the inflammatory markers interleukin-6 (IL-6) and leptin, explained Stephen P. Messier, Ph.D., at the World Congress on Osteoarthritis.

Exercise also plays a role, he stressed. In fact, "the pain data suggest the combination of diet and exercise is the best," because weight loss offsets the slight increase in joint loads and inflammation that is seen with exercise only. The combination packs a one-two punch: Weight loss impacts the mechanisms of OA, while the combination of diet and exercise impacts the clinical aspects of OA.

Dr. Messier, director of the J.B. Snow Biomechanics Laboratory at Wake Forest University, Winston-Salem, N.C., and his colleagues have been looking at the effects of different types of exercise for 20 years. The culmination of this work has resulted in exercise becoming the standard of care in knee OA. "We no longer expect people with knee OA to sit around and do nothing because it hurts. It actually hurts more if they don’t do anything and less if they do," he said

But because many people with OA are obese, Dr. Messier and his colleagues were spurred to investigate the effects of a combination of exercise and weight loss.

They initially carried out investigations with the aim of a 5% weight-loss target, and found clinically significant differences in the patients who followed the diet and exercise program.

But Dr. Messier also found that the 5% weight loss was insufficient to make an impact on the mechanical and physiological pathways. "So we decided to double the weight-loss target to 10%, and we’ve found it has made a difference."

Dr. Messier pointed out that he chose an 18-month over a 6-month program because he wanted this to be a change in lifestyle and something the participants do for the rest of their lives.

Dr. Messier presented primary results from the Intensive Diet and Exercise for Arthritis (IDEA) trial, which involved 454 overweight and obese (body mass index, 27-40.5 kg/m²) adults over age 55 with tibiofemoral OA (Kellgren-Lawrence grade of 2-3). Participants were randomly assigned to three groups: intensive dietary restriction (minimum 1,200 calories for men and 1,100 calories for women), intensive dietary restriction and exercise, or exercise only. More than 85% of participants in each group adhered to their regimen for the full 18-month period.

Exercise involved low- to moderate-intensity walking and resistance training for 3 days per week at 1 hour per day. High-speed motion analysis and musculoskeletal modeling were used to assess biomechanics during exercise and to calculate knee joint loads. Fasting serum concentrations of inflammatory biomarkers also were measured. Results from the three groups were compared at baseline, and at 6 and 18 months combined.

The investigators also conducted a gait analysis with six cameras and a force platform. Participants walked across the platform, and "from this we can determine the loads on the joints," Dr. Messier explained.

Mean weight loss over the 18 months was highest in the diet and exercise group at 11%. For participants on diet alone the loss was 10%, and for exercise alone, 2%.

At the American College of Rheumatology (ACR) meeting in November 2011, the researchers had reported that all three groups reduced pain over the 18 months, with the diet and exercise group reducing pain by approximately 50%. At the study’s end, 4 of 10 (38%) participants in the diet and exercise group reported little or no pain, with pain scores of 0 or 1 on a scale of 0-20, compared with about 2 of 10 for the diet-only and exercise-only groups.

"If you can tell someone you can cut their pain in half without taking drugs, that’s good," he noted.

Walking speed changed in those on the diet and exercise program, showing an increase from 1.20 m/second to 1.34 m/second. Those on diet alone changed from 1.18 meters/second to 1.30 m/second.

Measures of interleukin-6 (IL-6), the primary outcome, decreased significantly in the diet-alone group, with a mean change of –0.43 pg/mL; in the diet and exercise group, the mean change was –0.36 pg/mL; and in the exercise-alone group, it was +0.04 pg/mL (P = .005). Leptin levels also were affected, with changes of –13, –14, and –3 ng/mL in the groups, respectively.

The primary mechanical outcome, knee compressive force, decreased by 174 newtons/step (39.1 pounds/step) in the diet-only group, and by 51 newtons/step (11.5 pounds/step) in the exercise and diet group. Knee compressive force increased by 154 newtons/step (34.6 pounds/step) in the exercise-only group.

The decreases in both mechanical load and inflammation are posited to be the two factors that result in the reduction in pain.

"We spend so much on knee replacements, if we just took some of that money and invested it in prevention it would prevent some of these operations. That’s where I’m going with my research. I want to know how I can relate this to the real world," Dr. Messier said.

Dr. Marcia U. Rezende from the department of orthopedics and trauma at the University of São Paulo (Brazil) General Hospital, said she would make one alteration to the intervention: "Since these patients had knee pain, why not think about cycling rather than walking? It has less force and slower motion, and it is the sort of aerobic exercise that might not increase inflammatory reaction as the walking did. So you would have the aerobic part, the strengthening program, and it would be as effective."

The congress was sponsored by Osteoarthritis Research Society International. The IDEA study was funded by the Department of Health and Human Services, the National Institutes of Health, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Messier reported having no relevant conflicts of interest.

BARCELONA – Overweight women who follow a 2.5-year diet and exercise program showed a significant reduction in incident knee osteoarthritis, judging from the findings of a new Dutch study.

Jos Runhaar, a research scientist from the department of general practice at Erasmus University Medical Center, Rotterdam, the Netherlands, presented findings from the first-ever preventive randomized controlled trial on osteoarthritis (OA) at the World Congress on Osteoarthritis.

The already high number of people with OA worldwide is set to rise further with the growing incidence of obesity and an aging population. "Associated financial costs will also rise substantially to reflect this," he said.

Mr. Runhaar pointed out that the research community was already well informed in terms of the course and burden of OA, definitions of disease status, progression, and risk factors but lacked evidence on prevention. "We felt it was time to take the next step and investigate prevention of the disease and associated medical costs in people at risk," he noted.

The Prevention of Knee Osteoarthritis in Overweight Females (PROOF) study aimed to evaluate the preventive effects of a weight-loss program and of oral glucosamine sulphate on incident knee OA. After selection for study criteria, 407 women from the Rotterdam area were randomized to study interventions or placebo. "We selected a high-risk group of women between 50 to 60 years of age, BMI [body mass index] of at least 27, and without any clinical or radiographic signs of knee OA at baseline," said Mr. Runhaar. Half of the knees had a Kellgren-Lawrence (K&L) grade 0 at baseline.

The study assessed the effectiveness of two interventions: a weight-reduction program and oral glucosamine sulphate (1,500 mg/day). At the meeting, Mr. Runhaar presented only the results of the weight-reduction intervention.

The trial involved 200 women who received the weight-reduction intervention and 200 who served as controls, and in both groups half received glucosamine and half placebo.

"It was a pragmatic intervention. It was intended to be a regimen that could be easily implemented in daily life," Mr. Runhaar explained.

The weight-reduction program involved a weekly group session that featured a variety of low-impact sports to re-encourage interest and enjoyment in physical activity, and aimed to maintain this over the long term. "Women were referred to a dietician to develop dietary targets and have motivational discussions," he added.

"The supportive sessions were important because these women generally had inactive lifestyles and poor nutritional habits that were difficult to change, especially by the age of 50-60 years," he said.

Three possible incidence measures were used to represent the primary outcome of incident knee OA after 2.5 years. Participants needed to have a knee OA incidence with a K&L grade of at least 2; incidence of clinical knee OA according to clinical and radiographic American College of Rheumatology criteria; or joint-space narrowing of at least 1.0 mm.

The researchers combined both radiographic and clinical outcomes to ensure they had enough data to provide meaningful results.

After 2.5 years, women who complied with the weight-reduction program showed a mean weight reduction of 1.4 ± 5.5 kg, compared with 0.1 ± 6.3 kg in controls.

Also after 2.5 years of intervention, the researchers saw an incidence of knee OA, adjusted for BMI and K&L grade at baseline, of 22% in all knees, which equated to 36% of all women with one or more knees affected. On an intention-to-treat basis, 25% of the controls had knee OA versus 19% in the weight-reduction group (odds ratio, 0.62; 95% confidence interval, 0.38-1.04). The per-protocol analysis showed a greater difference of 25% incidence of knee OA in the controls versus 10% in the intervention arm (OR, 0.28).

"In the per-protocol analysis, we see the effect of the intervention in women who actually complied with the program. They exercised and followed the diet. This is what happens if you stay with the program. The incidence rate over halved with a statistically significant odds ratio," Mr. Runhaar reported at the meeting, which was sponsored by the Osteoarthritis Research Society International.

When asked whether this program really had practical application, he said that only a quarter of women were compliant with the intervention. "It is really difficult to change the habits of these women. This is one possible way of doing it, but we need to look at other ways of getting these women active and on a diet. If we can achieve this, then we are likely to prevent more OA."

Mr. Runhaar reported no relevant financial disclosures.

BARCELONA – Overweight women who follow a 2.5-year diet and exercise program showed a significant reduction in incident knee osteoarthritis, judging from the findings of a new Dutch study.

Jos Runhaar, a research scientist from the department of general practice at Erasmus University Medical Center, Rotterdam, the Netherlands, presented findings from the first-ever preventive randomized controlled trial on osteoarthritis (OA) at the World Congress on Osteoarthritis.

The already high number of people with OA worldwide is set to rise further with the growing incidence of obesity and an aging population. "Associated financial costs will also rise substantially to reflect this," he said.

Mr. Runhaar pointed out that the research community was already well informed in terms of the course and burden of OA, definitions of disease status, progression, and risk factors but lacked evidence on prevention. "We felt it was time to take the next step and investigate prevention of the disease and associated medical costs in people at risk," he noted.

The Prevention of Knee Osteoarthritis in Overweight Females (PROOF) study aimed to evaluate the preventive effects of a weight-loss program and of oral glucosamine sulphate on incident knee OA. After selection for study criteria, 407 women from the Rotterdam area were randomized to study interventions or placebo. "We selected a high-risk group of women between 50 to 60 years of age, BMI [body mass index] of at least 27, and without any clinical or radiographic signs of knee OA at baseline," said Mr. Runhaar. Half of the knees had a Kellgren-Lawrence (K&L) grade 0 at baseline.

The study assessed the effectiveness of two interventions: a weight-reduction program and oral glucosamine sulphate (1,500 mg/day). At the meeting, Mr. Runhaar presented only the results of the weight-reduction intervention.

The trial involved 200 women who received the weight-reduction intervention and 200 who served as controls, and in both groups half received glucosamine and half placebo.

"It was a pragmatic intervention. It was intended to be a regimen that could be easily implemented in daily life," Mr. Runhaar explained.

The weight-reduction program involved a weekly group session that featured a variety of low-impact sports to re-encourage interest and enjoyment in physical activity, and aimed to maintain this over the long term. "Women were referred to a dietician to develop dietary targets and have motivational discussions," he added.

"The supportive sessions were important because these women generally had inactive lifestyles and poor nutritional habits that were difficult to change, especially by the age of 50-60 years," he said.

Three possible incidence measures were used to represent the primary outcome of incident knee OA after 2.5 years. Participants needed to have a knee OA incidence with a K&L grade of at least 2; incidence of clinical knee OA according to clinical and radiographic American College of Rheumatology criteria; or joint-space narrowing of at least 1.0 mm.

The researchers combined both radiographic and clinical outcomes to ensure they had enough data to provide meaningful results.

