Rheumatoid Arthritis

The cardiovascular risk in rheumatoid arthritis is comparable to that of diabetes, a large Danish study has shown.

Further, the risk of myocardial infarction (MI) in rheumatoid arthritis patients corresponds to that observed in the general population of individuals without the musculoskeletal condition who are, on average, 10 years older and does not appear to be affected by the duration of drug treatment for the disease, Dr. Jesper Lindhardsen of Gentofte University Hospital in Copenhagen, Denmark, and colleagues reported.

Using nationwide registers encompassing the entire Danish population older than 16 years, the investigators identified individuals with new-onset rheumatoid arthritis (RA), new onset diabetes, and new MI during a 10-year period, excluding individuals with prior disease and incomplete data entries from the full cohort of 4,311,022 subjects, they wrote.

During the 10-year study period, 9,921 individuals developed RA and 129,659 developed diabetes, the authors reported. Compared with the diabetes patients, "RA patients were more often women, used less cardioprotective medications, and had less comorbidity, whereas age was similar in the two groups," they reported.

Regarding cardiovascular outcomes, 265 of the RA patients and 3,948 of the diabetes patients had new MI, representing in both cohorts a 1.7 increased incidence rate ratio (IRR) of MI in a fully adjusted model compared with the general population in which 75,870 individuals had new myocardial infarctions, they wrote. The IRR among patients with both RA and diabetes was 2.6, "which roughly equaled the predicted additive risk for the two separate diseases, they wrote (Ann. Rheum. Dis. 2011;70:929-34).

The investigators conducted a nested case-control study that corroborated the comparable risk of MI in the RA and diabetes patients. The findings demonstrated that the increased risk in these groups was independent of treatment duration within the timeframe of the current study, they wrote.

Stratified by gender, the MI risk estimates did not differ between women and men in the RA group. In the diabetes patients, however, women were at significantly higher risk than men for the adverse cardiovascular outcome, the authors wrote. An age-dependent pattern of MI risk was also observed. Specifically, among women with RA and diabetes, respectively, the risk of MI in those younger than 50 years old was 5.5 and 5.9 times that observed in the age-matched reference group, they reported. Additionally, for women between 50 and 65 years of age, the IRRs were 1.7 and 2.6 for RA and diabetes patients, respectively.

The age-stratified patterns observed in men were different, the authors stated, noting that "the IRRs in the two oldest age groups were comparable, and even tended to be slightly higher in the 50-65 years age group of RA patients compared to the same-aged [diabetes] patients." And while the youngest men with RA had a markedly raised IRR, diabetes patients in the same age stratum had a significantly higher risk, with an IRR of 4.9 compared with 2.1, they said.

In a fully adjusted regression model in which the IRRs for MI in RA patients were calculated according to 10-year subject age intervals, "RA patients had the same, or higher, risk of MI as control subjects who were, on average, 10 years older," the authors reported.

Although the study has several limitations, including the identification of RA patients based on dispensed prescriptions and diagnosis versus the 1987 American College of Rheumatology criteria, the reliance on the use of glucose-lowering drugs as a proxy for diabetes, and the lack of information about classic cardiovascular risk factors, "the results corroborate and expand previous findings in this area of research and indicate that patients with RA should be considered for more aggressive primary [cardiovascular disease] prevention," the authors stressed.

In an accompanying editorial, Dr. Michael T. Nurmohamed and Dr. George Kitas of VU University Medical Centre in Amsterdam wrote that the findings of the current study should put to bed any doubt or debate about an enhanced cardiovascular risk in RA. "Importantly, they also provide further evidence that the cardiovascular risk in RA is broadly similar to that of contemporarily managed diabetes," they stated. The results of the study, as well as the success of cardiovascular risk management in diabetes provides a clear incentive to identify and actively manage, if necessary, cardiovascular risk in all RA patients as part of quality routine rheumatological practice" (Ann. Rheum. Dis. 2011;70:881-3).

The study was sponsored by an unrestricted grant from the Danish Rheumatism Association. The authors of the study and the accompanying editorial reported having no conflicts of interest to disclose.

The cardiovascular risk in rheumatoid arthritis is comparable to that of diabetes, a large Danish study has shown.

Further, the risk of myocardial infarction (MI) in rheumatoid arthritis patients corresponds to that observed in the general population of individuals without the musculoskeletal condition who are, on average, 10 years older and does not appear to be affected by the duration of drug treatment for the disease, Dr. Jesper Lindhardsen of Gentofte University Hospital in Copenhagen, Denmark, and colleagues reported.

Using nationwide registers encompassing the entire Danish population older than 16 years, the investigators identified individuals with new-onset rheumatoid arthritis (RA), new onset diabetes, and new MI during a 10-year period, excluding individuals with prior disease and incomplete data entries from the full cohort of 4,311,022 subjects, they wrote.

During the 10-year study period, 9,921 individuals developed RA and 129,659 developed diabetes, the authors reported. Compared with the diabetes patients, "RA patients were more often women, used less cardioprotective medications, and had less comorbidity, whereas age was similar in the two groups," they reported.

Regarding cardiovascular outcomes, 265 of the RA patients and 3,948 of the diabetes patients had new MI, representing in both cohorts a 1.7 increased incidence rate ratio (IRR) of MI in a fully adjusted model compared with the general population in which 75,870 individuals had new myocardial infarctions, they wrote. The IRR among patients with both RA and diabetes was 2.6, "which roughly equaled the predicted additive risk for the two separate diseases, they wrote (Ann. Rheum. Dis. 2011;70:929-34).

The investigators conducted a nested case-control study that corroborated the comparable risk of MI in the RA and diabetes patients. The findings demonstrated that the increased risk in these groups was independent of treatment duration within the timeframe of the current study, they wrote.

Stratified by gender, the MI risk estimates did not differ between women and men in the RA group. In the diabetes patients, however, women were at significantly higher risk than men for the adverse cardiovascular outcome, the authors wrote. An age-dependent pattern of MI risk was also observed. Specifically, among women with RA and diabetes, respectively, the risk of MI in those younger than 50 years old was 5.5 and 5.9 times that observed in the age-matched reference group, they reported. Additionally, for women between 50 and 65 years of age, the IRRs were 1.7 and 2.6 for RA and diabetes patients, respectively.

The age-stratified patterns observed in men were different, the authors stated, noting that "the IRRs in the two oldest age groups were comparable, and even tended to be slightly higher in the 50-65 years age group of RA patients compared to the same-aged [diabetes] patients." And while the youngest men with RA had a markedly raised IRR, diabetes patients in the same age stratum had a significantly higher risk, with an IRR of 4.9 compared with 2.1, they said.

In a fully adjusted regression model in which the IRRs for MI in RA patients were calculated according to 10-year subject age intervals, "RA patients had the same, or higher, risk of MI as control subjects who were, on average, 10 years older," the authors reported.

Although the study has several limitations, including the identification of RA patients based on dispensed prescriptions and diagnosis versus the 1987 American College of Rheumatology criteria, the reliance on the use of glucose-lowering drugs as a proxy for diabetes, and the lack of information about classic cardiovascular risk factors, "the results corroborate and expand previous findings in this area of research and indicate that patients with RA should be considered for more aggressive primary [cardiovascular disease] prevention," the authors stressed.

In an accompanying editorial, Dr. Michael T. Nurmohamed and Dr. George Kitas of VU University Medical Centre in Amsterdam wrote that the findings of the current study should put to bed any doubt or debate about an enhanced cardiovascular risk in RA. "Importantly, they also provide further evidence that the cardiovascular risk in RA is broadly similar to that of contemporarily managed diabetes," they stated. The results of the study, as well as the success of cardiovascular risk management in diabetes provides a clear incentive to identify and actively manage, if necessary, cardiovascular risk in all RA patients as part of quality routine rheumatological practice" (Ann. Rheum. Dis. 2011;70:881-3).

The study was sponsored by an unrestricted grant from the Danish Rheumatism Association. The authors of the study and the accompanying editorial reported having no conflicts of interest to disclose.

The cardiovascular risk in rheumatoid arthritis is comparable to that of diabetes, a large Danish study has shown.

Further, the risk of myocardial infarction (MI) in rheumatoid arthritis patients corresponds to that observed in the general population of individuals without the musculoskeletal condition who are, on average, 10 years older and does not appear to be affected by the duration of drug treatment for the disease, Dr. Jesper Lindhardsen of Gentofte University Hospital in Copenhagen, Denmark, and colleagues reported.

Using nationwide registers encompassing the entire Danish population older than 16 years, the investigators identified individuals with new-onset rheumatoid arthritis (RA), new onset diabetes, and new MI during a 10-year period, excluding individuals with prior disease and incomplete data entries from the full cohort of 4,311,022 subjects, they wrote.

During the 10-year study period, 9,921 individuals developed RA and 129,659 developed diabetes, the authors reported. Compared with the diabetes patients, "RA patients were more often women, used less cardioprotective medications, and had less comorbidity, whereas age was similar in the two groups," they reported.

Regarding cardiovascular outcomes, 265 of the RA patients and 3,948 of the diabetes patients had new MI, representing in both cohorts a 1.7 increased incidence rate ratio (IRR) of MI in a fully adjusted model compared with the general population in which 75,870 individuals had new myocardial infarctions, they wrote. The IRR among patients with both RA and diabetes was 2.6, "which roughly equaled the predicted additive risk for the two separate diseases, they wrote (Ann. Rheum. Dis. 2011;70:929-34).

The investigators conducted a nested case-control study that corroborated the comparable risk of MI in the RA and diabetes patients. The findings demonstrated that the increased risk in these groups was independent of treatment duration within the timeframe of the current study, they wrote.

Stratified by gender, the MI risk estimates did not differ between women and men in the RA group. In the diabetes patients, however, women were at significantly higher risk than men for the adverse cardiovascular outcome, the authors wrote. An age-dependent pattern of MI risk was also observed. Specifically, among women with RA and diabetes, respectively, the risk of MI in those younger than 50 years old was 5.5 and 5.9 times that observed in the age-matched reference group, they reported. Additionally, for women between 50 and 65 years of age, the IRRs were 1.7 and 2.6 for RA and diabetes patients, respectively.

The age-stratified patterns observed in men were different, the authors stated, noting that "the IRRs in the two oldest age groups were comparable, and even tended to be slightly higher in the 50-65 years age group of RA patients compared to the same-aged [diabetes] patients." And while the youngest men with RA had a markedly raised IRR, diabetes patients in the same age stratum had a significantly higher risk, with an IRR of 4.9 compared with 2.1, they said.

In a fully adjusted regression model in which the IRRs for MI in RA patients were calculated according to 10-year subject age intervals, "RA patients had the same, or higher, risk of MI as control subjects who were, on average, 10 years older," the authors reported.

Although the study has several limitations, including the identification of RA patients based on dispensed prescriptions and diagnosis versus the 1987 American College of Rheumatology criteria, the reliance on the use of glucose-lowering drugs as a proxy for diabetes, and the lack of information about classic cardiovascular risk factors, "the results corroborate and expand previous findings in this area of research and indicate that patients with RA should be considered for more aggressive primary [cardiovascular disease] prevention," the authors stressed.

In an accompanying editorial, Dr. Michael T. Nurmohamed and Dr. George Kitas of VU University Medical Centre in Amsterdam wrote that the findings of the current study should put to bed any doubt or debate about an enhanced cardiovascular risk in RA. "Importantly, they also provide further evidence that the cardiovascular risk in RA is broadly similar to that of contemporarily managed diabetes," they stated. The results of the study, as well as the success of cardiovascular risk management in diabetes provides a clear incentive to identify and actively manage, if necessary, cardiovascular risk in all RA patients as part of quality routine rheumatological practice" (Ann. Rheum. Dis. 2011;70:881-3).

The study was sponsored by an unrestricted grant from the Danish Rheumatism Association. The authors of the study and the accompanying editorial reported having no conflicts of interest to disclose.

CHICAGO – The risk of both interstitial and obstructive lung disease is increased in patients with rheumatoid arthritis, as is mortality in affected, compared with unaffected, arthritis patients.

In a cohort of rheumatoid arthritis (RA) patients from a single county in Minnesota who have been followed since 1955, the risk of developing interstitial lung disease is about 8%, compared with less than 1% in the general population, Dr. Eric Matteson reported at a symposium sponsored by the American College of Rheumatology.

"The hazard ratio for developing interstitial lung disease, compared to non-RA patients, is about a ninefold increase, so this is an enormous difference," said Dr. Matteson, professor of medicine and chair of the division of rheumatology and health sciences research at the Mayo Clinic, Rochester, Minn.

Furthermore, these patients with interstitial lung disease have much higher mortality than RA patients who do not have interstitial lung disease (hazard ratio 2.14), he said.

The findings compare well with those from a recently completed survey, which used National Center for Health Statistics data and suggested that, while mortality in RA in general has declined, the rates of interstitial lung disease are increasing.

"We’re probably seeing more [interstitial lung disease in RA patients] today than we did maybe 10, 20, and certainly 30 years ago," Dr. Matteson said.

It is possible that the declines in RA mortality overall are outpacing those from interstitial lung disease. Although biologics being used to treat RA are helping joint disease and other extra-articular manifestations of RA, there is no evidence that they influence the development of interstitial lung disease, he suggested.

Obstructive lung disease is also a concern in RA patients, and although the difference in incidence between RA patients and the general population is smaller than with interstitial lung disease, this finding may be more surprising, Dr. Matteson said, noting that this information from the Minnesota cohort was new to him.

"It appears that rheumatoid arthritis is a risk factor for obstructive lung disease," he said. After correcting for age, sex, and smoking status, there is about a 50% increase in the incidence of obstructive lung disease in RA patients, compared with the general population.

The reason for this is unclear, but "intriguing new data" suggest that the cystic fibrosis genes and some related genes are risk factors for developing bronchiolitis and other forms of obstructive disease in RA, so that may be part of the biologic answer, he said.

