Rheumatoid Arthritis

SANTA MONICA, CALIF. — Rheumatoid arthritis patients with a true primary failure on a first-time trial of tumor necrosis factor inhibitor therapy should change to treatment with a biologic that has a different mechanism of action. The likelihood is great that trying a second anti-TNF agent will result in just another failure and delay the initiation of effective treatment, according to Dr. Daniel E. Furst.

The key is to be sure that failure to respond to the first anti-TNF agent is not secondary to another cause, such as too low a dose, he said at a meeting sponsored by Skin Disease Education Foundation and the University of Louisville.

An estimated 60%–70% of patients who begin treatment with an anti-TNF agent are still on the agent at the end of 1 year. Although some patients have to stop treatment because of problems with their insurance and other reasons, primary and secondary failure play a role, he said.

One cannot recognize a treatment failure unless one undertakes therapy with a treatment target in mind, usually remission or low disease activity levels. Treating-to-target goals have been shown to improve outcome and to lower rates of organ damage in diabetes and hypertension. Treating to target was the watchword of new treatment guidelines issued jointly earlier this year by the American College of Rheumatology and the European League Against Rheumatism (

Evidence that treating to target in RA is effective dates back to 1998, and this therapeutic approach has become more important in the biologics era of care. The goals of treating to target, as outlined by ACR/EULAR, are to aim for complete remission of low disease activity; to see the patient monthly for at least the first 3–6 months, depending on disease activity; to use a combination of validated response measures; to consider comorbidities; to aim for sustained remission; and to get informed consent.

So how does one tell whether a patient's lack of response to an anti-TNF agent is a true primary failure or is secondary to something else that may be correctable, such as a longer therapeutic trial?

Findings from a secondary analysis of TEMPO (Trial of Etanercept and Methotrexate With Radiographic Patient Outcomes) data show that about half of the patients who had not responded by 12 weeks to treatment with etanercept or methotrexate, either as monotherapy or in combination, were still likely to respond by 24 weeks with either treatment (Ann. Rheum. Dis. 2008;67:1444–7).

“If there is a hint of a response, treat beyond the usual 12 weeks,” advised Dr. Furst, who is the Carl M. Pearson Professor of Medicine at the University of California, Los Angeles.

Some patients may need a higher dose of the anti-TNF agent than they have been receiving. A chart review presented by Dr. Furst and colleagues at the 2008 annual meeting of the ACR showed that increasing the adalimumab dose from 40 mg subcutaneously every other week for 5 months to 40 mg every week for 6 months can increase the number of patients with good EULAR responses. Of 48 patients who originally had received 40 mg of adalimumab subcutaneously every other week for 5 months, 20 had good response and 28 achieved moderate or no EULAR responses. An increase in the dose to 40 mg every week for 6 months resulted in a good EULAR response in 8 of 28 nonresponders, which included 4 of 12 patients who originally had no response to the lower-dose adalimumab (Arthritis Rheum. 2008;58[suppl.]:abstract 999).

One can improve treatment response to infliximab by decreasing the interval between doses. But increasing the dose and leaving the interval the same does not have the desired effect. Other data from Dr. Furst's research suggest that in the case of etanercept, increasing dose does not improve efficacy (Arthritis Rheum. 2007;56[suppl.]:abstract 726).

Higher doses of anti-TNF agents are associated with higher rates of nonserious adverse events, especially with adalimumab and infliximab. Data from package inserts show that infliximab has a 5.3% rate of serious adverse events, which is higher than that seen with adalimumab (2%), etanercept (1%), golimumab (1.9%), and certolizumab (3%). Data from the French RATIO registry show that, during 57,711 people-years of biologic use in 2004–2007, there were 69 cases of tuberculosis in patients who took anti-TNF agents for a variety of reasons, including RA. After adjustment for confounding risk factors, the incidence rate for TB in patients on any anti-TNF drug was shown to be 116.7 cases per 100,000 person-years of use (Arthritis Rheum. 2009;60:1884–94).

The bottom line is that not only are anti-TNF agents less effective after a primary failure, but the rate of adverse events increases as well, judging from data reported at the annual meeting of the European League Against Rheumatism in 2008 by Dr. Luba Nalysnyk of United BioSource Corp. Dr. Nalysnyk and associates performed a meta-analysis of 16 articles and 15 abstracts involving 5,306 patients. In the meta-analysis, primary failure of an anti-TNF agent occurred in 48% of patients. A second anti-TNF agent did not work in 66% of those patients, and another 66% of those patients developed adverse events in response to the second agent.