After 2.5 years, women who complied with the weight-reduction program showed a mean weight reduction of 1.4 ± 5.5 kg, compared with 0.1 ± 6.3 kg in controls.

Also after 2.5 years of intervention, the researchers saw an incidence of knee OA, adjusted for BMI and K&L grade at baseline, of 22% in all knees, which equated to 36% of all women with one or more knees affected. On an intention-to-treat basis, 25% of the controls had knee OA versus 19% in the weight-reduction group (odds ratio, 0.62; 95% confidence interval, 0.38-1.04). The per-protocol analysis showed a greater difference of 25% incidence of knee OA in the controls versus 10% in the intervention arm (OR, 0.28).

"In the per-protocol analysis, we see the effect of the intervention in women who actually complied with the program. They exercised and followed the diet. This is what happens if you stay with the program. The incidence rate over halved with a statistically significant odds ratio," Mr. Runhaar reported at the meeting, which was sponsored by the Osteoarthritis Research Society International.

When asked whether this program really had practical application, he said that only a quarter of women were compliant with the intervention. "It is really difficult to change the habits of these women. This is one possible way of doing it, but we need to look at other ways of getting these women active and on a diet. If we can achieve this, then we are likely to prevent more OA."

Mr. Runhaar reported no relevant financial disclosures.

BARCELONA – Overweight women who follow a 2.5-year diet and exercise program showed a significant reduction in incident knee osteoarthritis, judging from the findings of a new Dutch study.

Jos Runhaar, a research scientist from the department of general practice at Erasmus University Medical Center, Rotterdam, the Netherlands, presented findings from the first-ever preventive randomized controlled trial on osteoarthritis (OA) at the World Congress on Osteoarthritis.

The already high number of people with OA worldwide is set to rise further with the growing incidence of obesity and an aging population. "Associated financial costs will also rise substantially to reflect this," he said.

Mr. Runhaar pointed out that the research community was already well informed in terms of the course and burden of OA, definitions of disease status, progression, and risk factors but lacked evidence on prevention. "We felt it was time to take the next step and investigate prevention of the disease and associated medical costs in people at risk," he noted.

The Prevention of Knee Osteoarthritis in Overweight Females (PROOF) study aimed to evaluate the preventive effects of a weight-loss program and of oral glucosamine sulphate on incident knee OA. After selection for study criteria, 407 women from the Rotterdam area were randomized to study interventions or placebo. "We selected a high-risk group of women between 50 to 60 years of age, BMI [body mass index] of at least 27, and without any clinical or radiographic signs of knee OA at baseline," said Mr. Runhaar. Half of the knees had a Kellgren-Lawrence (K&L) grade 0 at baseline.

The study assessed the effectiveness of two interventions: a weight-reduction program and oral glucosamine sulphate (1,500 mg/day). At the meeting, Mr. Runhaar presented only the results of the weight-reduction intervention.

The trial involved 200 women who received the weight-reduction intervention and 200 who served as controls, and in both groups half received glucosamine and half placebo.

"It was a pragmatic intervention. It was intended to be a regimen that could be easily implemented in daily life," Mr. Runhaar explained.

The weight-reduction program involved a weekly group session that featured a variety of low-impact sports to re-encourage interest and enjoyment in physical activity, and aimed to maintain this over the long term. "Women were referred to a dietician to develop dietary targets and have motivational discussions," he added.

"The supportive sessions were important because these women generally had inactive lifestyles and poor nutritional habits that were difficult to change, especially by the age of 50-60 years," he said.

Three possible incidence measures were used to represent the primary outcome of incident knee OA after 2.5 years. Participants needed to have a knee OA incidence with a K&L grade of at least 2; incidence of clinical knee OA according to clinical and radiographic American College of Rheumatology criteria; or joint-space narrowing of at least 1.0 mm.

The researchers combined both radiographic and clinical outcomes to ensure they had enough data to provide meaningful results.

After 2.5 years, women who complied with the weight-reduction program showed a mean weight reduction of 1.4 ± 5.5 kg, compared with 0.1 ± 6.3 kg in controls.

Also after 2.5 years of intervention, the researchers saw an incidence of knee OA, adjusted for BMI and K&L grade at baseline, of 22% in all knees, which equated to 36% of all women with one or more knees affected. On an intention-to-treat basis, 25% of the controls had knee OA versus 19% in the weight-reduction group (odds ratio, 0.62; 95% confidence interval, 0.38-1.04). The per-protocol analysis showed a greater difference of 25% incidence of knee OA in the controls versus 10% in the intervention arm (OR, 0.28).

"In the per-protocol analysis, we see the effect of the intervention in women who actually complied with the program. They exercised and followed the diet. This is what happens if you stay with the program. The incidence rate over halved with a statistically significant odds ratio," Mr. Runhaar reported at the meeting, which was sponsored by the Osteoarthritis Research Society International.

When asked whether this program really had practical application, he said that only a quarter of women were compliant with the intervention. "It is really difficult to change the habits of these women. This is one possible way of doing it, but we need to look at other ways of getting these women active and on a diet. If we can achieve this, then we are likely to prevent more OA."

Mr. Runhaar reported no relevant financial disclosures.

BARCELONA – People with osteoarthritis who are going to need knee replacement have markedly more cartilage loss earlier in the course of their disease than do osteoarthritis patients who keep their knees, judging from an image biomarker validation study presented at the World Congress on Osteoarthritis.

The finding that early loss of cartilage thickness predicts the need for future knee replacement is clinically significant, because some of the disease-modifying osteoarthritis drugs (DMOADs) that are under development aim both to ease or eliminate pain and to provide structural benefit in order to stop or reverse the structural changes, said Dr. Felix Eckstein, chief of the institute of anatomy and musculoskeletal research at Paracelsus Medical University, Salzburg, Austria.

"It’s unknown whether the modifying effect on joint structures will also provide clinical benefit for patients. The FDA would not approve a drug that improves structure without clinical benefit," said Dr. Eckstein, the lead investigator of the study.

The data presented were drawn from the U.S.-based Osteoarthritis Initiative (OAI), a multicenter, 4-year observational study of men and women that was designed to help improve treatment of knee osteoarthritis. Dr. Eckstein and his colleagues investigated structural changes that were detected using magnetic resonance imaging and observed their relationship to knee replacement in the year after measuring cartilage thickness.

In all, the study involved 109 knees from participants in the OAI who had received knee replacements between study years 1 and 4. A matched control knee was selected for each knee replacement case from OAI participants with the same Kellgren-Lawrence grade (KLG) at baseline.

The primary end point biomarker was loss of cartilage thickness after 1 year (taken as a time point prior to knee replacement and 1 year earlier) for the central medial compartment. The secondary end point was loss of cartilage thickness in the total medial compartment.

Segmentation of the cartilage using sagittal 3D dual-echo in steady state with water excitation (DESSwe) MRI sequence (3 Tesla) images provided measures of cartilage thickness. The investigators evaluated measurements of 16 subregions.

Dr. Eckstein and his associates matched participants according to their baseline radiographic disease stage, and looked within these strata for differentiation between those cases that progress to knee replacement and those that do not. "The new approach of this study was that we did not look at cases versus the rest of the cohort that may have been at a far earlier disease stage. We know that people at later radiographic disease stages have more cartilage loss than earlier disease stages."

They found that participants who had received knee replacement had lost three times as much cartilage as controls. "There was a lot variability, but it still discriminates with an area under the curve [AUC] of 0.59 (P = .007), so it is a significant differentiation," said Dr. Eckstein.

Breakdown by radiographic disease strata showed that the most marked differentiation occurred at the early disease stages. The AUC for KLG 2 was 0.67 (P = .009), versus an AUC of 0.55 (P = .16) for KLG 3, and an AUC of 0.53 (P = .65) for KLG 4. "At KLG 2, we see a relatively large difference in cartilage loss," he added.

Dr. Eckstein used ordered values as exploratory end points. "Rather than looking at the same region in every participant, we looked at the one region in each participant that changed the most over 1 year. Ordered values allow us look at the magnitude of change where it occurs with a specific risk factor set and then measure and compare this quantitatively between participants," he said.

The results showed that if magnitude of change is investigated wherever that change occurs, then the findings are greater in patients who progress to knee replacement, Dr. Eckstein said. "The differentiation for that particular order value is greater than a regional-based measure."

Looking ahead to the potential use of cartilage loss as a biomarker in trials, Dr. Eckstein said that "we think longitudinal, quantitative measures of cartilage loss predict knee replacement, particularly at the early radiographic stages. These MRI measures may be used in clinical trials to demonstrate the efficacy of DMOADs, with the large likelihood that these will translate into clinical benefits too."

The findings also lend support to the concept that treatments that slow cartilage loss may delay or prevent knee replacement. "We think that if a drug could reduce the cartilage loss, then this would also reduce the risk of knee replacement, because we’ve shown there is a link between cartilage loss and knee replacement," summarized Dr. Eckstein.

The meeting was sponsored by the Osteoarthritis Research Society International.

Dr. Eckstein reported ties with Medtronic, Merck Serono, Novartis, Perceptive, Pfizer, Sanofi-Aventis, and Synthes. He founded Chondrometrics in 2003. The study was funded by OAI, a public-private partnership of Novartis Pharma; the University of Pittsburgh’s Pivotal OAI MRI Analyses (POMA) study; the University of California, San Francisco; and the National Institutes of Health.

BARCELONA – People with osteoarthritis who are going to need knee replacement have markedly more cartilage loss earlier in the course of their disease than do osteoarthritis patients who keep their knees, judging from an image biomarker validation study presented at the World Congress on Osteoarthritis.

The finding that early loss of cartilage thickness predicts the need for future knee replacement is clinically significant, because some of the disease-modifying osteoarthritis drugs (DMOADs) that are under development aim both to ease or eliminate pain and to provide structural benefit in order to stop or reverse the structural changes, said Dr. Felix Eckstein, chief of the institute of anatomy and musculoskeletal research at Paracelsus Medical University, Salzburg, Austria.

"It’s unknown whether the modifying effect on joint structures will also provide clinical benefit for patients. The FDA would not approve a drug that improves structure without clinical benefit," said Dr. Eckstein, the lead investigator of the study.

The data presented were drawn from the U.S.-based Osteoarthritis Initiative (OAI), a multicenter, 4-year observational study of men and women that was designed to help improve treatment of knee osteoarthritis. Dr. Eckstein and his colleagues investigated structural changes that were detected using magnetic resonance imaging and observed their relationship to knee replacement in the year after measuring cartilage thickness.

In all, the study involved 109 knees from participants in the OAI who had received knee replacements between study years 1 and 4. A matched control knee was selected for each knee replacement case from OAI participants with the same Kellgren-Lawrence grade (KLG) at baseline.

The primary end point biomarker was loss of cartilage thickness after 1 year (taken as a time point prior to knee replacement and 1 year earlier) for the central medial compartment. The secondary end point was loss of cartilage thickness in the total medial compartment.

Segmentation of the cartilage using sagittal 3D dual-echo in steady state with water excitation (DESSwe) MRI sequence (3 Tesla) images provided measures of cartilage thickness. The investigators evaluated measurements of 16 subregions.