There is a biologic reason why these patients also may be at higher risk for obstructive lung disease as well as interstitial lung disease, he said.

And like interstitial lung disease, obstructive lung disease also adversely affects mortality in RA patients (hazard ratio of 1.87 for affected vs. nonaffected RA patients), he noted.

CHICAGO – The risk of both interstitial and obstructive lung disease is increased in patients with rheumatoid arthritis, as is mortality in affected, compared with unaffected, arthritis patients.

In a cohort of rheumatoid arthritis (RA) patients from a single county in Minnesota who have been followed since 1955, the risk of developing interstitial lung disease is about 8%, compared with less than 1% in the general population, Dr. Eric Matteson reported at a symposium sponsored by the American College of Rheumatology.

"The hazard ratio for developing interstitial lung disease, compared to non-RA patients, is about a ninefold increase, so this is an enormous difference," said Dr. Matteson, professor of medicine and chair of the division of rheumatology and health sciences research at the Mayo Clinic, Rochester, Minn.

Furthermore, these patients with interstitial lung disease have much higher mortality than RA patients who do not have interstitial lung disease (hazard ratio 2.14), he said.

The findings compare well with those from a recently completed survey, which used National Center for Health Statistics data and suggested that, while mortality in RA in general has declined, the rates of interstitial lung disease are increasing.

"We’re probably seeing more [interstitial lung disease in RA patients] today than we did maybe 10, 20, and certainly 30 years ago," Dr. Matteson said.

It is possible that the declines in RA mortality overall are outpacing those from interstitial lung disease. Although biologics being used to treat RA are helping joint disease and other extra-articular manifestations of RA, there is no evidence that they influence the development of interstitial lung disease, he suggested.

Obstructive lung disease is also a concern in RA patients, and although the difference in incidence between RA patients and the general population is smaller than with interstitial lung disease, this finding may be more surprising, Dr. Matteson said, noting that this information from the Minnesota cohort was new to him.

"It appears that rheumatoid arthritis is a risk factor for obstructive lung disease," he said. After correcting for age, sex, and smoking status, there is about a 50% increase in the incidence of obstructive lung disease in RA patients, compared with the general population.

The reason for this is unclear, but "intriguing new data" suggest that the cystic fibrosis genes and some related genes are risk factors for developing bronchiolitis and other forms of obstructive disease in RA, so that may be part of the biologic answer, he said.

There is a biologic reason why these patients also may be at higher risk for obstructive lung disease as well as interstitial lung disease, he said.

And like interstitial lung disease, obstructive lung disease also adversely affects mortality in RA patients (hazard ratio of 1.87 for affected vs. nonaffected RA patients), he noted.

CHICAGO – The risk of both interstitial and obstructive lung disease is increased in patients with rheumatoid arthritis, as is mortality in affected, compared with unaffected, arthritis patients.

In a cohort of rheumatoid arthritis (RA) patients from a single county in Minnesota who have been followed since 1955, the risk of developing interstitial lung disease is about 8%, compared with less than 1% in the general population, Dr. Eric Matteson reported at a symposium sponsored by the American College of Rheumatology.

"The hazard ratio for developing interstitial lung disease, compared to non-RA patients, is about a ninefold increase, so this is an enormous difference," said Dr. Matteson, professor of medicine and chair of the division of rheumatology and health sciences research at the Mayo Clinic, Rochester, Minn.

Furthermore, these patients with interstitial lung disease have much higher mortality than RA patients who do not have interstitial lung disease (hazard ratio 2.14), he said.

The findings compare well with those from a recently completed survey, which used National Center for Health Statistics data and suggested that, while mortality in RA in general has declined, the rates of interstitial lung disease are increasing.

"We’re probably seeing more [interstitial lung disease in RA patients] today than we did maybe 10, 20, and certainly 30 years ago," Dr. Matteson said.

It is possible that the declines in RA mortality overall are outpacing those from interstitial lung disease. Although biologics being used to treat RA are helping joint disease and other extra-articular manifestations of RA, there is no evidence that they influence the development of interstitial lung disease, he suggested.

Obstructive lung disease is also a concern in RA patients, and although the difference in incidence between RA patients and the general population is smaller than with interstitial lung disease, this finding may be more surprising, Dr. Matteson said, noting that this information from the Minnesota cohort was new to him.

"It appears that rheumatoid arthritis is a risk factor for obstructive lung disease," he said. After correcting for age, sex, and smoking status, there is about a 50% increase in the incidence of obstructive lung disease in RA patients, compared with the general population.

The reason for this is unclear, but "intriguing new data" suggest that the cystic fibrosis genes and some related genes are risk factors for developing bronchiolitis and other forms of obstructive disease in RA, so that may be part of the biologic answer, he said.

There is a biologic reason why these patients also may be at higher risk for obstructive lung disease as well as interstitial lung disease, he said.

And like interstitial lung disease, obstructive lung disease also adversely affects mortality in RA patients (hazard ratio of 1.87 for affected vs. nonaffected RA patients), he noted.

CHICAGO – Despite dramatic clinical benefit, the standard treatments for ankylosing spondylitis do not appear to alter the natural history of the disease.

"We’d like to believe we’re actually doing something substantial for our patients in addition to actually relieving symptoms," said Dr. Michael H. Weisman, adding that this is an area of "hot, current controversy."

Nonsteroidal anti-inflammatory drugs, for example, are clinically very useful for treating patients with ankylosing spondylitis (AS). In a study of NSAID treatment for AS and mechanical back pain, good clinical response occurred in 75% of the AS patients, compared with only about 15% of the patients with mechanical back pain (Rev. Rhum. Engl. Ed. 1995;62:10-5), Dr. Weisman said at a symposium sponsored by the American College of Rheumatology.

The response of AS patients to NSAIDs is so good, in fact, that it can be helpful for confirming the diagnosis. A greater complete response may indicate that AS is the cause of symptoms, he said.

Another study demonstrated that 70% of AS patients who received etoricoxib had a good clinical response, compared with about 20% who received placebo (Arthritis Rheum. 2005;52:1205-15).

However, the effects of NSAIDs on radiographic progression of disease are questionable, at best, said Dr. Weisman, director of the division of rheumatology and professor of medicine at Cedars-Sinai Medical Center, Los Angeles.

Although findings from one study showed that there was less radiographic progression of disease after 2 years in patients on continuous versus on-demand NSAIDs, with a mean change on the modified Stoke Ankylosing Spondylitis Spinal Score of 0.4 vs. 1.5, respectively (Arthritis Rheum. 2005;52:1756-65), most experts "take this particular study with a grain of salt," Dr. Weisman said.

That’s in part because the mean difference in dose between the continuous and on-demand patients was only 50 mg/day. It’s very difficult to believe that a difference of 50 mg in celecoxib could make a difference in actually reducing the amount of bone formation in AS, he said.

Tumor necrosis factor (TNF) blockers also provide excellent clinical benefit and are approved for use in AS. Patients experience tremendous response, perhaps to even a greater degree than do rheumatoid arthritis patients and, unlike RA patients, there appears to be no increased risk of serious infection with treatment, he noted.

In a recent meta-analysis of randomized, placebo-controlled studies of anti-TNF drugs in AS, no difference was seen in the rate of serious infections in those who received active treatment versus those who received placebo (Ann. Rheum. Dis. 2010; 69:1756-61).

However, while anti-TNF agents have the potential to alter the natural history and prognosis of AS, there is also no evidence in any studies of etanercept, infliximab, or adalimumab that treatment over 2 years inhibits radiographic progression of disease.

This is a source of frustration, Dr. Weisman said.

Disease progression in AS is generally very slow. Only about 25% of patients experience disease progression. Inflammation appears to play a role, with syndesmophytes developing significantly more frequently in vertebral corners in patients with inflammation versus those without inflammation (20% vs. 5% of patients in one study). Paradoxically, though, syndesmophytes develop more frequently in vertebral corners where inflammation has resolved than in those where it persisted after anti-TNF therapy, Dr. Weisman said.

This raises concerns about whether the control of inflammation using anti-TNF agents actually liberates bone formation in these patients, he noted.

In addition to the inflammation/syndesmophyte associations, syndesmophytes sometimes form in patients with normal x-rays or MRIs, he said.

"We really don’t know why syndesmophytes form in this disease," he added, noting that, while there has been some understanding of the fact that AS biology differs from RA biology (AS is a bone-forming disease, for example), new understanding of the biology is beginning to emerge. Perhaps this new understanding, along with the discovery of bone-related genes, will help define subsets of individual pathways that can be targeted, he suggested.

Dr. Weisman had no disclosures to report.

CHICAGO – Despite dramatic clinical benefit, the standard treatments for ankylosing spondylitis do not appear to alter the natural history of the disease.

"We’d like to believe we’re actually doing something substantial for our patients in addition to actually relieving symptoms," said Dr. Michael H. Weisman, adding that this is an area of "hot, current controversy."

Nonsteroidal anti-inflammatory drugs, for example, are clinically very useful for treating patients with ankylosing spondylitis (AS). In a study of NSAID treatment for AS and mechanical back pain, good clinical response occurred in 75% of the AS patients, compared with only about 15% of the patients with mechanical back pain (Rev. Rhum. Engl. Ed. 1995;62:10-5), Dr. Weisman said at a symposium sponsored by the American College of Rheumatology.

The response of AS patients to NSAIDs is so good, in fact, that it can be helpful for confirming the diagnosis. A greater complete response may indicate that AS is the cause of symptoms, he said.

Another study demonstrated that 70% of AS patients who received etoricoxib had a good clinical response, compared with about 20% who received placebo (Arthritis Rheum. 2005;52:1205-15).

However, the effects of NSAIDs on radiographic progression of disease are questionable, at best, said Dr. Weisman, director of the division of rheumatology and professor of medicine at Cedars-Sinai Medical Center, Los Angeles.

Although findings from one study showed that there was less radiographic progression of disease after 2 years in patients on continuous versus on-demand NSAIDs, with a mean change on the modified Stoke Ankylosing Spondylitis Spinal Score of 0.4 vs. 1.5, respectively (Arthritis Rheum. 2005;52:1756-65), most experts "take this particular study with a grain of salt," Dr. Weisman said.

That’s in part because the mean difference in dose between the continuous and on-demand patients was only 50 mg/day. It’s very difficult to believe that a difference of 50 mg in celecoxib could make a difference in actually reducing the amount of bone formation in AS, he said.

Tumor necrosis factor (TNF) blockers also provide excellent clinical benefit and are approved for use in AS. Patients experience tremendous response, perhaps to even a greater degree than do rheumatoid arthritis patients and, unlike RA patients, there appears to be no increased risk of serious infection with treatment, he noted.

In a recent meta-analysis of randomized, placebo-controlled studies of anti-TNF drugs in AS, no difference was seen in the rate of serious infections in those who received active treatment versus those who received placebo (Ann. Rheum. Dis. 2010; 69:1756-61).

However, while anti-TNF agents have the potential to alter the natural history and prognosis of AS, there is also no evidence in any studies of etanercept, infliximab, or adalimumab that treatment over 2 years inhibits radiographic progression of disease.

This is a source of frustration, Dr. Weisman said.

Disease progression in AS is generally very slow. Only about 25% of patients experience disease progression. Inflammation appears to play a role, with syndesmophytes developing significantly more frequently in vertebral corners in patients with inflammation versus those without inflammation (20% vs. 5% of patients in one study). Paradoxically, though, syndesmophytes develop more frequently in vertebral corners where inflammation has resolved than in those where it persisted after anti-TNF therapy, Dr. Weisman said.

This raises concerns about whether the control of inflammation using anti-TNF agents actually liberates bone formation in these patients, he noted.

In addition to the inflammation/syndesmophyte associations, syndesmophytes sometimes form in patients with normal x-rays or MRIs, he said.

"We really don’t know why syndesmophytes form in this disease," he added, noting that, while there has been some understanding of the fact that AS biology differs from RA biology (AS is a bone-forming disease, for example), new understanding of the biology is beginning to emerge. Perhaps this new understanding, along with the discovery of bone-related genes, will help define subsets of individual pathways that can be targeted, he suggested.

Dr. Weisman had no disclosures to report.

CHICAGO – Despite dramatic clinical benefit, the standard treatments for ankylosing spondylitis do not appear to alter the natural history of the disease.

"We’d like to believe we’re actually doing something substantial for our patients in addition to actually relieving symptoms," said Dr. Michael H. Weisman, adding that this is an area of "hot, current controversy."

Nonsteroidal anti-inflammatory drugs, for example, are clinically very useful for treating patients with ankylosing spondylitis (AS). In a study of NSAID treatment for AS and mechanical back pain, good clinical response occurred in 75% of the AS patients, compared with only about 15% of the patients with mechanical back pain (Rev. Rhum. Engl. Ed. 1995;62:10-5), Dr. Weisman said at a symposium sponsored by the American College of Rheumatology.

The response of AS patients to NSAIDs is so good, in fact, that it can be helpful for confirming the diagnosis. A greater complete response may indicate that AS is the cause of symptoms, he said.

Another study demonstrated that 70% of AS patients who received etoricoxib had a good clinical response, compared with about 20% who received placebo (Arthritis Rheum. 2005;52:1205-15).

However, the effects of NSAIDs on radiographic progression of disease are questionable, at best, said Dr. Weisman, director of the division of rheumatology and professor of medicine at Cedars-Sinai Medical Center, Los Angeles.

Although findings from one study showed that there was less radiographic progression of disease after 2 years in patients on continuous versus on-demand NSAIDs, with a mean change on the modified Stoke Ankylosing Spondylitis Spinal Score of 0.4 vs. 1.5, respectively (Arthritis Rheum. 2005;52:1756-65), most experts "take this particular study with a grain of salt," Dr. Weisman said.

That’s in part because the mean difference in dose between the continuous and on-demand patients was only 50 mg/day. It’s very difficult to believe that a difference of 50 mg in celecoxib could make a difference in actually reducing the amount of bone formation in AS, he said.