SDEF and

A video interview with Dr. Daniel E. Furst is available at

Source Sally Kubetin/ELsevier Global Medical Newswww.rheumatologynews.com/

SANTA MONICA, CALIF. — Rheumatoid arthritis patients with a true primary failure on a first-time trial of tumor necrosis factor inhibitor therapy should change to treatment with a biologic that has a different mechanism of action. The likelihood is great that trying a second anti-TNF agent will result in just another failure and delay the initiation of effective treatment, according to Dr. Daniel E. Furst.

The key is to be sure that failure to respond to the first anti-TNF agent is not secondary to another cause, such as too low a dose, he said at a meeting sponsored by Skin Disease Education Foundation and the University of Louisville.

An estimated 60%–70% of patients who begin treatment with an anti-TNF agent are still on the agent at the end of 1 year. Although some patients have to stop treatment because of problems with their insurance and other reasons, primary and secondary failure play a role, he said.

One cannot recognize a treatment failure unless one undertakes therapy with a treatment target in mind, usually remission or low disease activity levels. Treating-to-target goals have been shown to improve outcome and to lower rates of organ damage in diabetes and hypertension. Treating to target was the watchword of new treatment guidelines issued jointly earlier this year by the American College of Rheumatology and the European League Against Rheumatism (

Evidence that treating to target in RA is effective dates back to 1998, and this therapeutic approach has become more important in the biologics era of care. The goals of treating to target, as outlined by ACR/EULAR, are to aim for complete remission of low disease activity; to see the patient monthly for at least the first 3–6 months, depending on disease activity; to use a combination of validated response measures; to consider comorbidities; to aim for sustained remission; and to get informed consent.

So how does one tell whether a patient's lack of response to an anti-TNF agent is a true primary failure or is secondary to something else that may be correctable, such as a longer therapeutic trial?

Findings from a secondary analysis of TEMPO (Trial of Etanercept and Methotrexate With Radiographic Patient Outcomes) data show that about half of the patients who had not responded by 12 weeks to treatment with etanercept or methotrexate, either as monotherapy or in combination, were still likely to respond by 24 weeks with either treatment (Ann. Rheum. Dis. 2008;67:1444–7).

“If there is a hint of a response, treat beyond the usual 12 weeks,” advised Dr. Furst, who is the Carl M. Pearson Professor of Medicine at the University of California, Los Angeles.

Some patients may need a higher dose of the anti-TNF agent than they have been receiving. A chart review presented by Dr. Furst and colleagues at the 2008 annual meeting of the ACR showed that increasing the adalimumab dose from 40 mg subcutaneously every other week for 5 months to 40 mg every week for 6 months can increase the number of patients with good EULAR responses. Of 48 patients who originally had received 40 mg of adalimumab subcutaneously every other week for 5 months, 20 had good response and 28 achieved moderate or no EULAR responses. An increase in the dose to 40 mg every week for 6 months resulted in a good EULAR response in 8 of 28 nonresponders, which included 4 of 12 patients who originally had no response to the lower-dose adalimumab (Arthritis Rheum. 2008;58[suppl.]:abstract 999).

One can improve treatment response to infliximab by decreasing the interval between doses. But increasing the dose and leaving the interval the same does not have the desired effect. Other data from Dr. Furst's research suggest that in the case of etanercept, increasing dose does not improve efficacy (Arthritis Rheum. 2007;56[suppl.]:abstract 726).

Higher doses of anti-TNF agents are associated with higher rates of nonserious adverse events, especially with adalimumab and infliximab. Data from package inserts show that infliximab has a 5.3% rate of serious adverse events, which is higher than that seen with adalimumab (2%), etanercept (1%), golimumab (1.9%), and certolizumab (3%). Data from the French RATIO registry show that, during 57,711 people-years of biologic use in 2004–2007, there were 69 cases of tuberculosis in patients who took anti-TNF agents for a variety of reasons, including RA. After adjustment for confounding risk factors, the incidence rate for TB in patients on any anti-TNF drug was shown to be 116.7 cases per 100,000 person-years of use (Arthritis Rheum. 2009;60:1884–94).

The bottom line is that not only are anti-TNF agents less effective after a primary failure, but the rate of adverse events increases as well, judging from data reported at the annual meeting of the European League Against Rheumatism in 2008 by Dr. Luba Nalysnyk of United BioSource Corp. Dr. Nalysnyk and associates performed a meta-analysis of 16 articles and 15 abstracts involving 5,306 patients. In the meta-analysis, primary failure of an anti-TNF agent occurred in 48% of patients. A second anti-TNF agent did not work in 66% of those patients, and another 66% of those patients developed adverse events in response to the second agent.