Dr. Eckstein and his associates matched participants according to their baseline radiographic disease stage, and looked within these strata for differentiation between those cases that progress to knee replacement and those that do not. "The new approach of this study was that we did not look at cases versus the rest of the cohort that may have been at a far earlier disease stage. We know that people at later radiographic disease stages have more cartilage loss than earlier disease stages."

They found that participants who had received knee replacement had lost three times as much cartilage as controls. "There was a lot variability, but it still discriminates with an area under the curve [AUC] of 0.59 (P = .007), so it is a significant differentiation," said Dr. Eckstein.

Breakdown by radiographic disease strata showed that the most marked differentiation occurred at the early disease stages. The AUC for KLG 2 was 0.67 (P = .009), versus an AUC of 0.55 (P = .16) for KLG 3, and an AUC of 0.53 (P = .65) for KLG 4. "At KLG 2, we see a relatively large difference in cartilage loss," he added.

Dr. Eckstein used ordered values as exploratory end points. "Rather than looking at the same region in every participant, we looked at the one region in each participant that changed the most over 1 year. Ordered values allow us look at the magnitude of change where it occurs with a specific risk factor set and then measure and compare this quantitatively between participants," he said.

The results showed that if magnitude of change is investigated wherever that change occurs, then the findings are greater in patients who progress to knee replacement, Dr. Eckstein said. "The differentiation for that particular order value is greater than a regional-based measure."

Looking ahead to the potential use of cartilage loss as a biomarker in trials, Dr. Eckstein said that "we think longitudinal, quantitative measures of cartilage loss predict knee replacement, particularly at the early radiographic stages. These MRI measures may be used in clinical trials to demonstrate the efficacy of DMOADs, with the large likelihood that these will translate into clinical benefits too."

The findings also lend support to the concept that treatments that slow cartilage loss may delay or prevent knee replacement. "We think that if a drug could reduce the cartilage loss, then this would also reduce the risk of knee replacement, because we’ve shown there is a link between cartilage loss and knee replacement," summarized Dr. Eckstein.

The meeting was sponsored by the Osteoarthritis Research Society International.

Dr. Eckstein reported ties with Medtronic, Merck Serono, Novartis, Perceptive, Pfizer, Sanofi-Aventis, and Synthes. He founded Chondrometrics in 2003. The study was funded by OAI, a public-private partnership of Novartis Pharma; the University of Pittsburgh’s Pivotal OAI MRI Analyses (POMA) study; the University of California, San Francisco; and the National Institutes of Health.

BARCELONA – People with osteoarthritis who are going to need knee replacement have markedly more cartilage loss earlier in the course of their disease than do osteoarthritis patients who keep their knees, judging from an image biomarker validation study presented at the World Congress on Osteoarthritis.

The finding that early loss of cartilage thickness predicts the need for future knee replacement is clinically significant, because some of the disease-modifying osteoarthritis drugs (DMOADs) that are under development aim both to ease or eliminate pain and to provide structural benefit in order to stop or reverse the structural changes, said Dr. Felix Eckstein, chief of the institute of anatomy and musculoskeletal research at Paracelsus Medical University, Salzburg, Austria.

"It’s unknown whether the modifying effect on joint structures will also provide clinical benefit for patients. The FDA would not approve a drug that improves structure without clinical benefit," said Dr. Eckstein, the lead investigator of the study.

The data presented were drawn from the U.S.-based Osteoarthritis Initiative (OAI), a multicenter, 4-year observational study of men and women that was designed to help improve treatment of knee osteoarthritis. Dr. Eckstein and his colleagues investigated structural changes that were detected using magnetic resonance imaging and observed their relationship to knee replacement in the year after measuring cartilage thickness.

In all, the study involved 109 knees from participants in the OAI who had received knee replacements between study years 1 and 4. A matched control knee was selected for each knee replacement case from OAI participants with the same Kellgren-Lawrence grade (KLG) at baseline.

The primary end point biomarker was loss of cartilage thickness after 1 year (taken as a time point prior to knee replacement and 1 year earlier) for the central medial compartment. The secondary end point was loss of cartilage thickness in the total medial compartment.

Segmentation of the cartilage using sagittal 3D dual-echo in steady state with water excitation (DESSwe) MRI sequence (3 Tesla) images provided measures of cartilage thickness. The investigators evaluated measurements of 16 subregions.

Dr. Eckstein and his associates matched participants according to their baseline radiographic disease stage, and looked within these strata for differentiation between those cases that progress to knee replacement and those that do not. "The new approach of this study was that we did not look at cases versus the rest of the cohort that may have been at a far earlier disease stage. We know that people at later radiographic disease stages have more cartilage loss than earlier disease stages."

They found that participants who had received knee replacement had lost three times as much cartilage as controls. "There was a lot variability, but it still discriminates with an area under the curve [AUC] of 0.59 (P = .007), so it is a significant differentiation," said Dr. Eckstein.

Breakdown by radiographic disease strata showed that the most marked differentiation occurred at the early disease stages. The AUC for KLG 2 was 0.67 (P = .009), versus an AUC of 0.55 (P = .16) for KLG 3, and an AUC of 0.53 (P = .65) for KLG 4. "At KLG 2, we see a relatively large difference in cartilage loss," he added.

Dr. Eckstein used ordered values as exploratory end points. "Rather than looking at the same region in every participant, we looked at the one region in each participant that changed the most over 1 year. Ordered values allow us look at the magnitude of change where it occurs with a specific risk factor set and then measure and compare this quantitatively between participants," he said.

The results showed that if magnitude of change is investigated wherever that change occurs, then the findings are greater in patients who progress to knee replacement, Dr. Eckstein said. "The differentiation for that particular order value is greater than a regional-based measure."

Looking ahead to the potential use of cartilage loss as a biomarker in trials, Dr. Eckstein said that "we think longitudinal, quantitative measures of cartilage loss predict knee replacement, particularly at the early radiographic stages. These MRI measures may be used in clinical trials to demonstrate the efficacy of DMOADs, with the large likelihood that these will translate into clinical benefits too."

The findings also lend support to the concept that treatments that slow cartilage loss may delay or prevent knee replacement. "We think that if a drug could reduce the cartilage loss, then this would also reduce the risk of knee replacement, because we’ve shown there is a link between cartilage loss and knee replacement," summarized Dr. Eckstein.

The meeting was sponsored by the Osteoarthritis Research Society International.

Dr. Eckstein reported ties with Medtronic, Merck Serono, Novartis, Perceptive, Pfizer, Sanofi-Aventis, and Synthes. He founded Chondrometrics in 2003. The study was funded by OAI, a public-private partnership of Novartis Pharma; the University of Pittsburgh’s Pivotal OAI MRI Analyses (POMA) study; the University of California, San Francisco; and the National Institutes of Health.

In recent months, the discovery of the C9ORF72 mutation has added fresh insight into the causes of frontotemporal dementia and amyotrophic lateral sclerosis. Now, a series of new studies describes the frequency of the mutation and how the mutation reveals itself clinically in a spectrum of phenotypes in patients with either disease.

The series of studies found that the mutation most often is associated with behavioral variant frontotemporal dementia (FTD), and occurred in 2%-5% of patients with sporadic FTD and 15%-48% of patients with familial FTD. For amyotrophic lateral sclerosis (ALS) patients, the mutation occurred in 4%-7% of sporadic cases and 22%-43% of familial cases. Another 20%-40% of patients who show symptoms of both diseases had the mutation; the rate reached almost 50% among these patients with a family history of ALS or FTD. Some studies reported finding the mutation in 0%-28% of patients who present with the progressive nonfluent aphasia variant of FTD.

The eventual clinical impact of identifying the C9ORF72 mutation is the availability of a population of at-risk carriers of the mutation to aid research into the preclinical phase of disease, said Dr. Kevin Talbot, professor of motor neuron biology at the University of Oxford, England. "Rather than work in the phase of established disease, which may be intractable to disease-modifying therapy, this provides a new departure to ‘fill in’ a phase in the natural history of ALS which has hitherto not been amenable to study." Dr. Talbot was a coauthor on a study that screened 4,448 patients with ALS and 1,425 patients with FTD for the mutation (Lancet Neurol. 2012 March 9 [doi:10.1016/S1474-4422(12)70043-1]).

The discovery of the mutation and the subsequent characterization among patients who have FTD, ALS, both FTD and ALS, or primary progressive aphasia are just the first steps of many before treatments can be based on the new knowledge, said Dr. Paul Schulz of the department of neurology at the University of Texas, Houston, where his lab examines the mechanisms underlying normal cognition and neurodegenerative disorders.

To illustrate his point, Dr. Schulz cited how the genes for myotonic dystrophy and Huntington’s disease were discovered in 1992 and 1994, respectively, but researchers still know little about them. "We don’t know what they do, how the mutations cause problems, and how to replace them."

Preliminary findings underpinning the discovery of C9ORF72 were made in 2006 when investigators discovered that either FTD and ALS or a combination of both diseases were linked to a region on chromosome 9p21 in members of some families with the diseases. The big step came in September 2011 when two research groups independently identified the precise nature of the long-sought-after mutation (Neuron 2011;72:245-56; 257-68). It proved to be a GGGGCC hexanucleotide repeat in the noncoding region of the C9ORF72 gene.

Originally, no mutation had been found even after repeated sequencing of the investigational region on chromosome 9p21, but eventually, the two research groups examined the pattern of inheritance and noticed that only the good gene appeared to be inherited rather than one gene from each parent.

"After various experiments, it was realized that the abnormal gene was invisible to gene sequencing because the hexanucleotide bound to itself," related Dr. Schulz. "As a result, it was impenetrable by normal PCR [polymerase chain reaction] amplification. Now that this mechanism of mutation is known, I’m sure gene hunters are looking for others that are also ‘silent.’ "

Mutation Screening in FTD and ALS

In the Lancet Neurology study of 4,448 ALS patients and 1,425 FTD patients from the United States, Europe, and Australia, researchers found the C9ORF79 mutation in 7% of sporadic ALS in white patients and 4.1% of black patients. It was present in 6% of white patients with sporadic FTD. The results of those with familial FTD or ALS were more surprising, with the expansion present in 38% of all patients with familial ALS and 25% in white patients with familial FTD.

A series of four papers published in Brain by groups from the Netherlands; Manchester, England; London, England; and the Mayo Clinic in Rochester, Minn., and Jacksonville, Fla., reported the results of screening large cohorts of patients with FTD totaling nearly 1,200 cases. Overall, 7%-12% of the cohorts were found to have the mutation (Brain 2012;135:693-708; 723-35; 736-50; 765-83).

Another two papers and the same Mayo Clinic paper reported on the frequency of the mutation in patients with ALS. In 563 ALS patients from northern England, including 63 with a family history of ALS, the C9ORF72 expansion was found in 11%, but it occurred more often among patients with familial disease (43%) than with sporadic (7%) disease (Brain 2012;135:751-64).

Among patients with familial ALS, the mutation occurred in 38% of 141 Italian cases (including 57% in 21 Sardinian cases) and in 22% of 41 German cases (Brain 2012;135:784-93).

Mayo Clinic researchers detected the mutation in 7% of 229 ALS patients and in 24% of 34 patients with familial ALS, parkinsonism, or dementia. Only 4% of sporadic ALS cases had the mutation. Among patients with a clinical phenotype of FTD and ALS, the prevalence of the mutation was 22%, but it approached 50% among those with a positive family history (Brain 2012;135:765-83).