Tumor necrosis factor (TNF) blockers also provide excellent clinical benefit and are approved for use in AS. Patients experience tremendous response, perhaps to even a greater degree than do rheumatoid arthritis patients and, unlike RA patients, there appears to be no increased risk of serious infection with treatment, he noted.

In a recent meta-analysis of randomized, placebo-controlled studies of anti-TNF drugs in AS, no difference was seen in the rate of serious infections in those who received active treatment versus those who received placebo (Ann. Rheum. Dis. 2010; 69:1756-61).

However, while anti-TNF agents have the potential to alter the natural history and prognosis of AS, there is also no evidence in any studies of etanercept, infliximab, or adalimumab that treatment over 2 years inhibits radiographic progression of disease.

This is a source of frustration, Dr. Weisman said.

Disease progression in AS is generally very slow. Only about 25% of patients experience disease progression. Inflammation appears to play a role, with syndesmophytes developing significantly more frequently in vertebral corners in patients with inflammation versus those without inflammation (20% vs. 5% of patients in one study). Paradoxically, though, syndesmophytes develop more frequently in vertebral corners where inflammation has resolved than in those where it persisted after anti-TNF therapy, Dr. Weisman said.

This raises concerns about whether the control of inflammation using anti-TNF agents actually liberates bone formation in these patients, he noted.

In addition to the inflammation/syndesmophyte associations, syndesmophytes sometimes form in patients with normal x-rays or MRIs, he said.

"We really don’t know why syndesmophytes form in this disease," he added, noting that, while there has been some understanding of the fact that AS biology differs from RA biology (AS is a bone-forming disease, for example), new understanding of the biology is beginning to emerge. Perhaps this new understanding, along with the discovery of bone-related genes, will help define subsets of individual pathways that can be targeted, he suggested.

Dr. Weisman had no disclosures to report.

BRIGHTON, ENGLAND – Use of the 2010 classification criteria for rheumatoid arthritis that were developed jointly by the American College of Rheumatology and the European League Against Rheumatism could result in overdiagnosis and subsequent overtreatment of early disease.

Although the 2010 ACR/EULAR criteria for RA classification allow for the more rapid identification of patients early in the course of the disease, their widespread use could also mean that some people with an essentially self-limiting illness could be given unnecessary – and perhaps too aggressive – treatment.

Study findings that were presented April 12 at the annual meeting of the British Society for Rheumatology found that more than 30% of 265 patients with early synovitis were identified as having RA via the 2010 ACR/EULAR criteria only (Arthritis Rheum. 2010;62:2569-81). In comparison, around half the number of patients (17.7%) were identified using the 1987 ACR criteria (Arthritis Rheum. 1988;31:315-24) alone.

"When we look at the early, and often undifferentiated phase, of arthritis, this poses a potential dilemma to clinicians," study author Dr. Zaeem Cader of the Rheumatology Research Group at the University of Birmingham (England) commented.

"The disease of many patients will resolve without ever requiring treatment," he observed, "whilst others progress to a persistent arthritis. And within this category, some patients may convert to an established rheumatoid phenotype, with others developing a non-RA, but persistent, arthropathy."

It is within the latter group that the 1987 ACR classification criteria were originally developed, Dr. Cader explained; those criteria aimed to help differentiate RA from other rheumatologic joint conditions of several years’ duration.

In recent years, however, it has become clear that the earlier RA is treated, the better the outcome in terms of radiologic progression, which can be halted or prevented with the use of DMARDs (disease-modifying antirheumatic drugs) very early on in the course of the disease.

With this in mind, Dr. Cader and associates looked at whether the updated 2010 ACR/EULAR criteria could better identify patients within the first 3 months of symptom onset in their early RA cohort.

In all, 265 patients with clinically apparent synovial swelling in one or more joint were studied; they had a mean age of 49 years and median symptom duration of 42 days. The percentage of patients meeting 2010 criteria only at baseline was 17.4%, whereas 2.3% met ACR criteria only, 15.5% met both, 42.2% neither, and 22.6% had a clear, alternative diagnosis to RA.

After 18 months of treatment, however, reassessment of patients showed that only 6% and 7%, respectively, still met either the 2010 or 1987 criteria, with 28.8% fulfilling both sets of criteria, 29.9% fulfilling neither, and 27.9% not being diagnosed with RA.

Application of the new criteria vs. the old at baseline also detected significantly more patients who would later require methotrexate or another DMARD, but the use of the new criteria also detected significantly more patients whose disease spontaneously resolved (in both, P less than .01).

"Classification is not the same as diagnosis," Dr. Cader conceded. "However, two core goals of the new criteria were to identify patients who were at risk of progressing to persistent disease, and [to identify] patients who will require treatment with drugs such as methotrexate."

Although the authors of the 2010 criteria resisted a direct comparison, or even basing the new criteria on the old, Dr. Cader argued that this was an important comparison to make. Indeed, if the 2010 criteria are more widely used, it’s important to know if they do indeed meet the goal of more rapidly identifying patients. In addition, it might be hard to translate findings from epidemiologic and clinical research based on these old criteria.

"The early identification of patients at risk of developing RA will allow for the early institution of treatment and improved clinical outcomes," the senior author of the study Dr. Karim Raza said separately in a press statement.

Dr. Raza, a senior lecturer and honorary consultant rheumatologist at the University of Birmingham, cautioned however, that the use of the updated RA criteria could lead to the overdiagnosis and subsequent overtreatment of patients.

"The new 2010 ACR/EULAR criteria represent an important step in that direction. However, detailed testing of these criteria in other cohorts is needed to fully assess to what extent ‘overtreatment’ would be a problem if these were widely applied."

Dr. Cader stated that he had no conflicts of interest. Dr. Raza and other coauthors disclosed receiving research grants from Cellzome, UCB, and Wyeth.

BRIGHTON, ENGLAND – Use of the 2010 classification criteria for rheumatoid arthritis that were developed jointly by the American College of Rheumatology and the European League Against Rheumatism could result in overdiagnosis and subsequent overtreatment of early disease.

Although the 2010 ACR/EULAR criteria for RA classification allow for the more rapid identification of patients early in the course of the disease, their widespread use could also mean that some people with an essentially self-limiting illness could be given unnecessary – and perhaps too aggressive – treatment.

Study findings that were presented April 12 at the annual meeting of the British Society for Rheumatology found that more than 30% of 265 patients with early synovitis were identified as having RA via the 2010 ACR/EULAR criteria only (Arthritis Rheum. 2010;62:2569-81). In comparison, around half the number of patients (17.7%) were identified using the 1987 ACR criteria (Arthritis Rheum. 1988;31:315-24) alone.

"When we look at the early, and often undifferentiated phase, of arthritis, this poses a potential dilemma to clinicians," study author Dr. Zaeem Cader of the Rheumatology Research Group at the University of Birmingham (England) commented.

"The disease of many patients will resolve without ever requiring treatment," he observed, "whilst others progress to a persistent arthritis. And within this category, some patients may convert to an established rheumatoid phenotype, with others developing a non-RA, but persistent, arthropathy."

It is within the latter group that the 1987 ACR classification criteria were originally developed, Dr. Cader explained; those criteria aimed to help differentiate RA from other rheumatologic joint conditions of several years’ duration.

In recent years, however, it has become clear that the earlier RA is treated, the better the outcome in terms of radiologic progression, which can be halted or prevented with the use of DMARDs (disease-modifying antirheumatic drugs) very early on in the course of the disease.

With this in mind, Dr. Cader and associates looked at whether the updated 2010 ACR/EULAR criteria could better identify patients within the first 3 months of symptom onset in their early RA cohort.

In all, 265 patients with clinically apparent synovial swelling in one or more joint were studied; they had a mean age of 49 years and median symptom duration of 42 days. The percentage of patients meeting 2010 criteria only at baseline was 17.4%, whereas 2.3% met ACR criteria only, 15.5% met both, 42.2% neither, and 22.6% had a clear, alternative diagnosis to RA.

After 18 months of treatment, however, reassessment of patients showed that only 6% and 7%, respectively, still met either the 2010 or 1987 criteria, with 28.8% fulfilling both sets of criteria, 29.9% fulfilling neither, and 27.9% not being diagnosed with RA.

Application of the new criteria vs. the old at baseline also detected significantly more patients who would later require methotrexate or another DMARD, but the use of the new criteria also detected significantly more patients whose disease spontaneously resolved (in both, P less than .01).

"Classification is not the same as diagnosis," Dr. Cader conceded. "However, two core goals of the new criteria were to identify patients who were at risk of progressing to persistent disease, and [to identify] patients who will require treatment with drugs such as methotrexate."

Although the authors of the 2010 criteria resisted a direct comparison, or even basing the new criteria on the old, Dr. Cader argued that this was an important comparison to make. Indeed, if the 2010 criteria are more widely used, it’s important to know if they do indeed meet the goal of more rapidly identifying patients. In addition, it might be hard to translate findings from epidemiologic and clinical research based on these old criteria.

"The early identification of patients at risk of developing RA will allow for the early institution of treatment and improved clinical outcomes," the senior author of the study Dr. Karim Raza said separately in a press statement.

Dr. Raza, a senior lecturer and honorary consultant rheumatologist at the University of Birmingham, cautioned however, that the use of the updated RA criteria could lead to the overdiagnosis and subsequent overtreatment of patients.

"The new 2010 ACR/EULAR criteria represent an important step in that direction. However, detailed testing of these criteria in other cohorts is needed to fully assess to what extent ‘overtreatment’ would be a problem if these were widely applied."

Dr. Cader stated that he had no conflicts of interest. Dr. Raza and other coauthors disclosed receiving research grants from Cellzome, UCB, and Wyeth.

BRIGHTON, ENGLAND – Use of the 2010 classification criteria for rheumatoid arthritis that were developed jointly by the American College of Rheumatology and the European League Against Rheumatism could result in overdiagnosis and subsequent overtreatment of early disease.

Although the 2010 ACR/EULAR criteria for RA classification allow for the more rapid identification of patients early in the course of the disease, their widespread use could also mean that some people with an essentially self-limiting illness could be given unnecessary – and perhaps too aggressive – treatment.

Study findings that were presented April 12 at the annual meeting of the British Society for Rheumatology found that more than 30% of 265 patients with early synovitis were identified as having RA via the 2010 ACR/EULAR criteria only (Arthritis Rheum. 2010;62:2569-81). In comparison, around half the number of patients (17.7%) were identified using the 1987 ACR criteria (Arthritis Rheum. 1988;31:315-24) alone.

"When we look at the early, and often undifferentiated phase, of arthritis, this poses a potential dilemma to clinicians," study author Dr. Zaeem Cader of the Rheumatology Research Group at the University of Birmingham (England) commented.

"The disease of many patients will resolve without ever requiring treatment," he observed, "whilst others progress to a persistent arthritis. And within this category, some patients may convert to an established rheumatoid phenotype, with others developing a non-RA, but persistent, arthropathy."

It is within the latter group that the 1987 ACR classification criteria were originally developed, Dr. Cader explained; those criteria aimed to help differentiate RA from other rheumatologic joint conditions of several years’ duration.

In recent years, however, it has become clear that the earlier RA is treated, the better the outcome in terms of radiologic progression, which can be halted or prevented with the use of DMARDs (disease-modifying antirheumatic drugs) very early on in the course of the disease.

With this in mind, Dr. Cader and associates looked at whether the updated 2010 ACR/EULAR criteria could better identify patients within the first 3 months of symptom onset in their early RA cohort.

In all, 265 patients with clinically apparent synovial swelling in one or more joint were studied; they had a mean age of 49 years and median symptom duration of 42 days. The percentage of patients meeting 2010 criteria only at baseline was 17.4%, whereas 2.3% met ACR criteria only, 15.5% met both, 42.2% neither, and 22.6% had a clear, alternative diagnosis to RA.

After 18 months of treatment, however, reassessment of patients showed that only 6% and 7%, respectively, still met either the 2010 or 1987 criteria, with 28.8% fulfilling both sets of criteria, 29.9% fulfilling neither, and 27.9% not being diagnosed with RA.

Application of the new criteria vs. the old at baseline also detected significantly more patients who would later require methotrexate or another DMARD, but the use of the new criteria also detected significantly more patients whose disease spontaneously resolved (in both, P less than .01).

"Classification is not the same as diagnosis," Dr. Cader conceded. "However, two core goals of the new criteria were to identify patients who were at risk of progressing to persistent disease, and [to identify] patients who will require treatment with drugs such as methotrexate."

Although the authors of the 2010 criteria resisted a direct comparison, or even basing the new criteria on the old, Dr. Cader argued that this was an important comparison to make. Indeed, if the 2010 criteria are more widely used, it’s important to know if they do indeed meet the goal of more rapidly identifying patients. In addition, it might be hard to translate findings from epidemiologic and clinical research based on these old criteria.

"The early identification of patients at risk of developing RA will allow for the early institution of treatment and improved clinical outcomes," the senior author of the study Dr. Karim Raza said separately in a press statement.

Dr. Raza, a senior lecturer and honorary consultant rheumatologist at the University of Birmingham, cautioned however, that the use of the updated RA criteria could lead to the overdiagnosis and subsequent overtreatment of patients.

"The new 2010 ACR/EULAR criteria represent an important step in that direction. However, detailed testing of these criteria in other cohorts is needed to fully assess to what extent ‘overtreatment’ would be a problem if these were widely applied."

Dr. Cader stated that he had no conflicts of interest. Dr. Raza and other coauthors disclosed receiving research grants from Cellzome, UCB, and Wyeth.

Physicians considering the use of rituximab treatment of rheumatic diseases including rheumatoid arthritis should be aware that there is "a potential, albeit modest, risk of developing progressive multifocal leukoencephalopathy," according to a report published online May 9 in Archives of Neurology.