SDEF and

A video interview with Dr. Daniel E. Furst is available at

Source Sally Kubetin/ELsevier Global Medical Newswww.rheumatologynews.com/

SANTA MONICA, CALIF. — Rheumatoid arthritis patients with a true primary failure on a first-time trial of tumor necrosis factor inhibitor therapy should change to treatment with a biologic that has a different mechanism of action. The likelihood is great that trying a second anti-TNF agent will result in just another failure and delay the initiation of effective treatment, according to Dr. Daniel E. Furst.

The key is to be sure that failure to respond to the first anti-TNF agent is not secondary to another cause, such as too low a dose, he said at a meeting sponsored by Skin Disease Education Foundation and the University of Louisville.

An estimated 60%–70% of patients who begin treatment with an anti-TNF agent are still on the agent at the end of 1 year. Although some patients have to stop treatment because of problems with their insurance and other reasons, primary and secondary failure play a role, he said.

One cannot recognize a treatment failure unless one undertakes therapy with a treatment target in mind, usually remission or low disease activity levels. Treating-to-target goals have been shown to improve outcome and to lower rates of organ damage in diabetes and hypertension. Treating to target was the watchword of new treatment guidelines issued jointly earlier this year by the American College of Rheumatology and the European League Against Rheumatism (

Evidence that treating to target in RA is effective dates back to 1998, and this therapeutic approach has become more important in the biologics era of care. The goals of treating to target, as outlined by ACR/EULAR, are to aim for complete remission of low disease activity; to see the patient monthly for at least the first 3–6 months, depending on disease activity; to use a combination of validated response measures; to consider comorbidities; to aim for sustained remission; and to get informed consent.

So how does one tell whether a patient's lack of response to an anti-TNF agent is a true primary failure or is secondary to something else that may be correctable, such as a longer therapeutic trial?

Findings from a secondary analysis of TEMPO (Trial of Etanercept and Methotrexate With Radiographic Patient Outcomes) data show that about half of the patients who had not responded by 12 weeks to treatment with etanercept or methotrexate, either as monotherapy or in combination, were still likely to respond by 24 weeks with either treatment (Ann. Rheum. Dis. 2008;67:1444–7).

“If there is a hint of a response, treat beyond the usual 12 weeks,” advised Dr. Furst, who is the Carl M. Pearson Professor of Medicine at the University of California, Los Angeles.

Some patients may need a higher dose of the anti-TNF agent than they have been receiving. A chart review presented by Dr. Furst and colleagues at the 2008 annual meeting of the ACR showed that increasing the adalimumab dose from 40 mg subcutaneously every other week for 5 months to 40 mg every week for 6 months can increase the number of patients with good EULAR responses. Of 48 patients who originally had received 40 mg of adalimumab subcutaneously every other week for 5 months, 20 had good response and 28 achieved moderate or no EULAR responses. An increase in the dose to 40 mg every week for 6 months resulted in a good EULAR response in 8 of 28 nonresponders, which included 4 of 12 patients who originally had no response to the lower-dose adalimumab (Arthritis Rheum. 2008;58[suppl.]:abstract 999).

One can improve treatment response to infliximab by decreasing the interval between doses. But increasing the dose and leaving the interval the same does not have the desired effect. Other data from Dr. Furst's research suggest that in the case of etanercept, increasing dose does not improve efficacy (Arthritis Rheum. 2007;56[suppl.]:abstract 726).

Higher doses of anti-TNF agents are associated with higher rates of nonserious adverse events, especially with adalimumab and infliximab. Data from package inserts show that infliximab has a 5.3% rate of serious adverse events, which is higher than that seen with adalimumab (2%), etanercept (1%), golimumab (1.9%), and certolizumab (3%). Data from the French RATIO registry show that, during 57,711 people-years of biologic use in 2004–2007, there were 69 cases of tuberculosis in patients who took anti-TNF agents for a variety of reasons, including RA. After adjustment for confounding risk factors, the incidence rate for TB in patients on any anti-TNF drug was shown to be 116.7 cases per 100,000 person-years of use (Arthritis Rheum. 2009;60:1884–94).

The bottom line is that not only are anti-TNF agents less effective after a primary failure, but the rate of adverse events increases as well, judging from data reported at the annual meeting of the European League Against Rheumatism in 2008 by Dr. Luba Nalysnyk of United BioSource Corp. Dr. Nalysnyk and associates performed a meta-analysis of 16 articles and 15 abstracts involving 5,306 patients. In the meta-analysis, primary failure of an anti-TNF agent occurred in 48% of patients. A second anti-TNF agent did not work in 66% of those patients, and another 66% of those patients developed adverse events in response to the second agent.