Another study that will be reported April 25 at the annual meeting of the American Academy of Neurology focused on 1,488 patients (1,082 with FTD, 328 with ALS, and 78 with both) in the European Early-Onset Dementia consortium. In patients with a family history of dementia or ALS, the relative contribution of C9ORF72 was 10% in the FTD patients, 42% in the ALS patients, and 48% in the FTD-ALS patients.

"All of these statistics mean that this hexameric repeat is fairly common amongst those with familial FTD or ALS, or especially FTD with ALS," according to Dr. Schulz. But familial FTD was present in only 40% of those with FTD, and familial ALS was present in only 5% of ALS patients, he noted.

"This means that most sporadic FTD, ALS, or FTD-ALS patients are not accounted for. In sporadic FTD, which is more common than familial FTD, then the rate of C9ORF72 mutations appears to be between 2% and 5%," Dr. Schulz said.

Effect of Other FTD/ALS Mutations

The new C9ORF72 expansion joins two other mutations found in patients with FTD and/or ALS, namely those affecting the genes for microtubulin-associated protein tau (MAPT) and progranulin (GRN). In a commentary on the studies featured in Brain, Dr. John Hodges of Neuroscience Research Australia and the University of New South Wales in Sydney, NSW, Australia, noted that the results of the London-based group (Brain 2012;135:736-50) provide some insight into how likely it is that a patient would have a C9ORF72 mutation and whether this likelihood could be predicted based upon family history and clinical features.

The researchers found that the prevalences of the three mutations were roughly equal in their sample. They also found – based on their Goldman scoring method for quantifying family history – that 88% of patients with a score of 1 (representing an autosomal dominant family history of FTD or ALS) had a mutation in one of those three genes.

However, the Mayo Clinic samples suggest that the C9ORF72 mutation is the most common FTD mutation, present in one-third of people with a family history.

Links Between FTD and ALS

The C9ORF72 mutation may also provide some insight on the links between FTD and ALS. In all cohorts, the prevalence of C9ORF72 was highest in those with FTD/ALS at 20%-40%, and approached 50% among FTD/ALS cases with a positive family history. Dr. Brad Dickerson, director of the frontotemporal dementia unit and laboratory of neuroimaging at Massachusetts General Hospital in Boston, Mass., said that linking FTD and ALS through this gene was especially important because it would likely lead to research that sheds light on what causes cells in different parts of the brain to be vulnerable in both of these diseases.

"This once again underscores the value that studying one neurodegenerative disease can have for other neurodegenerative disease," he said. "In the case of this gene, advances in understanding its role in FTD will have direct implications for understanding its role in ALS, and vice versa."

Dr. Marsel Mesulam, director of the cognitive neurology and Alzheimer’s disease center at Northwestern University in Chicago, said that "exactly how the hopes raised by the C9ORF72 finding will be realized is currently unclear, since we do not yet fully understand the function of C9ORF72." He added that the discovery also generates new puzzles. "Why does the same type of mutation cause ALS in some patients, behavioral FTD in others, and PPA [primary progressive aphasia] in still others?"

Behavioral Variant FTD Most Common

The behavioral variant of FTD was the most common clinical phenotype associated with the C9ORF72 expansion, and was often accompanied by features of ALS as the disease progressed.

Some studies showed that patients with the C9ORF72 mutation also presented with progressive nonfluent aphasia, Dr. Hodges noted in his commentary. Major psychiatric symptoms also were very common, but more details are needed, he wrote. "It appears, therefore, that the majority of patients have the behavioral variant of FTD, although a pattern of progressive [nonfluent aphasia] should not mitigate against screening for the mutation in patients with a strong family history or concurrent features of ALS."

Who Should Undergo Screening?

Given that some patients had the C9ORF72 mutation even without a strong family history, "the most important immediate clinical implication is that we will likely begin screening patients for this mutation once a standard laboratory test for this gene becomes available," Dr. Dickerson said.

In a commentary, Rosa Rademakers, Ph.D., of the Mayo Clinic in Jacksonville, Fla., argued that the use of a clinical screening algorithm to decide whether to test for the C9ORF72 mutation in a patient with a family history of ALS or FTD – or when a patient is behaviorally impaired – may not work, because detailed information about family history is often unavailable. Instead, it should be considered in all patients, particularly because 6%-7% of whites with sporadic disease in the Lancet Neurology paper had the mutation, and the clinical phenotype associated with the C9ORF72 expansion extends beyond FTD and ALS. At the moment, however, caution is advised on testing because "our present understanding of the disease penetrance and range of clinical phenotypes associated with this mutation is poor and the smallest repeat size needed for pathogenicity is unknown," Dr. Rademakers wrote.

The sources interviewed for this article did not have any relevant financial disclosures. Dr. Rademakers disclosed that she has a patent pending on the discovery of the hexanucleotide repeat expansion in the C9ORF72 gene.

In recent months, the discovery of the C9ORF72 mutation has added fresh insight into the causes of frontotemporal dementia and amyotrophic lateral sclerosis. Now, a series of new studies describes the frequency of the mutation and how the mutation reveals itself clinically in a spectrum of phenotypes in patients with either disease.

The series of studies found that the mutation most often is associated with behavioral variant frontotemporal dementia (FTD), and occurred in 2%-5% of patients with sporadic FTD and 15%-48% of patients with familial FTD. For amyotrophic lateral sclerosis (ALS) patients, the mutation occurred in 4%-7% of sporadic cases and 22%-43% of familial cases. Another 20%-40% of patients who show symptoms of both diseases had the mutation; the rate reached almost 50% among these patients with a family history of ALS or FTD. Some studies reported finding the mutation in 0%-28% of patients who present with the progressive nonfluent aphasia variant of FTD.

The eventual clinical impact of identifying the C9ORF72 mutation is the availability of a population of at-risk carriers of the mutation to aid research into the preclinical phase of disease, said Dr. Kevin Talbot, professor of motor neuron biology at the University of Oxford, England. "Rather than work in the phase of established disease, which may be intractable to disease-modifying therapy, this provides a new departure to ‘fill in’ a phase in the natural history of ALS which has hitherto not been amenable to study." Dr. Talbot was a coauthor on a study that screened 4,448 patients with ALS and 1,425 patients with FTD for the mutation (Lancet Neurol. 2012 March 9 [doi:10.1016/S1474-4422(12)70043-1]).

The discovery of the mutation and the subsequent characterization among patients who have FTD, ALS, both FTD and ALS, or primary progressive aphasia are just the first steps of many before treatments can be based on the new knowledge, said Dr. Paul Schulz of the department of neurology at the University of Texas, Houston, where his lab examines the mechanisms underlying normal cognition and neurodegenerative disorders.

To illustrate his point, Dr. Schulz cited how the genes for myotonic dystrophy and Huntington’s disease were discovered in 1992 and 1994, respectively, but researchers still know little about them. "We don’t know what they do, how the mutations cause problems, and how to replace them."

Preliminary findings underpinning the discovery of C9ORF72 were made in 2006 when investigators discovered that either FTD and ALS or a combination of both diseases were linked to a region on chromosome 9p21 in members of some families with the diseases. The big step came in September 2011 when two research groups independently identified the precise nature of the long-sought-after mutation (Neuron 2011;72:245-56; 257-68). It proved to be a GGGGCC hexanucleotide repeat in the noncoding region of the C9ORF72 gene.

Originally, no mutation had been found even after repeated sequencing of the investigational region on chromosome 9p21, but eventually, the two research groups examined the pattern of inheritance and noticed that only the good gene appeared to be inherited rather than one gene from each parent.

"After various experiments, it was realized that the abnormal gene was invisible to gene sequencing because the hexanucleotide bound to itself," related Dr. Schulz. "As a result, it was impenetrable by normal PCR [polymerase chain reaction] amplification. Now that this mechanism of mutation is known, I’m sure gene hunters are looking for others that are also ‘silent.’ "

Mutation Screening in FTD and ALS

In the Lancet Neurology study of 4,448 ALS patients and 1,425 FTD patients from the United States, Europe, and Australia, researchers found the C9ORF79 mutation in 7% of sporadic ALS in white patients and 4.1% of black patients. It was present in 6% of white patients with sporadic FTD. The results of those with familial FTD or ALS were more surprising, with the expansion present in 38% of all patients with familial ALS and 25% in white patients with familial FTD.

A series of four papers published in Brain by groups from the Netherlands; Manchester, England; London, England; and the Mayo Clinic in Rochester, Minn., and Jacksonville, Fla., reported the results of screening large cohorts of patients with FTD totaling nearly 1,200 cases. Overall, 7%-12% of the cohorts were found to have the mutation (Brain 2012;135:693-708; 723-35; 736-50; 765-83).

Another two papers and the same Mayo Clinic paper reported on the frequency of the mutation in patients with ALS. In 563 ALS patients from northern England, including 63 with a family history of ALS, the C9ORF72 expansion was found in 11%, but it occurred more often among patients with familial disease (43%) than with sporadic (7%) disease (Brain 2012;135:751-64).

Among patients with familial ALS, the mutation occurred in 38% of 141 Italian cases (including 57% in 21 Sardinian cases) and in 22% of 41 German cases (Brain 2012;135:784-93).

Mayo Clinic researchers detected the mutation in 7% of 229 ALS patients and in 24% of 34 patients with familial ALS, parkinsonism, or dementia. Only 4% of sporadic ALS cases had the mutation. Among patients with a clinical phenotype of FTD and ALS, the prevalence of the mutation was 22%, but it approached 50% among those with a positive family history (Brain 2012;135:765-83).

Another study that will be reported April 25 at the annual meeting of the American Academy of Neurology focused on 1,488 patients (1,082 with FTD, 328 with ALS, and 78 with both) in the European Early-Onset Dementia consortium. In patients with a family history of dementia or ALS, the relative contribution of C9ORF72 was 10% in the FTD patients, 42% in the ALS patients, and 48% in the FTD-ALS patients.

"All of these statistics mean that this hexameric repeat is fairly common amongst those with familial FTD or ALS, or especially FTD with ALS," according to Dr. Schulz. But familial FTD was present in only 40% of those with FTD, and familial ALS was present in only 5% of ALS patients, he noted.

"This means that most sporadic FTD, ALS, or FTD-ALS patients are not accounted for. In sporadic FTD, which is more common than familial FTD, then the rate of C9ORF72 mutations appears to be between 2% and 5%," Dr. Schulz said.

Effect of Other FTD/ALS Mutations

The new C9ORF72 expansion joins two other mutations found in patients with FTD and/or ALS, namely those affecting the genes for microtubulin-associated protein tau (MAPT) and progranulin (GRN). In a commentary on the studies featured in Brain, Dr. John Hodges of Neuroscience Research Australia and the University of New South Wales in Sydney, NSW, Australia, noted that the results of the London-based group (Brain 2012;135:736-50) provide some insight into how likely it is that a patient would have a C9ORF72 mutation and whether this likelihood could be predicted based upon family history and clinical features.

The researchers found that the prevalences of the three mutations were roughly equal in their sample. They also found – based on their Goldman scoring method for quantifying family history – that 88% of patients with a score of 1 (representing an autosomal dominant family history of FTD or ALS) had a mutation in one of those three genes.