In addition, rheumatology patients who are already taking the drug should undergo "aggressive evaluation of new and progressing neurologic deficits ... to allow early diagnosis" of progressive multifocal leukoencephalopathy (PML), said Dr. David B. Clifford, professor of neurology and medicine at Washington University in St. Louis, and his associates.

PML is a serious, often fatal demyelinating infection of the brain, usually caused by reactivation of latent JC virus in people who are immunocompromised. It also has been reported as a complication of treatment with monoclonal antibodies such as natalizumab and efalizumab, among patients taking the drugs for disorders including multiple sclerosis, inflammatory bowel disease, and chronic plaque psoriasis.

The mechanism by which these agents facilitate the development of PML is not yet known, but it is presumed that some suppressive effect they exert on the immune system allows latent JC virus to reactivate. Primary JC virus infection usually occurs unnoticed during childhood and is very widespread; most adults are seropositive for JC virus, and many carry latent virus in kidney epithelial cells, lymphoid tissues, bone marrow, and possibly the brain.

"Until very recently, treatment of RA with rituximab had not been associated with development of PML," the investigators wrote. There was one case reported in 2009, but that "was complicated by a history of malignancy that had been treated with chemotherapy and irradiation a short time before PML onset," so the connection with rituximab was unclear, the researchers noted.

Dr. Clifford and his colleagues now report four additional cases of PML in RA patients treated with rituximab. To characterize the disorder in this patient population, they summarized their findings along with those for the previously reported case.

All of the patients were women aged 51-73 years who had moderate to severe RA of at least 3 years’ duration. All began taking rituximab after failing to respond adequately to other interventions including methotrexate, other biologics, or corticosteroids.

In all cases, rituximab was given at the recommended dose for refractory RA: Each course comprised two 1,000-mg infusions administered 2 weeks apart. Two patients received only a single course, and the maximal number of courses was five.

In two cases, patients may have been at increased risk of PML because of cancer. One woman had a history of breast cancer treated with surgery and chemotherapy; the other was the previously reported case in which the patient developed superficial squamous cell carcinoma of the oropharynx and received chemotherapy and irradiation after rituximab had been administered.

Symptom onset occurred at 5-7 months after a rituximab infusion in three cases. This timing is "interesting" because it occurs during the process of immune reconstitution, rather than earlier, when CD20 cells reach their nadir.

In a fourth case, PML onset was delayed until 16 months after rituximab infusion. However this also proved to be during immune reconstitution, as this patient had an unusually prolonged interval of CD-cell suppression. This suppression "only began to normalize after PML onset, when a clear immune reconstitution inflammatory syndrome (IRIS) was well documented on MR scans," the investigators said.

It appears that the immune reconstitution inflammatory syndrome may often complicate rituximab-associated PML, as it developed in three of these five cases. "This factor is critical for clinicians, since it impacts diagnosis and management," they added.

These five patients presented with a variety of central nervous system symptoms including dysesthesias, ataxia, dysphasia, cognitive decline, focal dystonic tremor, and segmental myoclonus.

JC virus DNA frequently was not detectable in the cerebrospinal fluid at presentation, "and was found only after repeated lumbar punctures as the disease progressed." In fact, one case required a brain biopsy to confirm PML.

Genentech, the maker of rituximab, estimates that these five cases of PML occurred against a background of approximately 129,000 exposures among RA patients. This puts the incidence of rituximab-associated PML at 1 in 25,000 exposed RA patients, Dr. Clifford and his associates said (Arch. Neurol. 2011 May 9 [doi:10.1001/archneurol.2011.103]).

This may be an underestimate because it’s likely that more patients have not been accurately diagnosed or reported to the company, they added.

This "modest" incidence is lower than that reported for natalizumab-associated PML (1 in 1,000 patients exposed for more than 2 years) or for efalizumab-associated PML (1 in 400 exposed patients).

The need for effective treatments of rituximab-associated PML is "urgent." Antiviral therapy has not been shown to be effective. Some clinicians still try using cytosine arabinoside and cidofovir, "in spite of significant evidence that they are not effective."

Mefloquine hydrochloride has shown in vitro activity against JC virus and was used "in several of our cases," but failed to show efficacy in a recent clinical trial. "Similarly, clinicians continue to prescribe mirtazapine on a theoretical basis, related to its potential efficacy in blocking serotonin receptors used for viral entry, despite absence of documented clinical efficacy," the investigators said.

Plasma exchange has become standard practice for natalizumab-associated PML, but it is only likely to speed immune recovery in RA patients taking rituximab if PML is discovered shortly after an infusion of the drug.

If patients develop immune reconstitution inflammatory syndrome, that "provides an additional potential therapeutic avenue." High-dose corticosteroid pulses – "often 1 g of IV methylprednisolone daily for 5 days, which is repeated if symptoms respond and then recur" – may halt neurologic decline and initiate recovery. "Physicians should be aware that this may be required even when the CD20 count suggests ongoing immune compromise" from the rituximab therapy, they added.

"The present cases support the possibility that with early diagnosis and careful management [of immune reconstitution inflammatory syndrome], patients may survive this complication, some with modest deficits," Dr. Clifford and his colleagues said.

"It is reasonable to encourage support and therapy for these patients, since the dire prognosis of PML acquired when associated with advanced malignancy or AIDS may be exaggerated when considering this disease in other settings. Indeed, current experience with natalizumab suggests survival of as many as 70%-80% of patients with PML with concentrated efforts for early detection and reversal of immunosuppression," they noted.

This study was supported by the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Institute of Allergy and Infectious Diseases. Dr. Clifford and his associates reported ties to Bavarian Nordic, Biogen Idec, Bristol-Myers Squibb, Genentech (maker of rituximab), Genzyme, GlaxoSmithKline, Lilly, Millennium, NeurogesX, Novartis, Pfizer, Schering-Plough, Tibotec, and Wyeth.

Physicians considering the use of rituximab treatment of rheumatic diseases including rheumatoid arthritis should be aware that there is "a potential, albeit modest, risk of developing progressive multifocal leukoencephalopathy," according to a report published online May 9 in Archives of Neurology.

In addition, rheumatology patients who are already taking the drug should undergo "aggressive evaluation of new and progressing neurologic deficits ... to allow early diagnosis" of progressive multifocal leukoencephalopathy (PML), said Dr. David B. Clifford, professor of neurology and medicine at Washington University in St. Louis, and his associates.

PML is a serious, often fatal demyelinating infection of the brain, usually caused by reactivation of latent JC virus in people who are immunocompromised. It also has been reported as a complication of treatment with monoclonal antibodies such as natalizumab and efalizumab, among patients taking the drugs for disorders including multiple sclerosis, inflammatory bowel disease, and chronic plaque psoriasis.

The mechanism by which these agents facilitate the development of PML is not yet known, but it is presumed that some suppressive effect they exert on the immune system allows latent JC virus to reactivate. Primary JC virus infection usually occurs unnoticed during childhood and is very widespread; most adults are seropositive for JC virus, and many carry latent virus in kidney epithelial cells, lymphoid tissues, bone marrow, and possibly the brain.

"Until very recently, treatment of RA with rituximab had not been associated with development of PML," the investigators wrote. There was one case reported in 2009, but that "was complicated by a history of malignancy that had been treated with chemotherapy and irradiation a short time before PML onset," so the connection with rituximab was unclear, the researchers noted.

Dr. Clifford and his colleagues now report four additional cases of PML in RA patients treated with rituximab. To characterize the disorder in this patient population, they summarized their findings along with those for the previously reported case.

All of the patients were women aged 51-73 years who had moderate to severe RA of at least 3 years’ duration. All began taking rituximab after failing to respond adequately to other interventions including methotrexate, other biologics, or corticosteroids.

In all cases, rituximab was given at the recommended dose for refractory RA: Each course comprised two 1,000-mg infusions administered 2 weeks apart. Two patients received only a single course, and the maximal number of courses was five.

In two cases, patients may have been at increased risk of PML because of cancer. One woman had a history of breast cancer treated with surgery and chemotherapy; the other was the previously reported case in which the patient developed superficial squamous cell carcinoma of the oropharynx and received chemotherapy and irradiation after rituximab had been administered.

Symptom onset occurred at 5-7 months after a rituximab infusion in three cases. This timing is "interesting" because it occurs during the process of immune reconstitution, rather than earlier, when CD20 cells reach their nadir.

In a fourth case, PML onset was delayed until 16 months after rituximab infusion. However this also proved to be during immune reconstitution, as this patient had an unusually prolonged interval of CD-cell suppression. This suppression "only began to normalize after PML onset, when a clear immune reconstitution inflammatory syndrome (IRIS) was well documented on MR scans," the investigators said.

It appears that the immune reconstitution inflammatory syndrome may often complicate rituximab-associated PML, as it developed in three of these five cases. "This factor is critical for clinicians, since it impacts diagnosis and management," they added.

These five patients presented with a variety of central nervous system symptoms including dysesthesias, ataxia, dysphasia, cognitive decline, focal dystonic tremor, and segmental myoclonus.

JC virus DNA frequently was not detectable in the cerebrospinal fluid at presentation, "and was found only after repeated lumbar punctures as the disease progressed." In fact, one case required a brain biopsy to confirm PML.

Genentech, the maker of rituximab, estimates that these five cases of PML occurred against a background of approximately 129,000 exposures among RA patients. This puts the incidence of rituximab-associated PML at 1 in 25,000 exposed RA patients, Dr. Clifford and his associates said (Arch. Neurol. 2011 May 9 [doi:10.1001/archneurol.2011.103]).

This may be an underestimate because it’s likely that more patients have not been accurately diagnosed or reported to the company, they added.

This "modest" incidence is lower than that reported for natalizumab-associated PML (1 in 1,000 patients exposed for more than 2 years) or for efalizumab-associated PML (1 in 400 exposed patients).

The need for effective treatments of rituximab-associated PML is "urgent." Antiviral therapy has not been shown to be effective. Some clinicians still try using cytosine arabinoside and cidofovir, "in spite of significant evidence that they are not effective."

Mefloquine hydrochloride has shown in vitro activity against JC virus and was used "in several of our cases," but failed to show efficacy in a recent clinical trial. "Similarly, clinicians continue to prescribe mirtazapine on a theoretical basis, related to its potential efficacy in blocking serotonin receptors used for viral entry, despite absence of documented clinical efficacy," the investigators said.

Plasma exchange has become standard practice for natalizumab-associated PML, but it is only likely to speed immune recovery in RA patients taking rituximab if PML is discovered shortly after an infusion of the drug.

If patients develop immune reconstitution inflammatory syndrome, that "provides an additional potential therapeutic avenue." High-dose corticosteroid pulses – "often 1 g of IV methylprednisolone daily for 5 days, which is repeated if symptoms respond and then recur" – may halt neurologic decline and initiate recovery. "Physicians should be aware that this may be required even when the CD20 count suggests ongoing immune compromise" from the rituximab therapy, they added.

"The present cases support the possibility that with early diagnosis and careful management [of immune reconstitution inflammatory syndrome], patients may survive this complication, some with modest deficits," Dr. Clifford and his colleagues said.

"It is reasonable to encourage support and therapy for these patients, since the dire prognosis of PML acquired when associated with advanced malignancy or AIDS may be exaggerated when considering this disease in other settings. Indeed, current experience with natalizumab suggests survival of as many as 70%-80% of patients with PML with concentrated efforts for early detection and reversal of immunosuppression," they noted.

This study was supported by the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Institute of Allergy and Infectious Diseases. Dr. Clifford and his associates reported ties to Bavarian Nordic, Biogen Idec, Bristol-Myers Squibb, Genentech (maker of rituximab), Genzyme, GlaxoSmithKline, Lilly, Millennium, NeurogesX, Novartis, Pfizer, Schering-Plough, Tibotec, and Wyeth.

Physicians considering the use of rituximab treatment of rheumatic diseases including rheumatoid arthritis should be aware that there is "a potential, albeit modest, risk of developing progressive multifocal leukoencephalopathy," according to a report published online May 9 in Archives of Neurology.

In addition, rheumatology patients who are already taking the drug should undergo "aggressive evaluation of new and progressing neurologic deficits ... to allow early diagnosis" of progressive multifocal leukoencephalopathy (PML), said Dr. David B. Clifford, professor of neurology and medicine at Washington University in St. Louis, and his associates.

PML is a serious, often fatal demyelinating infection of the brain, usually caused by reactivation of latent JC virus in people who are immunocompromised. It also has been reported as a complication of treatment with monoclonal antibodies such as natalizumab and efalizumab, among patients taking the drugs for disorders including multiple sclerosis, inflammatory bowel disease, and chronic plaque psoriasis.

The mechanism by which these agents facilitate the development of PML is not yet known, but it is presumed that some suppressive effect they exert on the immune system allows latent JC virus to reactivate. Primary JC virus infection usually occurs unnoticed during childhood and is very widespread; most adults are seropositive for JC virus, and many carry latent virus in kidney epithelial cells, lymphoid tissues, bone marrow, and possibly the brain.

"Until very recently, treatment of RA with rituximab had not been associated with development of PML," the investigators wrote. There was one case reported in 2009, but that "was complicated by a history of malignancy that had been treated with chemotherapy and irradiation a short time before PML onset," so the connection with rituximab was unclear, the researchers noted.

Dr. Clifford and his colleagues now report four additional cases of PML in RA patients treated with rituximab. To characterize the disorder in this patient population, they summarized their findings along with those for the previously reported case.

All of the patients were women aged 51-73 years who had moderate to severe RA of at least 3 years’ duration. All began taking rituximab after failing to respond adequately to other interventions including methotrexate, other biologics, or corticosteroids.

In all cases, rituximab was given at the recommended dose for refractory RA: Each course comprised two 1,000-mg infusions administered 2 weeks apart. Two patients received only a single course, and the maximal number of courses was five.

In two cases, patients may have been at increased risk of PML because of cancer. One woman had a history of breast cancer treated with surgery and chemotherapy; the other was the previously reported case in which the patient developed superficial squamous cell carcinoma of the oropharynx and received chemotherapy and irradiation after rituximab had been administered.