SDEF and

A video interview with Dr. Daniel E. Furst is available at

Source Sally Kubetin/ELsevier Global Medical Newswww.rheumatologynews.com/

SANTA MONICA, CALIF. — The fact that many patients with rheumatoid arthritis are not smokers, have normal lipid levels, are not overweight, and do not have a family history of heart disease belies their elevated risk for cardiovascular disease.

Rheumatoid arthritis (RA) is an inflammatory disease, and physicians need to screen patients with RA more closely for cardiovascular disease (CVD) risks. Unfortunately, practitioners currently lack a screening tool since the Framingham Heart Study risk score falls woefully short of accurately predicting CVD risk in patients with RA, Dr. Sherine E. Gabriel said at a meeting sponsored by Skin Disease Education Foundation (SDEF) and the University of Louisville.

With colleagues at the Mayo Clinic, Dr. Gabriel is developing just such a tool for screening RA patients. In an interview, Dr. Gabriel didn't divulge details of the tool, because it is still being tested. She advised physicians, for now, to screen their RA patients for CVD risks using standard laboratory tests and to intervene earlier than in other populations.

Severe, intractable RA often goes hand-in-hand with elevated risk for CVD. The patient who is positive for rheumatoid factor and always has an elevated level of C-reactive protein and a high erythrocyte sedimentation rate needs early intervention. Some physicians may want to consider using echocardiogram to screen for early signs of heart failure while it may be still treatable, said Dr. Gabriel, professor of medicine and epidemiology at the Mayo Clinic, Rochester, Minn.

Many of the insights into CVD risk in RA come from studies that Dr. Gabriel and other Mayo Clinic investigators have conducted over several years. The Mayo Clinic has followed a cohort of 1,179 residents of Olmsted County, Minn., who were diagnosed with RA between 1955 and 2007. The researchers compared the patients' rates of heart disease and survival with those of three other cohorts: 1,179 people without RA, 852 people with congestive heart failure, and 3,256 people with acute myocardial infarctions. Overall, survival among the RA patients was significantly shorter than would have been expected, particularly in women (Arthritis Rheum. 2003;48:54–8).

A second longitudinal study of residents of the city of Rochester, Minn., which is in Olmsted County, followed 603 patients with RA beginning when they were an average of 58 years old. During a mean follow-up of 15 years, 354 patients died, and CVD was the primary cause of death in 176 patients. The increased risk for CVD was associated with three markers of systemic inflammation: erythrocyte sedimentation rate above 60 mm/hour on three consecutive measurements, the presence of RA vasculitis, and the presence of RA lung disease (Arthritis Rheum. 2005;52:722–32).

In another study, 603 residents who were diagnosed with RA were significantly more likely to have been hospitalized for acute MI or to have experienced unrecognized MIs in the 2 years before diagnosis than were controls during a corresponding 2-year period. After diagnosis, RA patients were twice as likely to experience unrecognized MIs and sudden deaths and less likely to undergo coronary artery bypass grafting compared with non-RA subjects (Arthritis Rheum. 2005;52:402–11).

SDEF and

A new score is needed to predict CVD risk in RA, said Dr. Sherine E. Gabriel.

Source Sally Kubetin/Elsevier Global Medical News

SANTA MONICA, CALIF. — The fact that many patients with rheumatoid arthritis are not smokers, have normal lipid levels, are not overweight, and do not have a family history of heart disease belies their elevated risk for cardiovascular disease.

Rheumatoid arthritis (RA) is an inflammatory disease, and physicians need to screen patients with RA more closely for cardiovascular disease (CVD) risks. Unfortunately, practitioners currently lack a screening tool since the Framingham Heart Study risk score falls woefully short of accurately predicting CVD risk in patients with RA, Dr. Sherine E. Gabriel said at a meeting sponsored by Skin Disease Education Foundation (SDEF) and the University of Louisville.

With colleagues at the Mayo Clinic, Dr. Gabriel is developing just such a tool for screening RA patients. In an interview, Dr. Gabriel didn't divulge details of the tool, because it is still being tested. She advised physicians, for now, to screen their RA patients for CVD risks using standard laboratory tests and to intervene earlier than in other populations.