However, the Mayo Clinic samples suggest that the C9ORF72 mutation is the most common FTD mutation, present in one-third of people with a family history.

Links Between FTD and ALS

The C9ORF72 mutation may also provide some insight on the links between FTD and ALS. In all cohorts, the prevalence of C9ORF72 was highest in those with FTD/ALS at 20%-40%, and approached 50% among FTD/ALS cases with a positive family history. Dr. Brad Dickerson, director of the frontotemporal dementia unit and laboratory of neuroimaging at Massachusetts General Hospital in Boston, Mass., said that linking FTD and ALS through this gene was especially important because it would likely lead to research that sheds light on what causes cells in different parts of the brain to be vulnerable in both of these diseases.

"This once again underscores the value that studying one neurodegenerative disease can have for other neurodegenerative disease," he said. "In the case of this gene, advances in understanding its role in FTD will have direct implications for understanding its role in ALS, and vice versa."

Dr. Marsel Mesulam, director of the cognitive neurology and Alzheimer’s disease center at Northwestern University in Chicago, said that "exactly how the hopes raised by the C9ORF72 finding will be realized is currently unclear, since we do not yet fully understand the function of C9ORF72." He added that the discovery also generates new puzzles. "Why does the same type of mutation cause ALS in some patients, behavioral FTD in others, and PPA [primary progressive aphasia] in still others?"

Behavioral Variant FTD Most Common

The behavioral variant of FTD was the most common clinical phenotype associated with the C9ORF72 expansion, and was often accompanied by features of ALS as the disease progressed.

Some studies showed that patients with the C9ORF72 mutation also presented with progressive nonfluent aphasia, Dr. Hodges noted in his commentary. Major psychiatric symptoms also were very common, but more details are needed, he wrote. "It appears, therefore, that the majority of patients have the behavioral variant of FTD, although a pattern of progressive [nonfluent aphasia] should not mitigate against screening for the mutation in patients with a strong family history or concurrent features of ALS."

Who Should Undergo Screening?

Given that some patients had the C9ORF72 mutation even without a strong family history, "the most important immediate clinical implication is that we will likely begin screening patients for this mutation once a standard laboratory test for this gene becomes available," Dr. Dickerson said.

In a commentary, Rosa Rademakers, Ph.D., of the Mayo Clinic in Jacksonville, Fla., argued that the use of a clinical screening algorithm to decide whether to test for the C9ORF72 mutation in a patient with a family history of ALS or FTD – or when a patient is behaviorally impaired – may not work, because detailed information about family history is often unavailable. Instead, it should be considered in all patients, particularly because 6%-7% of whites with sporadic disease in the Lancet Neurology paper had the mutation, and the clinical phenotype associated with the C9ORF72 expansion extends beyond FTD and ALS. At the moment, however, caution is advised on testing because "our present understanding of the disease penetrance and range of clinical phenotypes associated with this mutation is poor and the smallest repeat size needed for pathogenicity is unknown," Dr. Rademakers wrote.

The sources interviewed for this article did not have any relevant financial disclosures. Dr. Rademakers disclosed that she has a patent pending on the discovery of the hexanucleotide repeat expansion in the C9ORF72 gene.

In recent months, the discovery of the C9ORF72 mutation has added fresh insight into the causes of frontotemporal dementia and amyotrophic lateral sclerosis. Now, a series of new studies describes the frequency of the mutation and how the mutation reveals itself clinically in a spectrum of phenotypes in patients with either disease.

The series of studies found that the mutation most often is associated with behavioral variant frontotemporal dementia (FTD), and occurred in 2%-5% of patients with sporadic FTD and 15%-48% of patients with familial FTD. For amyotrophic lateral sclerosis (ALS) patients, the mutation occurred in 4%-7% of sporadic cases and 22%-43% of familial cases. Another 20%-40% of patients who show symptoms of both diseases had the mutation; the rate reached almost 50% among these patients with a family history of ALS or FTD. Some studies reported finding the mutation in 0%-28% of patients who present with the progressive nonfluent aphasia variant of FTD.

The eventual clinical impact of identifying the C9ORF72 mutation is the availability of a population of at-risk carriers of the mutation to aid research into the preclinical phase of disease, said Dr. Kevin Talbot, professor of motor neuron biology at the University of Oxford, England. "Rather than work in the phase of established disease, which may be intractable to disease-modifying therapy, this provides a new departure to ‘fill in’ a phase in the natural history of ALS which has hitherto not been amenable to study." Dr. Talbot was a coauthor on a study that screened 4,448 patients with ALS and 1,425 patients with FTD for the mutation (Lancet Neurol. 2012 March 9 [doi:10.1016/S1474-4422(12)70043-1]).

The discovery of the mutation and the subsequent characterization among patients who have FTD, ALS, both FTD and ALS, or primary progressive aphasia are just the first steps of many before treatments can be based on the new knowledge, said Dr. Paul Schulz of the department of neurology at the University of Texas, Houston, where his lab examines the mechanisms underlying normal cognition and neurodegenerative disorders.

To illustrate his point, Dr. Schulz cited how the genes for myotonic dystrophy and Huntington’s disease were discovered in 1992 and 1994, respectively, but researchers still know little about them. "We don’t know what they do, how the mutations cause problems, and how to replace them."

Preliminary findings underpinning the discovery of C9ORF72 were made in 2006 when investigators discovered that either FTD and ALS or a combination of both diseases were linked to a region on chromosome 9p21 in members of some families with the diseases. The big step came in September 2011 when two research groups independently identified the precise nature of the long-sought-after mutation (Neuron 2011;72:245-56; 257-68). It proved to be a GGGGCC hexanucleotide repeat in the noncoding region of the C9ORF72 gene.

Originally, no mutation had been found even after repeated sequencing of the investigational region on chromosome 9p21, but eventually, the two research groups examined the pattern of inheritance and noticed that only the good gene appeared to be inherited rather than one gene from each parent.

"After various experiments, it was realized that the abnormal gene was invisible to gene sequencing because the hexanucleotide bound to itself," related Dr. Schulz. "As a result, it was impenetrable by normal PCR [polymerase chain reaction] amplification. Now that this mechanism of mutation is known, I’m sure gene hunters are looking for others that are also ‘silent.’ "

Mutation Screening in FTD and ALS

In the Lancet Neurology study of 4,448 ALS patients and 1,425 FTD patients from the United States, Europe, and Australia, researchers found the C9ORF79 mutation in 7% of sporadic ALS in white patients and 4.1% of black patients. It was present in 6% of white patients with sporadic FTD. The results of those with familial FTD or ALS were more surprising, with the expansion present in 38% of all patients with familial ALS and 25% in white patients with familial FTD.

A series of four papers published in Brain by groups from the Netherlands; Manchester, England; London, England; and the Mayo Clinic in Rochester, Minn., and Jacksonville, Fla., reported the results of screening large cohorts of patients with FTD totaling nearly 1,200 cases. Overall, 7%-12% of the cohorts were found to have the mutation (Brain 2012;135:693-708; 723-35; 736-50; 765-83).

Another two papers and the same Mayo Clinic paper reported on the frequency of the mutation in patients with ALS. In 563 ALS patients from northern England, including 63 with a family history of ALS, the C9ORF72 expansion was found in 11%, but it occurred more often among patients with familial disease (43%) than with sporadic (7%) disease (Brain 2012;135:751-64).

Among patients with familial ALS, the mutation occurred in 38% of 141 Italian cases (including 57% in 21 Sardinian cases) and in 22% of 41 German cases (Brain 2012;135:784-93).

Mayo Clinic researchers detected the mutation in 7% of 229 ALS patients and in 24% of 34 patients with familial ALS, parkinsonism, or dementia. Only 4% of sporadic ALS cases had the mutation. Among patients with a clinical phenotype of FTD and ALS, the prevalence of the mutation was 22%, but it approached 50% among those with a positive family history (Brain 2012;135:765-83).

Another study that will be reported April 25 at the annual meeting of the American Academy of Neurology focused on 1,488 patients (1,082 with FTD, 328 with ALS, and 78 with both) in the European Early-Onset Dementia consortium. In patients with a family history of dementia or ALS, the relative contribution of C9ORF72 was 10% in the FTD patients, 42% in the ALS patients, and 48% in the FTD-ALS patients.

"All of these statistics mean that this hexameric repeat is fairly common amongst those with familial FTD or ALS, or especially FTD with ALS," according to Dr. Schulz. But familial FTD was present in only 40% of those with FTD, and familial ALS was present in only 5% of ALS patients, he noted.

"This means that most sporadic FTD, ALS, or FTD-ALS patients are not accounted for. In sporadic FTD, which is more common than familial FTD, then the rate of C9ORF72 mutations appears to be between 2% and 5%," Dr. Schulz said.

Effect of Other FTD/ALS Mutations

The new C9ORF72 expansion joins two other mutations found in patients with FTD and/or ALS, namely those affecting the genes for microtubulin-associated protein tau (MAPT) and progranulin (GRN). In a commentary on the studies featured in Brain, Dr. John Hodges of Neuroscience Research Australia and the University of New South Wales in Sydney, NSW, Australia, noted that the results of the London-based group (Brain 2012;135:736-50) provide some insight into how likely it is that a patient would have a C9ORF72 mutation and whether this likelihood could be predicted based upon family history and clinical features.

The researchers found that the prevalences of the three mutations were roughly equal in their sample. They also found – based on their Goldman scoring method for quantifying family history – that 88% of patients with a score of 1 (representing an autosomal dominant family history of FTD or ALS) had a mutation in one of those three genes.

However, the Mayo Clinic samples suggest that the C9ORF72 mutation is the most common FTD mutation, present in one-third of people with a family history.

Links Between FTD and ALS

The C9ORF72 mutation may also provide some insight on the links between FTD and ALS. In all cohorts, the prevalence of C9ORF72 was highest in those with FTD/ALS at 20%-40%, and approached 50% among FTD/ALS cases with a positive family history. Dr. Brad Dickerson, director of the frontotemporal dementia unit and laboratory of neuroimaging at Massachusetts General Hospital in Boston, Mass., said that linking FTD and ALS through this gene was especially important because it would likely lead to research that sheds light on what causes cells in different parts of the brain to be vulnerable in both of these diseases.

"This once again underscores the value that studying one neurodegenerative disease can have for other neurodegenerative disease," he said. "In the case of this gene, advances in understanding its role in FTD will have direct implications for understanding its role in ALS, and vice versa."

Dr. Marsel Mesulam, director of the cognitive neurology and Alzheimer’s disease center at Northwestern University in Chicago, said that "exactly how the hopes raised by the C9ORF72 finding will be realized is currently unclear, since we do not yet fully understand the function of C9ORF72." He added that the discovery also generates new puzzles. "Why does the same type of mutation cause ALS in some patients, behavioral FTD in others, and PPA [primary progressive aphasia] in still others?"

Behavioral Variant FTD Most Common

The behavioral variant of FTD was the most common clinical phenotype associated with the C9ORF72 expansion, and was often accompanied by features of ALS as the disease progressed.