Symptom onset occurred at 5-7 months after a rituximab infusion in three cases. This timing is "interesting" because it occurs during the process of immune reconstitution, rather than earlier, when CD20 cells reach their nadir.

In a fourth case, PML onset was delayed until 16 months after rituximab infusion. However this also proved to be during immune reconstitution, as this patient had an unusually prolonged interval of CD-cell suppression. This suppression "only began to normalize after PML onset, when a clear immune reconstitution inflammatory syndrome (IRIS) was well documented on MR scans," the investigators said.

It appears that the immune reconstitution inflammatory syndrome may often complicate rituximab-associated PML, as it developed in three of these five cases. "This factor is critical for clinicians, since it impacts diagnosis and management," they added.

These five patients presented with a variety of central nervous system symptoms including dysesthesias, ataxia, dysphasia, cognitive decline, focal dystonic tremor, and segmental myoclonus.

JC virus DNA frequently was not detectable in the cerebrospinal fluid at presentation, "and was found only after repeated lumbar punctures as the disease progressed." In fact, one case required a brain biopsy to confirm PML.

Genentech, the maker of rituximab, estimates that these five cases of PML occurred against a background of approximately 129,000 exposures among RA patients. This puts the incidence of rituximab-associated PML at 1 in 25,000 exposed RA patients, Dr. Clifford and his associates said (Arch. Neurol. 2011 May 9 [doi:10.1001/archneurol.2011.103]).

This may be an underestimate because it’s likely that more patients have not been accurately diagnosed or reported to the company, they added.

This "modest" incidence is lower than that reported for natalizumab-associated PML (1 in 1,000 patients exposed for more than 2 years) or for efalizumab-associated PML (1 in 400 exposed patients).

The need for effective treatments of rituximab-associated PML is "urgent." Antiviral therapy has not been shown to be effective. Some clinicians still try using cytosine arabinoside and cidofovir, "in spite of significant evidence that they are not effective."

Mefloquine hydrochloride has shown in vitro activity against JC virus and was used "in several of our cases," but failed to show efficacy in a recent clinical trial. "Similarly, clinicians continue to prescribe mirtazapine on a theoretical basis, related to its potential efficacy in blocking serotonin receptors used for viral entry, despite absence of documented clinical efficacy," the investigators said.

Plasma exchange has become standard practice for natalizumab-associated PML, but it is only likely to speed immune recovery in RA patients taking rituximab if PML is discovered shortly after an infusion of the drug.

If patients develop immune reconstitution inflammatory syndrome, that "provides an additional potential therapeutic avenue." High-dose corticosteroid pulses – "often 1 g of IV methylprednisolone daily for 5 days, which is repeated if symptoms respond and then recur" – may halt neurologic decline and initiate recovery. "Physicians should be aware that this may be required even when the CD20 count suggests ongoing immune compromise" from the rituximab therapy, they added.

"The present cases support the possibility that with early diagnosis and careful management [of immune reconstitution inflammatory syndrome], patients may survive this complication, some with modest deficits," Dr. Clifford and his colleagues said.

"It is reasonable to encourage support and therapy for these patients, since the dire prognosis of PML acquired when associated with advanced malignancy or AIDS may be exaggerated when considering this disease in other settings. Indeed, current experience with natalizumab suggests survival of as many as 70%-80% of patients with PML with concentrated efforts for early detection and reversal of immunosuppression," they noted.

This study was supported by the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, and the National Institute of Allergy and Infectious Diseases. Dr. Clifford and his associates reported ties to Bavarian Nordic, Biogen Idec, Bristol-Myers Squibb, Genentech (maker of rituximab), Genzyme, GlaxoSmithKline, Lilly, Millennium, NeurogesX, Novartis, Pfizer, Schering-Plough, Tibotec, and Wyeth.

BRIGHTON, ENGLAND – Very obese patients with early rheumatoid arthritis appear to have higher disease activity at presentation, according to recent data presented at the annual meeting of the British Society for Rheumatology.

In a study of 216 individuals with early, clinically diagnosed rheumatoid arthritis (RA), those with a body mass index (BMI) of 35 kg/m² or higher were more likely than those with lower BMIs to have higher 28-joint count disease activity scores (DAS28), mainly because of higher erythrocyte sedimentation rates (ESRs).

Photo credit: ©geronimo/Fotolia.com

As a result, use of the DAS28 to guide clinical decision-making could result in disease-modifying antirheumatic drug (DMARD) therapy being given early on, suggested Stephanie Ling, who presented the findings.

Ms. Ling, a fifth-year medical student at the University of Liverpool, England, noted that earlier, more aggressive treatment of obese RA patients might explain why some studies have suggested that obesity, somewhat paradoxically, is actually beneficial in some patients with RA.

Indeed, studies have linked obesity with reduced mortality (Arch. Intern. Med. 2005;165:1624-9; Ann. Rheum. Dis. 2010;69:i61-4) and protection against radiographic joint damage (Ann. Rheum. Dis. 2008;67:769-74), although high levels of adiponectin – secreted from the fat tissue – are associated with increased joint inflammation (Arthritis Rheum. 2009;61:1248-56).

"Physiologically, obesity is characterized by the expansion of white adipose tissue, which is not a benign tissue," Ms. Ling explained. White adipose tissue secretes fatty acids, and its constituent cells, the adipocytes, also secrete proinflammatory proteins, or adipokines.

"Obesity can be thought of as a chronic inflammatory state," said Ms. Ling, adding that studies also indicate that "obesity could have adverse effect on RA disease activity."

In the current study, patients’ baseline disease characteristics, including DAS28 scores, rheumatoid factor status, and anti-cyclic citrullinated protein antibody status, were assessed according to BMI at presentation. All patients had early RA diagnosed by a consultant rheumatologist and had symptoms lasting for less than 1 year. The mean age of participants was 57 years and 57% of the cohort was female.

Patients were grouped according to their BMI category, as defined by World Health Organization (WHO) criteria. One-third fulfilled criteria for obesity, with approximately 22% in the obese I category (BMI more than 30 kg/m² but less than 35 kg/m²) and just over 11% in the obese II–III category (BMI of more than 35 kg/m²). One-third of patients were overweight and the remaining third were either normal weight or underweight.

Results showed that obese II–III patients were more likely to present with elevated (5.1 or higher) DAS28 scores than their lighter counterparts. Odds ratios (OR) adjusted for age, gender, and smoking status were 4.1 for DAS28 and 3.67 for ESR when comparing the very obese patients with the other BMI groups.

Considering each component of the DAS28 separately, a high ESR (32 mm/h or more) was the main factor that appeared to be significantly higher as body weight increased. There was no association with tender or swollen joint counts, global visual analog scale, symptom duration, or rheumatoid factor/anti-cyclic citrullinated protein antibody status, Ms. Ling said.

"There is a need for well-designed longitudinal studies to examine the effect of obesity on the extent of RA disease progression," she suggested.

Ms. Ling reported no conflicts of interest.

BRIGHTON, ENGLAND – Very obese patients with early rheumatoid arthritis appear to have higher disease activity at presentation, according to recent data presented at the annual meeting of the British Society for Rheumatology.

In a study of 216 individuals with early, clinically diagnosed rheumatoid arthritis (RA), those with a body mass index (BMI) of 35 kg/m² or higher were more likely than those with lower BMIs to have higher 28-joint count disease activity scores (DAS28), mainly because of higher erythrocyte sedimentation rates (ESRs).

Photo credit: ©geronimo/Fotolia.com

As a result, use of the DAS28 to guide clinical decision-making could result in disease-modifying antirheumatic drug (DMARD) therapy being given early on, suggested Stephanie Ling, who presented the findings.

Ms. Ling, a fifth-year medical student at the University of Liverpool, England, noted that earlier, more aggressive treatment of obese RA patients might explain why some studies have suggested that obesity, somewhat paradoxically, is actually beneficial in some patients with RA.

Indeed, studies have linked obesity with reduced mortality (Arch. Intern. Med. 2005;165:1624-9; Ann. Rheum. Dis. 2010;69:i61-4) and protection against radiographic joint damage (Ann. Rheum. Dis. 2008;67:769-74), although high levels of adiponectin – secreted from the fat tissue – are associated with increased joint inflammation (Arthritis Rheum. 2009;61:1248-56).

"Physiologically, obesity is characterized by the expansion of white adipose tissue, which is not a benign tissue," Ms. Ling explained. White adipose tissue secretes fatty acids, and its constituent cells, the adipocytes, also secrete proinflammatory proteins, or adipokines.

"Obesity can be thought of as a chronic inflammatory state," said Ms. Ling, adding that studies also indicate that "obesity could have adverse effect on RA disease activity."

In the current study, patients’ baseline disease characteristics, including DAS28 scores, rheumatoid factor status, and anti-cyclic citrullinated protein antibody status, were assessed according to BMI at presentation. All patients had early RA diagnosed by a consultant rheumatologist and had symptoms lasting for less than 1 year. The mean age of participants was 57 years and 57% of the cohort was female.

Patients were grouped according to their BMI category, as defined by World Health Organization (WHO) criteria. One-third fulfilled criteria for obesity, with approximately 22% in the obese I category (BMI more than 30 kg/m² but less than 35 kg/m²) and just over 11% in the obese II–III category (BMI of more than 35 kg/m²). One-third of patients were overweight and the remaining third were either normal weight or underweight.

Results showed that obese II–III patients were more likely to present with elevated (5.1 or higher) DAS28 scores than their lighter counterparts. Odds ratios (OR) adjusted for age, gender, and smoking status were 4.1 for DAS28 and 3.67 for ESR when comparing the very obese patients with the other BMI groups.

Considering each component of the DAS28 separately, a high ESR (32 mm/h or more) was the main factor that appeared to be significantly higher as body weight increased. There was no association with tender or swollen joint counts, global visual analog scale, symptom duration, or rheumatoid factor/anti-cyclic citrullinated protein antibody status, Ms. Ling said.

"There is a need for well-designed longitudinal studies to examine the effect of obesity on the extent of RA disease progression," she suggested.

Ms. Ling reported no conflicts of interest.

BRIGHTON, ENGLAND – Very obese patients with early rheumatoid arthritis appear to have higher disease activity at presentation, according to recent data presented at the annual meeting of the British Society for Rheumatology.

In a study of 216 individuals with early, clinically diagnosed rheumatoid arthritis (RA), those with a body mass index (BMI) of 35 kg/m² or higher were more likely than those with lower BMIs to have higher 28-joint count disease activity scores (DAS28), mainly because of higher erythrocyte sedimentation rates (ESRs).

Photo credit: ©geronimo/Fotolia.com

As a result, use of the DAS28 to guide clinical decision-making could result in disease-modifying antirheumatic drug (DMARD) therapy being given early on, suggested Stephanie Ling, who presented the findings.

Ms. Ling, a fifth-year medical student at the University of Liverpool, England, noted that earlier, more aggressive treatment of obese RA patients might explain why some studies have suggested that obesity, somewhat paradoxically, is actually beneficial in some patients with RA.

Indeed, studies have linked obesity with reduced mortality (Arch. Intern. Med. 2005;165:1624-9; Ann. Rheum. Dis. 2010;69:i61-4) and protection against radiographic joint damage (Ann. Rheum. Dis. 2008;67:769-74), although high levels of adiponectin – secreted from the fat tissue – are associated with increased joint inflammation (Arthritis Rheum. 2009;61:1248-56).

"Physiologically, obesity is characterized by the expansion of white adipose tissue, which is not a benign tissue," Ms. Ling explained. White adipose tissue secretes fatty acids, and its constituent cells, the adipocytes, also secrete proinflammatory proteins, or adipokines.

"Obesity can be thought of as a chronic inflammatory state," said Ms. Ling, adding that studies also indicate that "obesity could have adverse effect on RA disease activity."

In the current study, patients’ baseline disease characteristics, including DAS28 scores, rheumatoid factor status, and anti-cyclic citrullinated protein antibody status, were assessed according to BMI at presentation. All patients had early RA diagnosed by a consultant rheumatologist and had symptoms lasting for less than 1 year. The mean age of participants was 57 years and 57% of the cohort was female.

Patients were grouped according to their BMI category, as defined by World Health Organization (WHO) criteria. One-third fulfilled criteria for obesity, with approximately 22% in the obese I category (BMI more than 30 kg/m² but less than 35 kg/m²) and just over 11% in the obese II–III category (BMI of more than 35 kg/m²). One-third of patients were overweight and the remaining third were either normal weight or underweight.

Results showed that obese II–III patients were more likely to present with elevated (5.1 or higher) DAS28 scores than their lighter counterparts. Odds ratios (OR) adjusted for age, gender, and smoking status were 4.1 for DAS28 and 3.67 for ESR when comparing the very obese patients with the other BMI groups.

Considering each component of the DAS28 separately, a high ESR (32 mm/h or more) was the main factor that appeared to be significantly higher as body weight increased. There was no association with tender or swollen joint counts, global visual analog scale, symptom duration, or rheumatoid factor/anti-cyclic citrullinated protein antibody status, Ms. Ling said.

"There is a need for well-designed longitudinal studies to examine the effect of obesity on the extent of RA disease progression," she suggested.

Ms. Ling reported no conflicts of interest.

When it comes to disability in rheumatoid arthritis, it is cartilage loss – not bone damage – that seems to have the greater effect.

Accordingly, therapeutic interventions that aim to reduce disability should focus on cartilage preservation, "since even relatively little cartilage degradation can lead to significant impairment of physical functioning," wrote Dr. Daniel Aletaha of the Medical University of Vienna and his colleagues in the May issue of Annals of the Rheumatic Diseases.

The authors looked at data from a pool of 4,602 participants in various clinical trials of adalimumab, methotrexate, infliximab, and leflunomide. "To separate the reversible, RA activity–related component of disability from the irreversible component, we identified patients who achieved clinical remission during the trials [that is, a state of absence of significant RA activity and thus the absence of a reversible disability component]," Dr. Aletaha and his colleagues wrote (Ann. Rheum. Dis. 2011;70:733-9).