Severe, intractable RA often goes hand-in-hand with elevated risk for CVD. The patient who is positive for rheumatoid factor and always has an elevated level of C-reactive protein and a high erythrocyte sedimentation rate needs early intervention. Some physicians may want to consider using echocardiogram to screen for early signs of heart failure while it may be still treatable, said Dr. Gabriel, professor of medicine and epidemiology at the Mayo Clinic, Rochester, Minn.

Many of the insights into CVD risk in RA come from studies that Dr. Gabriel and other Mayo Clinic investigators have conducted over several years. The Mayo Clinic has followed a cohort of 1,179 residents of Olmsted County, Minn., who were diagnosed with RA between 1955 and 2007. The researchers compared the patients' rates of heart disease and survival with those of three other cohorts: 1,179 people without RA, 852 people with congestive heart failure, and 3,256 people with acute myocardial infarctions. Overall, survival among the RA patients was significantly shorter than would have been expected, particularly in women (Arthritis Rheum. 2003;48:54–8).

A second longitudinal study of residents of the city of Rochester, Minn., which is in Olmsted County, followed 603 patients with RA beginning when they were an average of 58 years old. During a mean follow-up of 15 years, 354 patients died, and CVD was the primary cause of death in 176 patients. The increased risk for CVD was associated with three markers of systemic inflammation: erythrocyte sedimentation rate above 60 mm/hour on three consecutive measurements, the presence of RA vasculitis, and the presence of RA lung disease (Arthritis Rheum. 2005;52:722–32).

In another study, 603 residents who were diagnosed with RA were significantly more likely to have been hospitalized for acute MI or to have experienced unrecognized MIs in the 2 years before diagnosis than were controls during a corresponding 2-year period. After diagnosis, RA patients were twice as likely to experience unrecognized MIs and sudden deaths and less likely to undergo coronary artery bypass grafting compared with non-RA subjects (Arthritis Rheum. 2005;52:402–11).

SDEF and

A new score is needed to predict CVD risk in RA, said Dr. Sherine E. Gabriel.

Source Sally Kubetin/Elsevier Global Medical News

SANTA MONICA, CALIF. — The fact that many patients with rheumatoid arthritis are not smokers, have normal lipid levels, are not overweight, and do not have a family history of heart disease belies their elevated risk for cardiovascular disease.

Rheumatoid arthritis (RA) is an inflammatory disease, and physicians need to screen patients with RA more closely for cardiovascular disease (CVD) risks. Unfortunately, practitioners currently lack a screening tool since the Framingham Heart Study risk score falls woefully short of accurately predicting CVD risk in patients with RA, Dr. Sherine E. Gabriel said at a meeting sponsored by Skin Disease Education Foundation (SDEF) and the University of Louisville.

With colleagues at the Mayo Clinic, Dr. Gabriel is developing just such a tool for screening RA patients. In an interview, Dr. Gabriel didn't divulge details of the tool, because it is still being tested. She advised physicians, for now, to screen their RA patients for CVD risks using standard laboratory tests and to intervene earlier than in other populations.

Severe, intractable RA often goes hand-in-hand with elevated risk for CVD. The patient who is positive for rheumatoid factor and always has an elevated level of C-reactive protein and a high erythrocyte sedimentation rate needs early intervention. Some physicians may want to consider using echocardiogram to screen for early signs of heart failure while it may be still treatable, said Dr. Gabriel, professor of medicine and epidemiology at the Mayo Clinic, Rochester, Minn.

Many of the insights into CVD risk in RA come from studies that Dr. Gabriel and other Mayo Clinic investigators have conducted over several years. The Mayo Clinic has followed a cohort of 1,179 residents of Olmsted County, Minn., who were diagnosed with RA between 1955 and 2007. The researchers compared the patients' rates of heart disease and survival with those of three other cohorts: 1,179 people without RA, 852 people with congestive heart failure, and 3,256 people with acute myocardial infarctions. Overall, survival among the RA patients was significantly shorter than would have been expected, particularly in women (Arthritis Rheum. 2003;48:54–8).

A second longitudinal study of residents of the city of Rochester, Minn., which is in Olmsted County, followed 603 patients with RA beginning when they were an average of 58 years old. During a mean follow-up of 15 years, 354 patients died, and CVD was the primary cause of death in 176 patients. The increased risk for CVD was associated with three markers of systemic inflammation: erythrocyte sedimentation rate above 60 mm/hour on three consecutive measurements, the presence of RA vasculitis, and the presence of RA lung disease (Arthritis Rheum. 2005;52:722–32).