Some studies showed that patients with the C9ORF72 mutation also presented with progressive nonfluent aphasia, Dr. Hodges noted in his commentary. Major psychiatric symptoms also were very common, but more details are needed, he wrote. "It appears, therefore, that the majority of patients have the behavioral variant of FTD, although a pattern of progressive [nonfluent aphasia] should not mitigate against screening for the mutation in patients with a strong family history or concurrent features of ALS."

Who Should Undergo Screening?

Given that some patients had the C9ORF72 mutation even without a strong family history, "the most important immediate clinical implication is that we will likely begin screening patients for this mutation once a standard laboratory test for this gene becomes available," Dr. Dickerson said.

In a commentary, Rosa Rademakers, Ph.D., of the Mayo Clinic in Jacksonville, Fla., argued that the use of a clinical screening algorithm to decide whether to test for the C9ORF72 mutation in a patient with a family history of ALS or FTD – or when a patient is behaviorally impaired – may not work, because detailed information about family history is often unavailable. Instead, it should be considered in all patients, particularly because 6%-7% of whites with sporadic disease in the Lancet Neurology paper had the mutation, and the clinical phenotype associated with the C9ORF72 expansion extends beyond FTD and ALS. At the moment, however, caution is advised on testing because "our present understanding of the disease penetrance and range of clinical phenotypes associated with this mutation is poor and the smallest repeat size needed for pathogenicity is unknown," Dr. Rademakers wrote.

The sources interviewed for this article did not have any relevant financial disclosures. Dr. Rademakers disclosed that she has a patent pending on the discovery of the hexanucleotide repeat expansion in the C9ORF72 gene.

Joint replacement surgery continues to become less common in patients with rheumatoid arthritis, probably reflecting the widespread adoption of disease modifying antirheumatic drugs, judging from findings of a population-based study published in this month’s Journal of Rheumatology.

Previous studies have found a trend for declining rates of joint surgery in patients with RA since 1985. In this study, "we examined whether the prior sex differences and use trends in reduced surgical intervention for RA persist in patients diagnosed after 1995, and evaluated the effect of RA surgery on survival in these patients," wrote Dr. Courtney A. Shourt and her associates from the Mayo Clinic in Rochester, Minn. (J. Rheumatol. 2012 Jan. 15 [doi:10.3899/jrheum.111056]).

"The possible contribution of RA-related joint surgery to excess mortality in patients with RA is largely unexplored," they pointed out.

A retrospective medical record review was performed using data from the Rochester Epidemiology Project (www.rochesterproject.org). The researchers reviewed records from a population-based cohort of 813 adult residents of Olmsted County, Minn., who had incident RA between Jan. 1, 1980, and Dec. 31, 2007. All cases were followed longitudinally until Dec. 31, 2008; death; or migration out of the county.

All joint surgeries were marginally associated with mortality (hazard ratio, 1.3; 95% confidence interval, 0.96-1.8; P = .09), but joint reconstructive procedures (JRPs) showed a significant association with mortality, adjusted for known RA mortality risk factors, compared with findings in patients not requiring JRP (HR, 2.8; 95% CI, 1.9-4.1; P less than .001). "The need for joint replacement surgery is still a marker of bad disease," commented Dr. Eric L. Matteson, professor of medicine and chair of rheumatology at the Mayo Clinic, in an interview.

The proportion of patients undergoing RA-related surgeries dropped between the two time periods of 1980-94 and 1995-2007. Of the 813 Olmsted County residents in the analysis, 189 underwent at least one surgical procedure involving joints, during a mean follow up of 9.6 years. The cumulative incidence of any joint surgery at 10 years after RA incidence for the 1980-94 cohort was 27.3%, compared with 19.5% for the 1995-2007 cohort (P = 0.08), which was not statistically significant.

More aggressive use of effective DMARDs with a reduction in the progression of radiographic joint damage was suggested as a possible reason for the decline in surgical procedures. "These findings reveal that modern medical management strategy has had markedly beneficial effects on the disease course," with less damage to the target small- and medium-size joints such as the hands, wrists, and feet than in past decades, noted Dr. Matteson, one of the report’s authors.

The greatest reduction in surgeries was seen in soft tissue procedures (synovectomy, tendon repair, tendon transfer, meniscus repair, ligament release, and/or cartilage repair). These decreased from 12% in 1980-94 to 6% in 1995-2007 at 10 years after RA incidence (P = .012).

No differences were found in the cumulative incidence of total hip arthroplasty (P = .77) or total knee arthroplasty (P = .18) between the time periods, reported the authors. Addressing the continued need for surgery on weight-bearing joints, particularly total knee and total hip arthroplasties, Dr. Matteson added, "in this respect patients are beginning to be more like people from the general population who have hip and knee replacements for osteoarthritis."

Study coinvestigator Cynthia Crowson of the Mayo Clinic’s biostatistics division noted in an interview that "persons with RA are requiring fewer surgeries, which may indicate [that] current management strategies are leading to less disability among patients who have developed RA since 1995" compared with previous times.

The study was supported by a grant from the National Institutes of Health, and was made possible by the Rochester Epidemiology Project. The authors reported having no financial disclosures.

Joint replacement surgery continues to become less common in patients with rheumatoid arthritis, probably reflecting the widespread adoption of disease modifying antirheumatic drugs, judging from findings of a population-based study published in this month’s Journal of Rheumatology.

Previous studies have found a trend for declining rates of joint surgery in patients with RA since 1985. In this study, "we examined whether the prior sex differences and use trends in reduced surgical intervention for RA persist in patients diagnosed after 1995, and evaluated the effect of RA surgery on survival in these patients," wrote Dr. Courtney A. Shourt and her associates from the Mayo Clinic in Rochester, Minn. (J. Rheumatol. 2012 Jan. 15 [doi:10.3899/jrheum.111056]).

"The possible contribution of RA-related joint surgery to excess mortality in patients with RA is largely unexplored," they pointed out.

A retrospective medical record review was performed using data from the Rochester Epidemiology Project (www.rochesterproject.org). The researchers reviewed records from a population-based cohort of 813 adult residents of Olmsted County, Minn., who had incident RA between Jan. 1, 1980, and Dec. 31, 2007. All cases were followed longitudinally until Dec. 31, 2008; death; or migration out of the county.

All joint surgeries were marginally associated with mortality (hazard ratio, 1.3; 95% confidence interval, 0.96-1.8; P = .09), but joint reconstructive procedures (JRPs) showed a significant association with mortality, adjusted for known RA mortality risk factors, compared with findings in patients not requiring JRP (HR, 2.8; 95% CI, 1.9-4.1; P less than .001). "The need for joint replacement surgery is still a marker of bad disease," commented Dr. Eric L. Matteson, professor of medicine and chair of rheumatology at the Mayo Clinic, in an interview.

The proportion of patients undergoing RA-related surgeries dropped between the two time periods of 1980-94 and 1995-2007. Of the 813 Olmsted County residents in the analysis, 189 underwent at least one surgical procedure involving joints, during a mean follow up of 9.6 years. The cumulative incidence of any joint surgery at 10 years after RA incidence for the 1980-94 cohort was 27.3%, compared with 19.5% for the 1995-2007 cohort (P = 0.08), which was not statistically significant.

More aggressive use of effective DMARDs with a reduction in the progression of radiographic joint damage was suggested as a possible reason for the decline in surgical procedures. "These findings reveal that modern medical management strategy has had markedly beneficial effects on the disease course," with less damage to the target small- and medium-size joints such as the hands, wrists, and feet than in past decades, noted Dr. Matteson, one of the report’s authors.

The greatest reduction in surgeries was seen in soft tissue procedures (synovectomy, tendon repair, tendon transfer, meniscus repair, ligament release, and/or cartilage repair). These decreased from 12% in 1980-94 to 6% in 1995-2007 at 10 years after RA incidence (P = .012).

No differences were found in the cumulative incidence of total hip arthroplasty (P = .77) or total knee arthroplasty (P = .18) between the time periods, reported the authors. Addressing the continued need for surgery on weight-bearing joints, particularly total knee and total hip arthroplasties, Dr. Matteson added, "in this respect patients are beginning to be more like people from the general population who have hip and knee replacements for osteoarthritis."

Study coinvestigator Cynthia Crowson of the Mayo Clinic’s biostatistics division noted in an interview that "persons with RA are requiring fewer surgeries, which may indicate [that] current management strategies are leading to less disability among patients who have developed RA since 1995" compared with previous times.

The study was supported by a grant from the National Institutes of Health, and was made possible by the Rochester Epidemiology Project. The authors reported having no financial disclosures.

Joint replacement surgery continues to become less common in patients with rheumatoid arthritis, probably reflecting the widespread adoption of disease modifying antirheumatic drugs, judging from findings of a population-based study published in this month’s Journal of Rheumatology.

Previous studies have found a trend for declining rates of joint surgery in patients with RA since 1985. In this study, "we examined whether the prior sex differences and use trends in reduced surgical intervention for RA persist in patients diagnosed after 1995, and evaluated the effect of RA surgery on survival in these patients," wrote Dr. Courtney A. Shourt and her associates from the Mayo Clinic in Rochester, Minn. (J. Rheumatol. 2012 Jan. 15 [doi:10.3899/jrheum.111056]).

"The possible contribution of RA-related joint surgery to excess mortality in patients with RA is largely unexplored," they pointed out.

A retrospective medical record review was performed using data from the Rochester Epidemiology Project (www.rochesterproject.org). The researchers reviewed records from a population-based cohort of 813 adult residents of Olmsted County, Minn., who had incident RA between Jan. 1, 1980, and Dec. 31, 2007. All cases were followed longitudinally until Dec. 31, 2008; death; or migration out of the county.

All joint surgeries were marginally associated with mortality (hazard ratio, 1.3; 95% confidence interval, 0.96-1.8; P = .09), but joint reconstructive procedures (JRPs) showed a significant association with mortality, adjusted for known RA mortality risk factors, compared with findings in patients not requiring JRP (HR, 2.8; 95% CI, 1.9-4.1; P less than .001). "The need for joint replacement surgery is still a marker of bad disease," commented Dr. Eric L. Matteson, professor of medicine and chair of rheumatology at the Mayo Clinic, in an interview.

The proportion of patients undergoing RA-related surgeries dropped between the two time periods of 1980-94 and 1995-2007. Of the 813 Olmsted County residents in the analysis, 189 underwent at least one surgical procedure involving joints, during a mean follow up of 9.6 years. The cumulative incidence of any joint surgery at 10 years after RA incidence for the 1980-94 cohort was 27.3%, compared with 19.5% for the 1995-2007 cohort (P = 0.08), which was not statistically significant.

More aggressive use of effective DMARDs with a reduction in the progression of radiographic joint damage was suggested as a possible reason for the decline in surgical procedures. "These findings reveal that modern medical management strategy has had markedly beneficial effects on the disease course," with less damage to the target small- and medium-size joints such as the hands, wrists, and feet than in past decades, noted Dr. Matteson, one of the report’s authors.

The greatest reduction in surgeries was seen in soft tissue procedures (synovectomy, tendon repair, tendon transfer, meniscus repair, ligament release, and/or cartilage repair). These decreased from 12% in 1980-94 to 6% in 1995-2007 at 10 years after RA incidence (P = .012).