Remission was defined as an SDAI (Simplified Disease Activity Index) score of 3.3 or less.

In all, 748 patients were included in the current analysis. Patient data were assessed at the first visit in which a patient was in remission, and that visit’s corresponding HAQ-DI (Health Assessment Questionnaire–Disability Index) score was used as "the best estimate of the patient’s irreversible functional disability" for the current study, they wrote.

The HAQ-DI scale has a 0-3 range, with 0 indicating no difficulty in the activities of daily living, and 3 indicating complete disability.

Patients were divided into tertiles according to the degree of both joint space narrowing (JSN), which is a function of cartilage loss, and bone erosion (ERO). As expected, in univariate analysis, the mean scores on the HAQ-DI increased – indicating greater disability – as JSN/ERO tertiles increased (0.21, 0.24, and 0.35, respectively, for the first, second, and third tertiles; P less than .0001).

"Likewise and even to a numerically greater extent, with increasing tertiles by JSN, residual (irreversible) HAQ-DI scores increased," wrote the authors, with a mean of 0.18, 0.24, and 0.38 for the first, second, and third tertiles, respectively (P less than .0001).

To assess the independent disability contribution of erosion vs. narrowing, the authors then looked at the effects of higher erosion tertiles within each of the JSN tertiles. In other words, within each tertile of JSN, patients were further stratified into tertiles of ERO, and the HAQ-DI scores were compared.

"In the first and second tertiles formed according to JSN, higher degrees of erosive changes did not contribute at all to irreversible disability," such that HAQ-DI scores did not differ significantly between ERO tertiles (P = .99 and .77, respectively), they said.

Although patients in the third quartiles of both JSN and ERO did have significantly greater HAQ-DI scores than did patients with less-severe bone erosion (0.417; P = .07), this was an expected finding, wrote the authors, as this group includes patients with severe joint damage.

However, when patients were first divided into ERO tertiles, and then further subdivided according to JSN severity within each tertile, the authors did find a significant effect on disability according to the HAQ-DI.

Indeed, within all three ERO strata, increasing JSN significantly corresponded with increasing HAQ-DI scores (P less than .05, P = .19, and P less than .001 for the first, second, and third ERO tertiles, respectively).

Despite the fact that bony erosion is considered "prototypic for RA," whereas joint space narrowing (which occurs in other disorders) is considered less characteristic of the disease, "in the present study we have been able to show that the clinical impact of joint destruction cartilage loss seems to be of much higher relevance than damage to the bone," Dr. Aletaha and his coauthors wrote.

"The data presented here provide sufficient evidence for developing, and further testing of, the hypothesis that cartilage damage, rather than bone destruction, may constitute the pivotal cause of physical functional impairment in RA," they concluded.

Data were provided by Abbott, Amgen, Centocor, Sanofi-Aventis and Wyeth (later acquired by Pfizer). None of the authors disclosed any personal competing interests in relation to this study.

When it comes to disability in rheumatoid arthritis, it is cartilage loss – not bone damage – that seems to have the greater effect.

Accordingly, therapeutic interventions that aim to reduce disability should focus on cartilage preservation, "since even relatively little cartilage degradation can lead to significant impairment of physical functioning," wrote Dr. Daniel Aletaha of the Medical University of Vienna and his colleagues in the May issue of Annals of the Rheumatic Diseases.

The authors looked at data from a pool of 4,602 participants in various clinical trials of adalimumab, methotrexate, infliximab, and leflunomide. "To separate the reversible, RA activity–related component of disability from the irreversible component, we identified patients who achieved clinical remission during the trials [that is, a state of absence of significant RA activity and thus the absence of a reversible disability component]," Dr. Aletaha and his colleagues wrote (Ann. Rheum. Dis. 2011;70:733-9).

Remission was defined as an SDAI (Simplified Disease Activity Index) score of 3.3 or less.

In all, 748 patients were included in the current analysis. Patient data were assessed at the first visit in which a patient was in remission, and that visit’s corresponding HAQ-DI (Health Assessment Questionnaire–Disability Index) score was used as "the best estimate of the patient’s irreversible functional disability" for the current study, they wrote.

The HAQ-DI scale has a 0-3 range, with 0 indicating no difficulty in the activities of daily living, and 3 indicating complete disability.

Patients were divided into tertiles according to the degree of both joint space narrowing (JSN), which is a function of cartilage loss, and bone erosion (ERO). As expected, in univariate analysis, the mean scores on the HAQ-DI increased – indicating greater disability – as JSN/ERO tertiles increased (0.21, 0.24, and 0.35, respectively, for the first, second, and third tertiles; P less than .0001).

"Likewise and even to a numerically greater extent, with increasing tertiles by JSN, residual (irreversible) HAQ-DI scores increased," wrote the authors, with a mean of 0.18, 0.24, and 0.38 for the first, second, and third tertiles, respectively (P less than .0001).

To assess the independent disability contribution of erosion vs. narrowing, the authors then looked at the effects of higher erosion tertiles within each of the JSN tertiles. In other words, within each tertile of JSN, patients were further stratified into tertiles of ERO, and the HAQ-DI scores were compared.

"In the first and second tertiles formed according to JSN, higher degrees of erosive changes did not contribute at all to irreversible disability," such that HAQ-DI scores did not differ significantly between ERO tertiles (P = .99 and .77, respectively), they said.

Although patients in the third quartiles of both JSN and ERO did have significantly greater HAQ-DI scores than did patients with less-severe bone erosion (0.417; P = .07), this was an expected finding, wrote the authors, as this group includes patients with severe joint damage.

However, when patients were first divided into ERO tertiles, and then further subdivided according to JSN severity within each tertile, the authors did find a significant effect on disability according to the HAQ-DI.

Indeed, within all three ERO strata, increasing JSN significantly corresponded with increasing HAQ-DI scores (P less than .05, P = .19, and P less than .001 for the first, second, and third ERO tertiles, respectively).

Despite the fact that bony erosion is considered "prototypic for RA," whereas joint space narrowing (which occurs in other disorders) is considered less characteristic of the disease, "in the present study we have been able to show that the clinical impact of joint destruction cartilage loss seems to be of much higher relevance than damage to the bone," Dr. Aletaha and his coauthors wrote.

"The data presented here provide sufficient evidence for developing, and further testing of, the hypothesis that cartilage damage, rather than bone destruction, may constitute the pivotal cause of physical functional impairment in RA," they concluded.

Data were provided by Abbott, Amgen, Centocor, Sanofi-Aventis and Wyeth (later acquired by Pfizer). None of the authors disclosed any personal competing interests in relation to this study.

When it comes to disability in rheumatoid arthritis, it is cartilage loss – not bone damage – that seems to have the greater effect.

Accordingly, therapeutic interventions that aim to reduce disability should focus on cartilage preservation, "since even relatively little cartilage degradation can lead to significant impairment of physical functioning," wrote Dr. Daniel Aletaha of the Medical University of Vienna and his colleagues in the May issue of Annals of the Rheumatic Diseases.

The authors looked at data from a pool of 4,602 participants in various clinical trials of adalimumab, methotrexate, infliximab, and leflunomide. "To separate the reversible, RA activity–related component of disability from the irreversible component, we identified patients who achieved clinical remission during the trials [that is, a state of absence of significant RA activity and thus the absence of a reversible disability component]," Dr. Aletaha and his colleagues wrote (Ann. Rheum. Dis. 2011;70:733-9).

Remission was defined as an SDAI (Simplified Disease Activity Index) score of 3.3 or less.

In all, 748 patients were included in the current analysis. Patient data were assessed at the first visit in which a patient was in remission, and that visit’s corresponding HAQ-DI (Health Assessment Questionnaire–Disability Index) score was used as "the best estimate of the patient’s irreversible functional disability" for the current study, they wrote.

The HAQ-DI scale has a 0-3 range, with 0 indicating no difficulty in the activities of daily living, and 3 indicating complete disability.

Patients were divided into tertiles according to the degree of both joint space narrowing (JSN), which is a function of cartilage loss, and bone erosion (ERO). As expected, in univariate analysis, the mean scores on the HAQ-DI increased – indicating greater disability – as JSN/ERO tertiles increased (0.21, 0.24, and 0.35, respectively, for the first, second, and third tertiles; P less than .0001).

"Likewise and even to a numerically greater extent, with increasing tertiles by JSN, residual (irreversible) HAQ-DI scores increased," wrote the authors, with a mean of 0.18, 0.24, and 0.38 for the first, second, and third tertiles, respectively (P less than .0001).

To assess the independent disability contribution of erosion vs. narrowing, the authors then looked at the effects of higher erosion tertiles within each of the JSN tertiles. In other words, within each tertile of JSN, patients were further stratified into tertiles of ERO, and the HAQ-DI scores were compared.

"In the first and second tertiles formed according to JSN, higher degrees of erosive changes did not contribute at all to irreversible disability," such that HAQ-DI scores did not differ significantly between ERO tertiles (P = .99 and .77, respectively), they said.

Although patients in the third quartiles of both JSN and ERO did have significantly greater HAQ-DI scores than did patients with less-severe bone erosion (0.417; P = .07), this was an expected finding, wrote the authors, as this group includes patients with severe joint damage.

However, when patients were first divided into ERO tertiles, and then further subdivided according to JSN severity within each tertile, the authors did find a significant effect on disability according to the HAQ-DI.

Indeed, within all three ERO strata, increasing JSN significantly corresponded with increasing HAQ-DI scores (P less than .05, P = .19, and P less than .001 for the first, second, and third ERO tertiles, respectively).

Despite the fact that bony erosion is considered "prototypic for RA," whereas joint space narrowing (which occurs in other disorders) is considered less characteristic of the disease, "in the present study we have been able to show that the clinical impact of joint destruction cartilage loss seems to be of much higher relevance than damage to the bone," Dr. Aletaha and his coauthors wrote.

"The data presented here provide sufficient evidence for developing, and further testing of, the hypothesis that cartilage damage, rather than bone destruction, may constitute the pivotal cause of physical functional impairment in RA," they concluded.

Data were provided by Abbott, Amgen, Centocor, Sanofi-Aventis and Wyeth (later acquired by Pfizer). None of the authors disclosed any personal competing interests in relation to this study.

Applying more stringent remission thresholds among rheumatoid arthritis patients lowered the percentage of those with lingering swollen and tender joints; however, the proportion of patients with synovitis on power Doppler ultrasound remained unchanged.

"Therefore, as clinical criteria cannot exclude the presence of active disease, the current remission criteria are more appropriate for defining low disease activity states," concluded Dr. Benazir Saleem in the May issue of Annals of the Rheumatic Diseases.

According to Dr. Saleem, patients who are currently judged by American College of Rheumatology and European League Against Rheumatism criteria to be in remission – with a DAS28 (disease activity score based on a 28-joints count) less than 2.6 – may still have tender and swollen joints, and corresponding structural progression of disease.

It may therefore be expected that more stringent criteria – that is, the use of lower cut-points for DAS28/SDAI (Simplified Disease Activity Index) to define remission – "would be associated with less ... imaging-detected synovitis," postulated Dr. Saleem, a clinical research fellow at the University of Leeds (England) and colleagues (Ann. Rheum. Dis. 2011;70:792-8).

"This would, for example, permit fewer (ideally zero) tender and swollen joints to be present in patients in remission, and thus there would be a better correlation with the absence of structural progression."

To test this theory, the researchers looked at 128 outpatients from the Chapel Allerton Hospital in Leeds who had DAS28 scores less than 2.6. Patients’ mean age was 54 years, and the median disease duration was 8 years.

All participants had been in remission for at least 6 months. Roughly half had achieved remission through the use of disease-modifying antirheumatic drugs; the remainder had been treated with combination tumor necrosis factor blocker and methotrexate (45% infliximab, 45% etanercept, and 10% adalimumab).

Overall, 31% of these patients who were classified as being in remission still had swollen joints, and 18% reported tender joints. More than half (51%) had synovitis that was detectable on power Doppler ultrasound, the "gold standard" of imaging for synovitis.

Dr. Saleem then divided patients into four subcategories: In all, 32 patients had a DAS28 less than 1.17; 31 had a score of 1.17-1.70; 32 patients registered a DAS28 of 1.71-2.03; and the remaining 33 had a DAS score greater than 2.03.

"As was to be expected, both swollen joint count in 28 joints [P less than .001] and tender joint count in 28 joints [P less than 0.001] decreased with decreasing DAS28," the investigators wrote.

However, the proportions of patients in imaging remission did not have a corresponding consistent decrease; indeed, only 9% of those in the lowest category were in strict imaging remission (defined as no joints showing synovitis in the dominant hand’s metacarpophalangeal joints 2-5, plus the wrist, according to grey scale and power Doppler ultrasound).

The stratification of patients into increasingly stringent SDAI categories resulted in a similar, predictable decrease in the number of swollen and tender joints as the score decreased. However, only 25% of those in the lowest SDAI category (score less than 1.51) were in strictly defined imaging remission.

"The use of the term remission in other areas of medicine implies the absence of active disease," wrote the authors. The rheumatologic equivalent of this true remission "would therefore not rely solely on clinical examination but would require imaging to confirm the absence of subclinical inflammation."

And although the widely used, easy-to-calculate DAS28 is a good tool, it is "insufficiently sensitive to exclude [clinically important] levels of inflammation," concluded the authors. They added that the relevance of this finding is not clear, since "the threshold level of ultrasound-determined inflammation that is of importance for subsequent clinical and radiographic progression has not yet been established."

Dr. Saleem and colleagues stated that they had no competing interests to declare in relation to this study.

Applying more stringent remission thresholds among rheumatoid arthritis patients lowered the percentage of those with lingering swollen and tender joints; however, the proportion of patients with synovitis on power Doppler ultrasound remained unchanged.