In another study, 603 residents who were diagnosed with RA were significantly more likely to have been hospitalized for acute MI or to have experienced unrecognized MIs in the 2 years before diagnosis than were controls during a corresponding 2-year period. After diagnosis, RA patients were twice as likely to experience unrecognized MIs and sudden deaths and less likely to undergo coronary artery bypass grafting compared with non-RA subjects (Arthritis Rheum. 2005;52:402–11).

SDEF and

A new score is needed to predict CVD risk in RA, said Dr. Sherine E. Gabriel.

Source Sally Kubetin/Elsevier Global Medical News

Major Finding: A single, 150-mg intra-articular injection of anakinra an average of 15 days after knee injury led to a statistically and clinically significant 10.5-point improvement in the KOOS activity of daily living score 4 days after injection. Patients receiving a placebo injection showed no significant improvement.

Data Source: Randomized, placebo-controlled pilot study with 11 patients.

Disclosures: Dr. Kraus's study did not have commercial funding. She said she had no relevant financial conflicts.

BRUSSELS — The clinical response seen to injection of a targeted anti-inflammatory drug into an acutely damaged knee joint within a few weeks of injury in a controlled pilot study with 11 patients provided a step toward the development of a new approach to treating traumatic joint injury.

“We should start to treat joint injury much more emergently, like an acute myocardial infarction.” Acute joint injury “is a critical event where early intervention might improve long-term outcome,” including heading off the eventual development of osteoarthritis, Dr. Virginia Byers Kraus said at the meeting.

“Blocking sterile inflammation early in acute, joint injury may be a means to stop development of chronic tissue injury and post-traumatic osteoarthritis,” said Dr. Kraus, professor of medicine at Duke University in Durham, N.C. “The early phase of acute joint injury represents a window of opportunity for providing treatment to promote healing and to prevent a subsequent cascade of joint destructive processes.

The study enrolled 11 patients younger than 40 within the first month following an MRI-confirmed tear of their anterior cruciate ligament in one knee. Following randomization, six patients received a single, 150-mg intra-articular injection of anakinra, which is an interleukin-1 (IL-1) receptor antagonist that blocks the effects of IL-1, a primary proinflammatory cytokine. The other five patients received saline injections. Anakinra (Kineret) has U.S. approval for the treatment of rheumatoid arthritis by subcutaneous injection, but carries no approval for the treatment of osteoarthritis or for intra-articular injection.

The age of the 11 patients averaged 24 years (range, 18–29 years). They received their injections an average of 15 days after their injury (range, 6–27 days).

Four days after treatment, patients who received an anakinra injection had significant and clinically meaningful improvements in several measures on the Knee Injury and Osteoarthritis Outcome Score (KOOS), improvements not seen in placebo patients, she reported.

The KOOS pain subscore fell by an average of 3.8 points in anakinra-treated patients, a statistically significant 23% relative improvement, compared with no significant change in placebo patients. The KOOS activities of daily living subscore showed a similar pattern, falling by a statistically significant 10.5 points in the anakinra-treated group, a 46% relative improvement compared with baseline.

Prior results showed that a change of 8–10 points in this measure corresponded to a clinically significant change after reconstruction of the anterior cruciate ligament, Dr. Kraus said at the congress, sponsored by the Osteoarthritis Research Society International.

The total KOOS score improved by an average of 20 points in the drug-treated patients, a significant 24% relative improvement, compared with no significant change in the placebo patients.

The anakinra-treated patients also showed strong trends toward further improvements in total KOOS score and activity subscore when they underwent another assessment 14 days after their injection, while the placebo patients continued to show no substantial changes.

Major Finding: A single, 150-mg intra-articular injection of anakinra an average of 15 days after knee injury led to a statistically and clinically significant 10.5-point improvement in the KOOS activity of daily living score 4 days after injection. Patients receiving a placebo injection showed no significant improvement.

Data Source: Randomized, placebo-controlled pilot study with 11 patients.

Disclosures: Dr. Kraus's study did not have commercial funding. She said she had no relevant financial conflicts.

BRUSSELS — The clinical response seen to injection of a targeted anti-inflammatory drug into an acutely damaged knee joint within a few weeks of injury in a controlled pilot study with 11 patients provided a step toward the development of a new approach to treating traumatic joint injury.

“We should start to treat joint injury much more emergently, like an acute myocardial infarction.” Acute joint injury “is a critical event where early intervention might improve long-term outcome,” including heading off the eventual development of osteoarthritis, Dr. Virginia Byers Kraus said at the meeting.