No differences were found in the cumulative incidence of total hip arthroplasty (P = .77) or total knee arthroplasty (P = .18) between the time periods, reported the authors. Addressing the continued need for surgery on weight-bearing joints, particularly total knee and total hip arthroplasties, Dr. Matteson added, "in this respect patients are beginning to be more like people from the general population who have hip and knee replacements for osteoarthritis."

Study coinvestigator Cynthia Crowson of the Mayo Clinic’s biostatistics division noted in an interview that "persons with RA are requiring fewer surgeries, which may indicate [that] current management strategies are leading to less disability among patients who have developed RA since 1995" compared with previous times.

The study was supported by a grant from the National Institutes of Health, and was made possible by the Rochester Epidemiology Project. The authors reported having no financial disclosures.

The incidence of total knee arthroplasties increased from 0.5 operations per 100,000 inhabitants to 65 operations per 100,000 inhabitants aged 30-59 years during 1980-2006 in patients with primary knee osteoarthritis, according to a Finnish study.

Patients born shortly after World War II showed the most dramatic increases.

Incidences of unicondylar or partial knee arthroplasties (UKAs) were also found to grow from 0.2 operations per 100,000 inhabitants to 10 operations per 100,000 inhabitants over the same period in the same Finnish patient age group.

"This phenomenon has been especially strong during the 21st century. There is no single explanatory factor for this growth. Some of the increase in incidence can be explained by hospital volume," wrote Dr. Jarkko Leskinen, Consultant Orthopedic Surgeon, Peijas Hospital, Helsinki University Central Hospital, who was lead author of the study published in the January issue of Arthritis & Rheumatism (Arthritis Rheum. 2012;64:423-8).

"The demand for primary TKA [total knee arthroplasty] has been estimated to grow by 673 percent to 3.48 million procedures in the United States by the year 2030," reported Dr. Leskinen. Previous studies reported increases in the incidence of TKA in younger patients in Australia and the United States in the 1980s and 1990s. This study aimed to analyze the changes in age group as well as the sex-standardized incidence of UKAs and TKAs in Finland between the years 1980 and 2006.

Patient data were drawn from the Finnish Arthroplasty Registry, and population data were obtained from Statistics Finland. A total of 8,961 knee arthroplasties were performed for primary osteoarthritis in patients under age 60 during 1980-2006. In addition to evaluating the effects of age and gender on the incidences of knee arthroplasties, Dr. Leskinen and his colleagues evaluated the effects of hospital volume.

Overall, the incidence rate ratio (IRR) for the annual increase in general incidence of UKAs was lower than that of TKAs, with an IRR of 1.26 for UKAs (95% confidence interval, 1.24-1.28; P less than .001) and 6.92 for TKAs (95% CI, 6.50-7.36; P less than .001).

In particular, the study found that the TKA incidence rose sharply from 18 per 100,000 in 2001 to 65 per 100,000 in 2006. TKAs were performed more often in women than men, with a 1.6- to 2.4-fold higher incidence in women than men during the past 10 years. Since 2000, a greater number of UKAs also were performed in women than men. Most of the increased incidence in TKAs and UKAs was in women aged 50-59 years.

Regarding the incidence of TKAs by age group, patients aged 50-59 years showed the largest increase, from 1.5 TKAs per 100,000 in 1980 to 160 per 100,000 in 2006. Incidences of UKAs by age group showed a similar pattern to TKAs, with the most marked growth in patients aged 50-59 years, increasing from 0.5 to 24 operations per 100,000. Growth was most rapid after the year 2000.

"Possible explanations for this phenomenon include the high functional and quality of life demands of younger patients aged less than 60 years," the authors wrote. "Another reason could be that the baby boomers may opt for elective operations at an earlier stage with milder symptoms, than the situation that was faced by earlier generations."

Hospitals were divided into low-, intermediate-, and high-volume centers, according to the number of TKAs performed in all the hospitals in Finland in 2006. The incidence of TKAs grew more rapidly in low- and intermediate-volume hospitals, while the incidence of UKAs grew in low-volume hospitals. The IRR for TKAs was 1.23 in both comparisons of low- to high-volume centers (95% CI, 1.13-1.34; P less than .001), and intermediate- to high-volume centers (95%CI, 1.16-1.31; P less than .001).

The authors warned against the widespread use of TKAs in younger patients. "Long-term results in young patients may differ from those reported in older patients, and risk for revision may be higher," they concluded.

Dr. Leskinen and his colleagues reported having no financial disclosures.

The incidence of total knee arthroplasties increased from 0.5 operations per 100,000 inhabitants to 65 operations per 100,000 inhabitants aged 30-59 years during 1980-2006 in patients with primary knee osteoarthritis, according to a Finnish study.

Patients born shortly after World War II showed the most dramatic increases.

Incidences of unicondylar or partial knee arthroplasties (UKAs) were also found to grow from 0.2 operations per 100,000 inhabitants to 10 operations per 100,000 inhabitants over the same period in the same Finnish patient age group.

"This phenomenon has been especially strong during the 21st century. There is no single explanatory factor for this growth. Some of the increase in incidence can be explained by hospital volume," wrote Dr. Jarkko Leskinen, Consultant Orthopedic Surgeon, Peijas Hospital, Helsinki University Central Hospital, who was lead author of the study published in the January issue of Arthritis & Rheumatism (Arthritis Rheum. 2012;64:423-8).

"The demand for primary TKA [total knee arthroplasty] has been estimated to grow by 673 percent to 3.48 million procedures in the United States by the year 2030," reported Dr. Leskinen. Previous studies reported increases in the incidence of TKA in younger patients in Australia and the United States in the 1980s and 1990s. This study aimed to analyze the changes in age group as well as the sex-standardized incidence of UKAs and TKAs in Finland between the years 1980 and 2006.

Patient data were drawn from the Finnish Arthroplasty Registry, and population data were obtained from Statistics Finland. A total of 8,961 knee arthroplasties were performed for primary osteoarthritis in patients under age 60 during 1980-2006. In addition to evaluating the effects of age and gender on the incidences of knee arthroplasties, Dr. Leskinen and his colleagues evaluated the effects of hospital volume.

Overall, the incidence rate ratio (IRR) for the annual increase in general incidence of UKAs was lower than that of TKAs, with an IRR of 1.26 for UKAs (95% confidence interval, 1.24-1.28; P less than .001) and 6.92 for TKAs (95% CI, 6.50-7.36; P less than .001).

In particular, the study found that the TKA incidence rose sharply from 18 per 100,000 in 2001 to 65 per 100,000 in 2006. TKAs were performed more often in women than men, with a 1.6- to 2.4-fold higher incidence in women than men during the past 10 years. Since 2000, a greater number of UKAs also were performed in women than men. Most of the increased incidence in TKAs and UKAs was in women aged 50-59 years.

Regarding the incidence of TKAs by age group, patients aged 50-59 years showed the largest increase, from 1.5 TKAs per 100,000 in 1980 to 160 per 100,000 in 2006. Incidences of UKAs by age group showed a similar pattern to TKAs, with the most marked growth in patients aged 50-59 years, increasing from 0.5 to 24 operations per 100,000. Growth was most rapid after the year 2000.

"Possible explanations for this phenomenon include the high functional and quality of life demands of younger patients aged less than 60 years," the authors wrote. "Another reason could be that the baby boomers may opt for elective operations at an earlier stage with milder symptoms, than the situation that was faced by earlier generations."

Hospitals were divided into low-, intermediate-, and high-volume centers, according to the number of TKAs performed in all the hospitals in Finland in 2006. The incidence of TKAs grew more rapidly in low- and intermediate-volume hospitals, while the incidence of UKAs grew in low-volume hospitals. The IRR for TKAs was 1.23 in both comparisons of low- to high-volume centers (95% CI, 1.13-1.34; P less than .001), and intermediate- to high-volume centers (95%CI, 1.16-1.31; P less than .001).

The authors warned against the widespread use of TKAs in younger patients. "Long-term results in young patients may differ from those reported in older patients, and risk for revision may be higher," they concluded.

Dr. Leskinen and his colleagues reported having no financial disclosures.

The incidence of total knee arthroplasties increased from 0.5 operations per 100,000 inhabitants to 65 operations per 100,000 inhabitants aged 30-59 years during 1980-2006 in patients with primary knee osteoarthritis, according to a Finnish study.

Patients born shortly after World War II showed the most dramatic increases.

Incidences of unicondylar or partial knee arthroplasties (UKAs) were also found to grow from 0.2 operations per 100,000 inhabitants to 10 operations per 100,000 inhabitants over the same period in the same Finnish patient age group.

"This phenomenon has been especially strong during the 21st century. There is no single explanatory factor for this growth. Some of the increase in incidence can be explained by hospital volume," wrote Dr. Jarkko Leskinen, Consultant Orthopedic Surgeon, Peijas Hospital, Helsinki University Central Hospital, who was lead author of the study published in the January issue of Arthritis & Rheumatism (Arthritis Rheum. 2012;64:423-8).

"The demand for primary TKA [total knee arthroplasty] has been estimated to grow by 673 percent to 3.48 million procedures in the United States by the year 2030," reported Dr. Leskinen. Previous studies reported increases in the incidence of TKA in younger patients in Australia and the United States in the 1980s and 1990s. This study aimed to analyze the changes in age group as well as the sex-standardized incidence of UKAs and TKAs in Finland between the years 1980 and 2006.

Patient data were drawn from the Finnish Arthroplasty Registry, and population data were obtained from Statistics Finland. A total of 8,961 knee arthroplasties were performed for primary osteoarthritis in patients under age 60 during 1980-2006. In addition to evaluating the effects of age and gender on the incidences of knee arthroplasties, Dr. Leskinen and his colleagues evaluated the effects of hospital volume.

Overall, the incidence rate ratio (IRR) for the annual increase in general incidence of UKAs was lower than that of TKAs, with an IRR of 1.26 for UKAs (95% confidence interval, 1.24-1.28; P less than .001) and 6.92 for TKAs (95% CI, 6.50-7.36; P less than .001).

In particular, the study found that the TKA incidence rose sharply from 18 per 100,000 in 2001 to 65 per 100,000 in 2006. TKAs were performed more often in women than men, with a 1.6- to 2.4-fold higher incidence in women than men during the past 10 years. Since 2000, a greater number of UKAs also were performed in women than men. Most of the increased incidence in TKAs and UKAs was in women aged 50-59 years.

Regarding the incidence of TKAs by age group, patients aged 50-59 years showed the largest increase, from 1.5 TKAs per 100,000 in 1980 to 160 per 100,000 in 2006. Incidences of UKAs by age group showed a similar pattern to TKAs, with the most marked growth in patients aged 50-59 years, increasing from 0.5 to 24 operations per 100,000. Growth was most rapid after the year 2000.

"Possible explanations for this phenomenon include the high functional and quality of life demands of younger patients aged less than 60 years," the authors wrote. "Another reason could be that the baby boomers may opt for elective operations at an earlier stage with milder symptoms, than the situation that was faced by earlier generations."