"Therefore, as clinical criteria cannot exclude the presence of active disease, the current remission criteria are more appropriate for defining low disease activity states," concluded Dr. Benazir Saleem in the May issue of Annals of the Rheumatic Diseases.

According to Dr. Saleem, patients who are currently judged by American College of Rheumatology and European League Against Rheumatism criteria to be in remission – with a DAS28 (disease activity score based on a 28-joints count) less than 2.6 – may still have tender and swollen joints, and corresponding structural progression of disease.

It may therefore be expected that more stringent criteria – that is, the use of lower cut-points for DAS28/SDAI (Simplified Disease Activity Index) to define remission – "would be associated with less ... imaging-detected synovitis," postulated Dr. Saleem, a clinical research fellow at the University of Leeds (England) and colleagues (Ann. Rheum. Dis. 2011;70:792-8).

"This would, for example, permit fewer (ideally zero) tender and swollen joints to be present in patients in remission, and thus there would be a better correlation with the absence of structural progression."

To test this theory, the researchers looked at 128 outpatients from the Chapel Allerton Hospital in Leeds who had DAS28 scores less than 2.6. Patients’ mean age was 54 years, and the median disease duration was 8 years.

All participants had been in remission for at least 6 months. Roughly half had achieved remission through the use of disease-modifying antirheumatic drugs; the remainder had been treated with combination tumor necrosis factor blocker and methotrexate (45% infliximab, 45% etanercept, and 10% adalimumab).

Overall, 31% of these patients who were classified as being in remission still had swollen joints, and 18% reported tender joints. More than half (51%) had synovitis that was detectable on power Doppler ultrasound, the "gold standard" of imaging for synovitis.

Dr. Saleem then divided patients into four subcategories: In all, 32 patients had a DAS28 less than 1.17; 31 had a score of 1.17-1.70; 32 patients registered a DAS28 of 1.71-2.03; and the remaining 33 had a DAS score greater than 2.03.

"As was to be expected, both swollen joint count in 28 joints [P less than .001] and tender joint count in 28 joints [P less than 0.001] decreased with decreasing DAS28," the investigators wrote.

However, the proportions of patients in imaging remission did not have a corresponding consistent decrease; indeed, only 9% of those in the lowest category were in strict imaging remission (defined as no joints showing synovitis in the dominant hand’s metacarpophalangeal joints 2-5, plus the wrist, according to grey scale and power Doppler ultrasound).

The stratification of patients into increasingly stringent SDAI categories resulted in a similar, predictable decrease in the number of swollen and tender joints as the score decreased. However, only 25% of those in the lowest SDAI category (score less than 1.51) were in strictly defined imaging remission.

"The use of the term remission in other areas of medicine implies the absence of active disease," wrote the authors. The rheumatologic equivalent of this true remission "would therefore not rely solely on clinical examination but would require imaging to confirm the absence of subclinical inflammation."

And although the widely used, easy-to-calculate DAS28 is a good tool, it is "insufficiently sensitive to exclude [clinically important] levels of inflammation," concluded the authors. They added that the relevance of this finding is not clear, since "the threshold level of ultrasound-determined inflammation that is of importance for subsequent clinical and radiographic progression has not yet been established."

Dr. Saleem and colleagues stated that they had no competing interests to declare in relation to this study.

Applying more stringent remission thresholds among rheumatoid arthritis patients lowered the percentage of those with lingering swollen and tender joints; however, the proportion of patients with synovitis on power Doppler ultrasound remained unchanged.

"Therefore, as clinical criteria cannot exclude the presence of active disease, the current remission criteria are more appropriate for defining low disease activity states," concluded Dr. Benazir Saleem in the May issue of Annals of the Rheumatic Diseases.

According to Dr. Saleem, patients who are currently judged by American College of Rheumatology and European League Against Rheumatism criteria to be in remission – with a DAS28 (disease activity score based on a 28-joints count) less than 2.6 – may still have tender and swollen joints, and corresponding structural progression of disease.

It may therefore be expected that more stringent criteria – that is, the use of lower cut-points for DAS28/SDAI (Simplified Disease Activity Index) to define remission – "would be associated with less ... imaging-detected synovitis," postulated Dr. Saleem, a clinical research fellow at the University of Leeds (England) and colleagues (Ann. Rheum. Dis. 2011;70:792-8).

"This would, for example, permit fewer (ideally zero) tender and swollen joints to be present in patients in remission, and thus there would be a better correlation with the absence of structural progression."

To test this theory, the researchers looked at 128 outpatients from the Chapel Allerton Hospital in Leeds who had DAS28 scores less than 2.6. Patients’ mean age was 54 years, and the median disease duration was 8 years.

All participants had been in remission for at least 6 months. Roughly half had achieved remission through the use of disease-modifying antirheumatic drugs; the remainder had been treated with combination tumor necrosis factor blocker and methotrexate (45% infliximab, 45% etanercept, and 10% adalimumab).

Overall, 31% of these patients who were classified as being in remission still had swollen joints, and 18% reported tender joints. More than half (51%) had synovitis that was detectable on power Doppler ultrasound, the "gold standard" of imaging for synovitis.

Dr. Saleem then divided patients into four subcategories: In all, 32 patients had a DAS28 less than 1.17; 31 had a score of 1.17-1.70; 32 patients registered a DAS28 of 1.71-2.03; and the remaining 33 had a DAS score greater than 2.03.

"As was to be expected, both swollen joint count in 28 joints [P less than .001] and tender joint count in 28 joints [P less than 0.001] decreased with decreasing DAS28," the investigators wrote.

However, the proportions of patients in imaging remission did not have a corresponding consistent decrease; indeed, only 9% of those in the lowest category were in strict imaging remission (defined as no joints showing synovitis in the dominant hand’s metacarpophalangeal joints 2-5, plus the wrist, according to grey scale and power Doppler ultrasound).

The stratification of patients into increasingly stringent SDAI categories resulted in a similar, predictable decrease in the number of swollen and tender joints as the score decreased. However, only 25% of those in the lowest SDAI category (score less than 1.51) were in strictly defined imaging remission.

"The use of the term remission in other areas of medicine implies the absence of active disease," wrote the authors. The rheumatologic equivalent of this true remission "would therefore not rely solely on clinical examination but would require imaging to confirm the absence of subclinical inflammation."

And although the widely used, easy-to-calculate DAS28 is a good tool, it is "insufficiently sensitive to exclude [clinically important] levels of inflammation," concluded the authors. They added that the relevance of this finding is not clear, since "the threshold level of ultrasound-determined inflammation that is of importance for subsequent clinical and radiographic progression has not yet been established."

Dr. Saleem and colleagues stated that they had no competing interests to declare in relation to this study.

BRIGHTON, ENGLAND – The use of biologic agents in adults with juvenile idiopathic arthritis needs guidance, a situation that the British Society for Rheumatology and British Society for Pediatric and Adolescent Rheumatology are set to address.

The two British Societies will publish a statement on the use of biologics in adults with juvenile idiopathic arthritis (JIA) very soon, said Dr. Helen Foster at the annual meeting of the British Society for Rheumatology (BSR).

Dr. Foster, professor of pediatric rheumatology at Newcastle University, England, commented that the current use of biologics in adult JIA patients is based on a paucity of data, with only one biologic agent, etanercept, currently approved for use by the National Institute for Health and Clinical Excellence (NICE).

"Clearly adults with JIA are receiving biologic treatments, and data so far, albeit from registries, are actually quite encouraging of a good response," Dr. Foster said.

Indeed, data from the BSR Biologics Register (BSRBR) show that of 495 patients registered in adulthood one third had disease onset reported before the age of 16 years, with one fifth (21%) officially diagnosed with JIA. Importantly, Dr. Foster noted that these data showed that disease flares were still possible after many years of remission, at a median of 20 years for de novo biologic use.

Last year, NICE issued guidance link to on how to improve commissioning of biologic drugs to treat inflammatory diseases in the United Kingdom. In the report, the estimated need for biologic agents in adults who had JIA was just 15% – a likely underestimate, Dr. Foster suggested.

"Undoubtedly, the proportion of patients with JIA who reach adulthood and who will require either ongoing treatment with a biologic agent or de novo treatment for disease flares is going to increase," she observed.

However, despite the need for continued or first-time biologic use in adults with JIA, these patients often fall into a gap between pediatric and adult care. Anecdotal evidence suggests that funding for treatment might be withdrawn when a JIA patient reaches 18 years of age and that if continued treatment is needed, a new application for funding must be made to adult services.

With this in mind, better links between juvenile and adult rheumatology services are sorely needed. The new BSR/British Society for Paediatric and Adolescent Rheumatology (BSPAR) statement will note that patients transferring to adult care are likely to need continued treatment with a biologic agent and that treatment should not be stopped solely on the basis of age. The process of ongoing funding needs to be in place before transfer, Dr. Foster said.

The BSR/BSPAR statement will also comment on eligibility for biologic agents, noting that appropriate tools for adults with JIA are specifically needed. Currently, the only guidance on use of biologics in JIA is for etanercept in the pediatric population and, clearly, adults with JIA are a distinct patient population.

"The management of JIA has changed dramatically in the last decade, and it’s going to change again towards a more individualized approach in the future," Dr. Foster said. She added that the choice of biologic is very much down to a variety of factors – clinician’s experience, patient choice, and clinical scenario, but that there is an obvious need for consensus on which agent or agents to use.

There is also a need for improved surveillance, and existing juvenile and adult biologics registries provide important information about the long-term safety of these agents, and these need to be linked up, both in the United Kingdom and in Europe.

"Optimal care requires adult rheumatologists who have experience or training in adolescent rheumatology," Dr. Foster further advised. Adults with JIA have multiple and often complex issues, she added, and these need to be addressed by appropriately trained staff.

Dr. Foster has received honoraria from Abbott, Pfizer, and Schering-Plough.

BRIGHTON, ENGLAND – The use of biologic agents in adults with juvenile idiopathic arthritis needs guidance, a situation that the British Society for Rheumatology and British Society for Pediatric and Adolescent Rheumatology are set to address.

The two British Societies will publish a statement on the use of biologics in adults with juvenile idiopathic arthritis (JIA) very soon, said Dr. Helen Foster at the annual meeting of the British Society for Rheumatology (BSR).

Dr. Foster, professor of pediatric rheumatology at Newcastle University, England, commented that the current use of biologics in adult JIA patients is based on a paucity of data, with only one biologic agent, etanercept, currently approved for use by the National Institute for Health and Clinical Excellence (NICE).

"Clearly adults with JIA are receiving biologic treatments, and data so far, albeit from registries, are actually quite encouraging of a good response," Dr. Foster said.

Indeed, data from the BSR Biologics Register (BSRBR) show that of 495 patients registered in adulthood one third had disease onset reported before the age of 16 years, with one fifth (21%) officially diagnosed with JIA. Importantly, Dr. Foster noted that these data showed that disease flares were still possible after many years of remission, at a median of 20 years for de novo biologic use.

Last year, NICE issued guidance link to on how to improve commissioning of biologic drugs to treat inflammatory diseases in the United Kingdom. In the report, the estimated need for biologic agents in adults who had JIA was just 15% – a likely underestimate, Dr. Foster suggested.

"Undoubtedly, the proportion of patients with JIA who reach adulthood and who will require either ongoing treatment with a biologic agent or de novo treatment for disease flares is going to increase," she observed.

However, despite the need for continued or first-time biologic use in adults with JIA, these patients often fall into a gap between pediatric and adult care. Anecdotal evidence suggests that funding for treatment might be withdrawn when a JIA patient reaches 18 years of age and that if continued treatment is needed, a new application for funding must be made to adult services.

With this in mind, better links between juvenile and adult rheumatology services are sorely needed. The new BSR/British Society for Paediatric and Adolescent Rheumatology (BSPAR) statement will note that patients transferring to adult care are likely to need continued treatment with a biologic agent and that treatment should not be stopped solely on the basis of age. The process of ongoing funding needs to be in place before transfer, Dr. Foster said.

The BSR/BSPAR statement will also comment on eligibility for biologic agents, noting that appropriate tools for adults with JIA are specifically needed. Currently, the only guidance on use of biologics in JIA is for etanercept in the pediatric population and, clearly, adults with JIA are a distinct patient population.

"The management of JIA has changed dramatically in the last decade, and it’s going to change again towards a more individualized approach in the future," Dr. Foster said. She added that the choice of biologic is very much down to a variety of factors – clinician’s experience, patient choice, and clinical scenario, but that there is an obvious need for consensus on which agent or agents to use.

There is also a need for improved surveillance, and existing juvenile and adult biologics registries provide important information about the long-term safety of these agents, and these need to be linked up, both in the United Kingdom and in Europe.

"Optimal care requires adult rheumatologists who have experience or training in adolescent rheumatology," Dr. Foster further advised. Adults with JIA have multiple and often complex issues, she added, and these need to be addressed by appropriately trained staff.

Dr. Foster has received honoraria from Abbott, Pfizer, and Schering-Plough.

BRIGHTON, ENGLAND – The use of biologic agents in adults with juvenile idiopathic arthritis needs guidance, a situation that the British Society for Rheumatology and British Society for Pediatric and Adolescent Rheumatology are set to address.

The two British Societies will publish a statement on the use of biologics in adults with juvenile idiopathic arthritis (JIA) very soon, said Dr. Helen Foster at the annual meeting of the British Society for Rheumatology (BSR).

Dr. Foster, professor of pediatric rheumatology at Newcastle University, England, commented that the current use of biologics in adult JIA patients is based on a paucity of data, with only one biologic agent, etanercept, currently approved for use by the National Institute for Health and Clinical Excellence (NICE).

"Clearly adults with JIA are receiving biologic treatments, and data so far, albeit from registries, are actually quite encouraging of a good response," Dr. Foster said.