“Blocking sterile inflammation early in acute, joint injury may be a means to stop development of chronic tissue injury and post-traumatic osteoarthritis,” said Dr. Kraus, professor of medicine at Duke University in Durham, N.C. “The early phase of acute joint injury represents a window of opportunity for providing treatment to promote healing and to prevent a subsequent cascade of joint destructive processes.

The study enrolled 11 patients younger than 40 within the first month following an MRI-confirmed tear of their anterior cruciate ligament in one knee. Following randomization, six patients received a single, 150-mg intra-articular injection of anakinra, which is an interleukin-1 (IL-1) receptor antagonist that blocks the effects of IL-1, a primary proinflammatory cytokine. The other five patients received saline injections. Anakinra (Kineret) has U.S. approval for the treatment of rheumatoid arthritis by subcutaneous injection, but carries no approval for the treatment of osteoarthritis or for intra-articular injection.

The age of the 11 patients averaged 24 years (range, 18–29 years). They received their injections an average of 15 days after their injury (range, 6–27 days).

Four days after treatment, patients who received an anakinra injection had significant and clinically meaningful improvements in several measures on the Knee Injury and Osteoarthritis Outcome Score (KOOS), improvements not seen in placebo patients, she reported.

The KOOS pain subscore fell by an average of 3.8 points in anakinra-treated patients, a statistically significant 23% relative improvement, compared with no significant change in placebo patients. The KOOS activities of daily living subscore showed a similar pattern, falling by a statistically significant 10.5 points in the anakinra-treated group, a 46% relative improvement compared with baseline.

Prior results showed that a change of 8–10 points in this measure corresponded to a clinically significant change after reconstruction of the anterior cruciate ligament, Dr. Kraus said at the congress, sponsored by the Osteoarthritis Research Society International.

The total KOOS score improved by an average of 20 points in the drug-treated patients, a significant 24% relative improvement, compared with no significant change in the placebo patients.

The anakinra-treated patients also showed strong trends toward further improvements in total KOOS score and activity subscore when they underwent another assessment 14 days after their injection, while the placebo patients continued to show no substantial changes.

Major Finding: A single, 150-mg intra-articular injection of anakinra an average of 15 days after knee injury led to a statistically and clinically significant 10.5-point improvement in the KOOS activity of daily living score 4 days after injection. Patients receiving a placebo injection showed no significant improvement.

Data Source: Randomized, placebo-controlled pilot study with 11 patients.

Disclosures: Dr. Kraus's study did not have commercial funding. She said she had no relevant financial conflicts.

BRUSSELS — The clinical response seen to injection of a targeted anti-inflammatory drug into an acutely damaged knee joint within a few weeks of injury in a controlled pilot study with 11 patients provided a step toward the development of a new approach to treating traumatic joint injury.

“We should start to treat joint injury much more emergently, like an acute myocardial infarction.” Acute joint injury “is a critical event where early intervention might improve long-term outcome,” including heading off the eventual development of osteoarthritis, Dr. Virginia Byers Kraus said at the meeting.

“Blocking sterile inflammation early in acute, joint injury may be a means to stop development of chronic tissue injury and post-traumatic osteoarthritis,” said Dr. Kraus, professor of medicine at Duke University in Durham, N.C. “The early phase of acute joint injury represents a window of opportunity for providing treatment to promote healing and to prevent a subsequent cascade of joint destructive processes.

The study enrolled 11 patients younger than 40 within the first month following an MRI-confirmed tear of their anterior cruciate ligament in one knee. Following randomization, six patients received a single, 150-mg intra-articular injection of anakinra, which is an interleukin-1 (IL-1) receptor antagonist that blocks the effects of IL-1, a primary proinflammatory cytokine. The other five patients received saline injections. Anakinra (Kineret) has U.S. approval for the treatment of rheumatoid arthritis by subcutaneous injection, but carries no approval for the treatment of osteoarthritis or for intra-articular injection.

The age of the 11 patients averaged 24 years (range, 18–29 years). They received their injections an average of 15 days after their injury (range, 6–27 days).

Four days after treatment, patients who received an anakinra injection had significant and clinically meaningful improvements in several measures on the Knee Injury and Osteoarthritis Outcome Score (KOOS), improvements not seen in placebo patients, she reported.

The KOOS pain subscore fell by an average of 3.8 points in anakinra-treated patients, a statistically significant 23% relative improvement, compared with no significant change in placebo patients. The KOOS activities of daily living subscore showed a similar pattern, falling by a statistically significant 10.5 points in the anakinra-treated group, a 46% relative improvement compared with baseline.