Hospitals were divided into low-, intermediate-, and high-volume centers, according to the number of TKAs performed in all the hospitals in Finland in 2006. The incidence of TKAs grew more rapidly in low- and intermediate-volume hospitals, while the incidence of UKAs grew in low-volume hospitals. The IRR for TKAs was 1.23 in both comparisons of low- to high-volume centers (95% CI, 1.13-1.34; P less than .001), and intermediate- to high-volume centers (95%CI, 1.16-1.31; P less than .001).

The authors warned against the widespread use of TKAs in younger patients. "Long-term results in young patients may differ from those reported in older patients, and risk for revision may be higher," they concluded.

Dr. Leskinen and his colleagues reported having no financial disclosures.

Oral glucocorticoid therapy increases the risk of serious infection in elderly patients with rheumatoid arthritis, even when the drugs were stopped as long as 2.5 years earlier, according to findings from a recently published study.

The researchers used a novel, weighted cumulative dose model to assess serious infection risk associated with glucocorticoid exposure, providing greater accuracy over conventional models.

Conducted in Quebec, the case-control analysis assessed the infection risk in 16,207 patients who were at least 65 years of age and who had rheumatoid arthritis (RA). The findings showed that taking a 5 mg/day dose of prednisolone for 12 months increases risk of serious infection by 55%, compared to non-users. Furthermore, this risk was found to increase cumulatively to 100% (odds ratio, 2.00; 95% confidence interval, 1.69 to 2.26) in patients who took prednisolone for 3 years (Ann. Rheum. Dis. 2012 Jan. 12 [doi:10.1136/annrheumdis-2011-200702]).

"This is important as many physicians consider a 5 mg [daily prednisolone equivalent dosage] a ‘physiological dose’ that may not have important harms," according to Dr. William G. Dixon, Medical Research Council Clinician Scientist at the University of Manchester (England).

The investigators noted that 1,927 patients developed a first serious infection after an average 3.8 years of follow up. Patients who are currently or recently taking glucocorticoid therapy had the greatest risk of serious infection. The analysis showed that a current user on 5 mg/day prednisolone had an increased risk over non-users of 11% (OR, 1.11), 30% (OR, 1.30), and 55% (OR, 1.46) after 1 month, 3 months, and 12 months of use respectively.

"The risk associated with 5 mg prednisolone taken for the last 3 years was similar to that associated with 30 mg taken for the last month," noted Dr. Dixon and his associates.

The impact of discontinuation of glucocorticoid therapy was also investigated. Discontinuing a 2-year course of a 10-mg daily dose of prednisolone for 6 months was found to halve risk compared to continued use (OR, 1.87; CI, 1.32 to 2.63).

Dr. Dixon used a weighted, cumulative-dose model to assess the risk of serious infection associated with glucocorticoid exposure. This enabled doses to be given a weighting determined by how recently the patient took that dose. The authors note that this model "provides a far superior fit than all conventional models."

Dr. Jeffrey Curtis commented in an interview that the weighted cumulative dose model represents an advance. "The advance here is that there may be preferable ways to model steroid dose that allow for different estimations of risk, and presumably more accurate estimations. In the model used here, the researchers take into account the patients’ history of steroid therapy."

However, the study did not resolve the issue of confounding by indication, in which the effects of more active and severe disease can be difficult to disentangle from the effects of drugs, noted Dr. Curtis, who is director of the Arthritis Clinical Intervention Program Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham.

"I think the risks with steroid therapy may produce different estimations of risk depending on the data source used, and the pattern of use in any particular disease. Analysis needs to be done by disease."

Addressing the issue of whether serious infection risk in patients with autoimmune diseases was associated with glucocorticoids, biologics, or non-biologic treatments, Dr. Curtis referred to a recently published paper he coauthored (JAMA 2011;306:2331-9). "We found a significantly increased risk of serious infection for steroid therapy but no greater risk overall for tumor necrosis factor (TNF)–alpha antagonists compared to patients receiving non-biologic treatments in a range of autoimmune diseases."

The study was funded by the Canadian Institutes of Health Research and the Canadian Foundation for Innovation. The lead author received support from a Medical Research Council Clinician Scientist Fellowship. The authors did not report having any other financial disclosures. Dr. Curtis is a consultant to various pharmaceutical companies that manufacture biologic therapies but he has no disclosures of relevance to glucocorticoids.

Oral glucocorticoid therapy increases the risk of serious infection in elderly patients with rheumatoid arthritis, even when the drugs were stopped as long as 2.5 years earlier, according to findings from a recently published study.

The researchers used a novel, weighted cumulative dose model to assess serious infection risk associated with glucocorticoid exposure, providing greater accuracy over conventional models.

Conducted in Quebec, the case-control analysis assessed the infection risk in 16,207 patients who were at least 65 years of age and who had rheumatoid arthritis (RA). The findings showed that taking a 5 mg/day dose of prednisolone for 12 months increases risk of serious infection by 55%, compared to non-users. Furthermore, this risk was found to increase cumulatively to 100% (odds ratio, 2.00; 95% confidence interval, 1.69 to 2.26) in patients who took prednisolone for 3 years (Ann. Rheum. Dis. 2012 Jan. 12 [doi:10.1136/annrheumdis-2011-200702]).

"This is important as many physicians consider a 5 mg [daily prednisolone equivalent dosage] a ‘physiological dose’ that may not have important harms," according to Dr. William G. Dixon, Medical Research Council Clinician Scientist at the University of Manchester (England).

The investigators noted that 1,927 patients developed a first serious infection after an average 3.8 years of follow up. Patients who are currently or recently taking glucocorticoid therapy had the greatest risk of serious infection. The analysis showed that a current user on 5 mg/day prednisolone had an increased risk over non-users of 11% (OR, 1.11), 30% (OR, 1.30), and 55% (OR, 1.46) after 1 month, 3 months, and 12 months of use respectively.

"The risk associated with 5 mg prednisolone taken for the last 3 years was similar to that associated with 30 mg taken for the last month," noted Dr. Dixon and his associates.

The impact of discontinuation of glucocorticoid therapy was also investigated. Discontinuing a 2-year course of a 10-mg daily dose of prednisolone for 6 months was found to halve risk compared to continued use (OR, 1.87; CI, 1.32 to 2.63).

Dr. Dixon used a weighted, cumulative-dose model to assess the risk of serious infection associated with glucocorticoid exposure. This enabled doses to be given a weighting determined by how recently the patient took that dose. The authors note that this model "provides a far superior fit than all conventional models."

Dr. Jeffrey Curtis commented in an interview that the weighted cumulative dose model represents an advance. "The advance here is that there may be preferable ways to model steroid dose that allow for different estimations of risk, and presumably more accurate estimations. In the model used here, the researchers take into account the patients’ history of steroid therapy."

However, the study did not resolve the issue of confounding by indication, in which the effects of more active and severe disease can be difficult to disentangle from the effects of drugs, noted Dr. Curtis, who is director of the Arthritis Clinical Intervention Program Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham.

"I think the risks with steroid therapy may produce different estimations of risk depending on the data source used, and the pattern of use in any particular disease. Analysis needs to be done by disease."

Addressing the issue of whether serious infection risk in patients with autoimmune diseases was associated with glucocorticoids, biologics, or non-biologic treatments, Dr. Curtis referred to a recently published paper he coauthored (JAMA 2011;306:2331-9). "We found a significantly increased risk of serious infection for steroid therapy but no greater risk overall for tumor necrosis factor (TNF)–alpha antagonists compared to patients receiving non-biologic treatments in a range of autoimmune diseases."

The study was funded by the Canadian Institutes of Health Research and the Canadian Foundation for Innovation. The lead author received support from a Medical Research Council Clinician Scientist Fellowship. The authors did not report having any other financial disclosures. Dr. Curtis is a consultant to various pharmaceutical companies that manufacture biologic therapies but he has no disclosures of relevance to glucocorticoids.

Oral glucocorticoid therapy increases the risk of serious infection in elderly patients with rheumatoid arthritis, even when the drugs were stopped as long as 2.5 years earlier, according to findings from a recently published study.

The researchers used a novel, weighted cumulative dose model to assess serious infection risk associated with glucocorticoid exposure, providing greater accuracy over conventional models.

Conducted in Quebec, the case-control analysis assessed the infection risk in 16,207 patients who were at least 65 years of age and who had rheumatoid arthritis (RA). The findings showed that taking a 5 mg/day dose of prednisolone for 12 months increases risk of serious infection by 55%, compared to non-users. Furthermore, this risk was found to increase cumulatively to 100% (odds ratio, 2.00; 95% confidence interval, 1.69 to 2.26) in patients who took prednisolone for 3 years (Ann. Rheum. Dis. 2012 Jan. 12 [doi:10.1136/annrheumdis-2011-200702]).

"This is important as many physicians consider a 5 mg [daily prednisolone equivalent dosage] a ‘physiological dose’ that may not have important harms," according to Dr. William G. Dixon, Medical Research Council Clinician Scientist at the University of Manchester (England).

The investigators noted that 1,927 patients developed a first serious infection after an average 3.8 years of follow up. Patients who are currently or recently taking glucocorticoid therapy had the greatest risk of serious infection. The analysis showed that a current user on 5 mg/day prednisolone had an increased risk over non-users of 11% (OR, 1.11), 30% (OR, 1.30), and 55% (OR, 1.46) after 1 month, 3 months, and 12 months of use respectively.

"The risk associated with 5 mg prednisolone taken for the last 3 years was similar to that associated with 30 mg taken for the last month," noted Dr. Dixon and his associates.

The impact of discontinuation of glucocorticoid therapy was also investigated. Discontinuing a 2-year course of a 10-mg daily dose of prednisolone for 6 months was found to halve risk compared to continued use (OR, 1.87; CI, 1.32 to 2.63).

Dr. Dixon used a weighted, cumulative-dose model to assess the risk of serious infection associated with glucocorticoid exposure. This enabled doses to be given a weighting determined by how recently the patient took that dose. The authors note that this model "provides a far superior fit than all conventional models."

Dr. Jeffrey Curtis commented in an interview that the weighted cumulative dose model represents an advance. "The advance here is that there may be preferable ways to model steroid dose that allow for different estimations of risk, and presumably more accurate estimations. In the model used here, the researchers take into account the patients’ history of steroid therapy."

However, the study did not resolve the issue of confounding by indication, in which the effects of more active and severe disease can be difficult to disentangle from the effects of drugs, noted Dr. Curtis, who is director of the Arthritis Clinical Intervention Program Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham.

"I think the risks with steroid therapy may produce different estimations of risk depending on the data source used, and the pattern of use in any particular disease. Analysis needs to be done by disease."

Addressing the issue of whether serious infection risk in patients with autoimmune diseases was associated with glucocorticoids, biologics, or non-biologic treatments, Dr. Curtis referred to a recently published paper he coauthored (JAMA 2011;306:2331-9). "We found a significantly increased risk of serious infection for steroid therapy but no greater risk overall for tumor necrosis factor (TNF)–alpha antagonists compared to patients receiving non-biologic treatments in a range of autoimmune diseases."

The study was funded by the Canadian Institutes of Health Research and the Canadian Foundation for Innovation. The lead author received support from a Medical Research Council Clinician Scientist Fellowship. The authors did not report having any other financial disclosures. Dr. Curtis is a consultant to various pharmaceutical companies that manufacture biologic therapies but he has no disclosures of relevance to glucocorticoids.