Indeed, data from the BSR Biologics Register (BSRBR) show that of 495 patients registered in adulthood one third had disease onset reported before the age of 16 years, with one fifth (21%) officially diagnosed with JIA. Importantly, Dr. Foster noted that these data showed that disease flares were still possible after many years of remission, at a median of 20 years for de novo biologic use.

Last year, NICE issued guidance link to on how to improve commissioning of biologic drugs to treat inflammatory diseases in the United Kingdom. In the report, the estimated need for biologic agents in adults who had JIA was just 15% – a likely underestimate, Dr. Foster suggested.

"Undoubtedly, the proportion of patients with JIA who reach adulthood and who will require either ongoing treatment with a biologic agent or de novo treatment for disease flares is going to increase," she observed.

However, despite the need for continued or first-time biologic use in adults with JIA, these patients often fall into a gap between pediatric and adult care. Anecdotal evidence suggests that funding for treatment might be withdrawn when a JIA patient reaches 18 years of age and that if continued treatment is needed, a new application for funding must be made to adult services.

With this in mind, better links between juvenile and adult rheumatology services are sorely needed. The new BSR/British Society for Paediatric and Adolescent Rheumatology (BSPAR) statement will note that patients transferring to adult care are likely to need continued treatment with a biologic agent and that treatment should not be stopped solely on the basis of age. The process of ongoing funding needs to be in place before transfer, Dr. Foster said.

The BSR/BSPAR statement will also comment on eligibility for biologic agents, noting that appropriate tools for adults with JIA are specifically needed. Currently, the only guidance on use of biologics in JIA is for etanercept in the pediatric population and, clearly, adults with JIA are a distinct patient population.

"The management of JIA has changed dramatically in the last decade, and it’s going to change again towards a more individualized approach in the future," Dr. Foster said. She added that the choice of biologic is very much down to a variety of factors – clinician’s experience, patient choice, and clinical scenario, but that there is an obvious need for consensus on which agent or agents to use.

There is also a need for improved surveillance, and existing juvenile and adult biologics registries provide important information about the long-term safety of these agents, and these need to be linked up, both in the United Kingdom and in Europe.

"Optimal care requires adult rheumatologists who have experience or training in adolescent rheumatology," Dr. Foster further advised. Adults with JIA have multiple and often complex issues, she added, and these need to be addressed by appropriately trained staff.

Dr. Foster has received honoraria from Abbott, Pfizer, and Schering-Plough.

Major Finding: Among RA patients in remission, only 9% with DAS28 scores less than 1.17 were found to be free of synovitis on power Doppler imaging; among patients with correspondingly low SDAI scores, just 25% had similarly clear scans, with the remainder showing some degree of inflammation.

Data Source: A cohort of 128 outpatients seen at a clinic in Leeds, England.

Disclosures: The authors stated that they had no competing interests to declare in relation to this study.

Applying more stringent remission thresholds among rheumatoid arthritis patients lowered the percentage of those with lingering swollen and tender joints; however, the proportion of patients with synovitis on power Doppler ultrasound remained unchanged.

“Therefore, as clinical criteria cannot exclude the presence of active disease, the current remission criteria are more appropriate for defining low disease activity states,” concluded Dr. Benazir Saleem and colleagues.

According to the investigators, patients who are currently judged by American College of Rheumatology and European League Against Rheumatism criteria to be in remission – with a DAS28 (disease activity score based on a 28-joints count) less than 2.6 – may still have tender and swollen joints, and corresponding structural progression of disease.

It may therefore be expected that more stringent criteria – that is, the use of lower cut-points for DAS28/SDAI (Simplified Disease Activity Index) to define remission – “would be associated with less … imaging-detected synovitis,” postulated Dr. Saleem, a clinical research fellow at the University of Leeds (England) and colleagues (Ann. Rheum. Dis. 2011;70:792–8).

“This would, for example, permit fewer (ideally zero) tender and swollen joints to be present in patients in remission, and thus there would be a better correlation with the absence of structural progression,” according to Dr. Saleem and coauthors.

To test this theory, the researchers looked at 128 outpatients from the Chapel Allerton Hospital in Leeds who had DAS28 scores less than 2.6. Patients' mean age was 54 years, and the median disease duration was 8 years.

All study participants had been in remission for a period of at least 6 months. Roughly half of them had achieved remission through the use of disease-modifying antirheumatic drugs; the remainder had been treated with a regimen consisting of combination tumor necrosis factor blocker and methotrexate (45% infliximab, 45% etanercept, and 10% adalimumab).

Overall, a total of 31% of these patients who were classified as being in remission still had swollen joints, and 18% reported tender joints. In addition, more than half of the patients (51%) had synovitis that was detectable on power Doppler ultrasound, which is considered the “gold standard” of imaging for synovitis.

Dr. Saleem then divided the patients into four subcategories: In all, 32 patients had a DAS28 less than 1.17; 31 had a score of 1.17–1.70; 32 patients registered a DAS28 of 1.71–2.03; and the remaining 33 patients had a DAS score greater than 2.03.

“As was to be expected, both swollen joint count in 28 joints [P less than .001] and tender joint count in 28 joints [P less than 0.001] decreased with decreasing DAS28,” Dr. Saleem and coinvestigators wrote.

However, the proportions of patients in imaging remission did not have a corresponding consistent decrease; indeed, only 9% of those in the lowest category were in strict imaging remission (defined as no joints showing synovitis in the dominant hand's metacarpophalangeal joints 2–5, plus the wrist, according to gray scale and power Doppler ultrasound).

The stratification of the study participants into increasingly stringent SDAI categories resulted in a similar, predictable decrease in the number of swollen and tender joints as the score decreased.

However, only 25% of those in the lowest SDAI category (score less than 1.51) were in strictly defined imaging remission.

“The use of the term remission in other areas of medicine implies the absence of active disease,” wrote the researchers.

The rheumatologic equivalent of this true remission “would therefore not rely solely on clinical examination but would require imaging to confirm the absence of subclinical inflammation,” according to Dr. Saleem and coinvestigators.

And although the widely used, easy-to-calculate DAS28 is a good tool, it is “insufficiently sensitive to exclude [clinically important] levels of inflammation,” they concluded.

The relevance of this finding is not clear, because “the threshold level of ultrasound-determined inflammation that is of importance for subsequent clinical and radiographic progression has not yet been established,” according to the investigators.

Major Finding: Among RA patients in remission, only 9% with DAS28 scores less than 1.17 were found to be free of synovitis on power Doppler imaging; among patients with correspondingly low SDAI scores, just 25% had similarly clear scans, with the remainder showing some degree of inflammation.

Data Source: A cohort of 128 outpatients seen at a clinic in Leeds, England.

Disclosures: The authors stated that they had no competing interests to declare in relation to this study.

Applying more stringent remission thresholds among rheumatoid arthritis patients lowered the percentage of those with lingering swollen and tender joints; however, the proportion of patients with synovitis on power Doppler ultrasound remained unchanged.

“Therefore, as clinical criteria cannot exclude the presence of active disease, the current remission criteria are more appropriate for defining low disease activity states,” concluded Dr. Benazir Saleem and colleagues.

According to the investigators, patients who are currently judged by American College of Rheumatology and European League Against Rheumatism criteria to be in remission – with a DAS28 (disease activity score based on a 28-joints count) less than 2.6 – may still have tender and swollen joints, and corresponding structural progression of disease.

It may therefore be expected that more stringent criteria – that is, the use of lower cut-points for DAS28/SDAI (Simplified Disease Activity Index) to define remission – “would be associated with less … imaging-detected synovitis,” postulated Dr. Saleem, a clinical research fellow at the University of Leeds (England) and colleagues (Ann. Rheum. Dis. 2011;70:792–8).

“This would, for example, permit fewer (ideally zero) tender and swollen joints to be present in patients in remission, and thus there would be a better correlation with the absence of structural progression,” according to Dr. Saleem and coauthors.

To test this theory, the researchers looked at 128 outpatients from the Chapel Allerton Hospital in Leeds who had DAS28 scores less than 2.6. Patients' mean age was 54 years, and the median disease duration was 8 years.

All study participants had been in remission for a period of at least 6 months. Roughly half of them had achieved remission through the use of disease-modifying antirheumatic drugs; the remainder had been treated with a regimen consisting of combination tumor necrosis factor blocker and methotrexate (45% infliximab, 45% etanercept, and 10% adalimumab).

Overall, a total of 31% of these patients who were classified as being in remission still had swollen joints, and 18% reported tender joints. In addition, more than half of the patients (51%) had synovitis that was detectable on power Doppler ultrasound, which is considered the “gold standard” of imaging for synovitis.

Dr. Saleem then divided the patients into four subcategories: In all, 32 patients had a DAS28 less than 1.17; 31 had a score of 1.17–1.70; 32 patients registered a DAS28 of 1.71–2.03; and the remaining 33 patients had a DAS score greater than 2.03.

“As was to be expected, both swollen joint count in 28 joints [P less than .001] and tender joint count in 28 joints [P less than 0.001] decreased with decreasing DAS28,” Dr. Saleem and coinvestigators wrote.

However, the proportions of patients in imaging remission did not have a corresponding consistent decrease; indeed, only 9% of those in the lowest category were in strict imaging remission (defined as no joints showing synovitis in the dominant hand's metacarpophalangeal joints 2–5, plus the wrist, according to gray scale and power Doppler ultrasound).

The stratification of the study participants into increasingly stringent SDAI categories resulted in a similar, predictable decrease in the number of swollen and tender joints as the score decreased.

However, only 25% of those in the lowest SDAI category (score less than 1.51) were in strictly defined imaging remission.

“The use of the term remission in other areas of medicine implies the absence of active disease,” wrote the researchers.

The rheumatologic equivalent of this true remission “would therefore not rely solely on clinical examination but would require imaging to confirm the absence of subclinical inflammation,” according to Dr. Saleem and coinvestigators.

And although the widely used, easy-to-calculate DAS28 is a good tool, it is “insufficiently sensitive to exclude [clinically important] levels of inflammation,” they concluded.

The relevance of this finding is not clear, because “the threshold level of ultrasound-determined inflammation that is of importance for subsequent clinical and radiographic progression has not yet been established,” according to the investigators.

Major Finding: Among RA patients in remission, only 9% with DAS28 scores less than 1.17 were found to be free of synovitis on power Doppler imaging; among patients with correspondingly low SDAI scores, just 25% had similarly clear scans, with the remainder showing some degree of inflammation.

Data Source: A cohort of 128 outpatients seen at a clinic in Leeds, England.

Disclosures: The authors stated that they had no competing interests to declare in relation to this study.

Applying more stringent remission thresholds among rheumatoid arthritis patients lowered the percentage of those with lingering swollen and tender joints; however, the proportion of patients with synovitis on power Doppler ultrasound remained unchanged.

“Therefore, as clinical criteria cannot exclude the presence of active disease, the current remission criteria are more appropriate for defining low disease activity states,” concluded Dr. Benazir Saleem and colleagues.

According to the investigators, patients who are currently judged by American College of Rheumatology and European League Against Rheumatism criteria to be in remission – with a DAS28 (disease activity score based on a 28-joints count) less than 2.6 – may still have tender and swollen joints, and corresponding structural progression of disease.

It may therefore be expected that more stringent criteria – that is, the use of lower cut-points for DAS28/SDAI (Simplified Disease Activity Index) to define remission – “would be associated with less … imaging-detected synovitis,” postulated Dr. Saleem, a clinical research fellow at the University of Leeds (England) and colleagues (Ann. Rheum. Dis. 2011;70:792–8).

“This would, for example, permit fewer (ideally zero) tender and swollen joints to be present in patients in remission, and thus there would be a better correlation with the absence of structural progression,” according to Dr. Saleem and coauthors.

To test this theory, the researchers looked at 128 outpatients from the Chapel Allerton Hospital in Leeds who had DAS28 scores less than 2.6. Patients' mean age was 54 years, and the median disease duration was 8 years.

All study participants had been in remission for a period of at least 6 months. Roughly half of them had achieved remission through the use of disease-modifying antirheumatic drugs; the remainder had been treated with a regimen consisting of combination tumor necrosis factor blocker and methotrexate (45% infliximab, 45% etanercept, and 10% adalimumab).

Overall, a total of 31% of these patients who were classified as being in remission still had swollen joints, and 18% reported tender joints. In addition, more than half of the patients (51%) had synovitis that was detectable on power Doppler ultrasound, which is considered the “gold standard” of imaging for synovitis.

Dr. Saleem then divided the patients into four subcategories: In all, 32 patients had a DAS28 less than 1.17; 31 had a score of 1.17–1.70; 32 patients registered a DAS28 of 1.71–2.03; and the remaining 33 patients had a DAS score greater than 2.03.

“As was to be expected, both swollen joint count in 28 joints [P less than .001] and tender joint count in 28 joints [P less than 0.001] decreased with decreasing DAS28,” Dr. Saleem and coinvestigators wrote.

However, the proportions of patients in imaging remission did not have a corresponding consistent decrease; indeed, only 9% of those in the lowest category were in strict imaging remission (defined as no joints showing synovitis in the dominant hand's metacarpophalangeal joints 2–5, plus the wrist, according to gray scale and power Doppler ultrasound).

The stratification of the study participants into increasingly stringent SDAI categories resulted in a similar, predictable decrease in the number of swollen and tender joints as the score decreased.

However, only 25% of those in the lowest SDAI category (score less than 1.51) were in strictly defined imaging remission.

“The use of the term remission in other areas of medicine implies the absence of active disease,” wrote the researchers.

The rheumatologic equivalent of this true remission “would therefore not rely solely on clinical examination but would require imaging to confirm the absence of subclinical inflammation,” according to Dr. Saleem and coinvestigators.

And although the widely used, easy-to-calculate DAS28 is a good tool, it is “insufficiently sensitive to exclude [clinically important] levels of inflammation,” they concluded.

The relevance of this finding is not clear, because “the threshold level of ultrasound-determined inflammation that is of importance for subsequent clinical and radiographic progression has not yet been established,” according to the investigators.