Prior results showed that a change of 8–10 points in this measure corresponded to a clinically significant change after reconstruction of the anterior cruciate ligament, Dr. Kraus said at the congress, sponsored by the Osteoarthritis Research Society International.

The total KOOS score improved by an average of 20 points in the drug-treated patients, a significant 24% relative improvement, compared with no significant change in the placebo patients.

The anakinra-treated patients also showed strong trends toward further improvements in total KOOS score and activity subscore when they underwent another assessment 14 days after their injection, while the placebo patients continued to show no substantial changes.

BRUSSELS — The use of magnetic resonance imaging may enable earlier recognition of knee osteoarthritis, and should be incorporated into recommended diagnostic criteria, a panel of 16 osteoarthritis experts concluded.

Using MRI to define knee osteoarthritis (OA) may allow detection of the disease before radiographic changes occur. But despite a growing body of literature on the role of MRI in OA, little uniformity exists for its diagnostic application, perhaps because of the absence of criteria for an MRI-based structural diagnosis of OA, the group said.

The Osteoarthritis Research Society International (OARSI) organized the 16-member panel, the OA Imaging Working Group, to develop an MRI-based definition of structural OA. The working group sought to identify structural changes on MRI that defined a structural diagnosis of knee OA, Dr. David J. Hunter and the other members of the working group wrote in a poster presented at the congress, which was organized by OARSI.

The working group began with a literature review through April 2009, a process that yielded 25 studies that met the group's inclusion criteria and evaluated MRI diagnostic performance. Through a multiphase process of discussion and voting, the group agreed on a set of nine propositions and two OA definitions based on MRI criteria. (See boxes.) These constitute “statements of preamble and context setting.” The two definitions “offer an opportunity for formal testing against other diagnostic constructs,” said Dr. Hunter of the University of Sydney and his associates in the working group.

The working group noted that the American College of Rheumatology in 1986 first released the current standard criteria for diagnosing OA, which deal only with radiographic imaging (Arthritis Rheum. 1986;29:1039–49). The European League Against Rheumatism published more current recommendations this year, but focused on a clinical diagnosis that did not involve imaging (Ann. Rheum. Dis. 2010;69:483–9).

The working group aimed to “include MRI as a means to define the disease with the intent that one may be able to identify early, pre-radiographic disease, thus enabling recruitment of study populations where structure modification (or structure maintenance) may be realistic in a more preventive manner.”

The group stressed that “the propositions have been developed for structural OA, not for a clinical diagnosis, not for early OA, and not to facilitate staging of the disease.”

An osteoarthritis specialist who was not involved with the working group cautioned that waiting for MRI structural changes that are specific for OA may still miss a truly early diagnosis, before irreversible pathology occurred.

“There are early changes [seen with MRI] that are not picked up on radiographs, but we don't yet have a standardized, validated definition of an earlier stage” on MRI, Dr. Tuhina Neogi, a rheumatologist at Boston University, said in an interview.

Dr. Hunter said that he has received research support from AstraZeneca, DJO Inc. (DonJoy), Eli Lilly & Co., Merck & Co., Pfizer Inc., Stryker Corp., and Wyeth. Eight of the other members of the working group also provided disclosures, whereas the remaining seven members said they had no disclosures. Dr. Neogi had no disclosures.

The OARSI Panel's Propositions

The following are nine propositions on MRI diagnosis of knee OA:

1. MRI changes of OA may occur in the absence of radiographic findings of OA.

2. MRI may add to the diagnosis and should be incorporated into the ACR diagnostic criteria including x-ray, clinical, and laboratory parameters.

3. MRI may be included in clinical studies according to the criteria detailed above, but should not be a primary diagnostic tool.

4. Certain MRI changes that occur in isolation are not diagnostic of OA. These include cartilage loss, change in cartilage composition, cystic change and development of bone marrow lesions, ligamentous and tendinous damage, meniscal damage, and effusion and synovitis.

5. No single finding is diagnostic of knee OA.

6. MRI findings indicative of knee OA may include abnormalities in all tissues of the joint (bone, cartilage, meniscus, synovium, ligament, and capsule).

7. Given the multiple tissue abnormalities detected by MRI in OA, diagnostic criteria are likely to involve several possible combinations of features.

8. Definite osteophyte production is indicative of OA.

9. Joint space narrowing as assessed by (nonweight-bearing) MRI cannot be used as a diagnostic criterion.

Two MRI-Based Definitions

The panel arrived at the following two definitions for MRI findings that were diagnostic of knee osteoarthritis:

1. Tibiofemoral OA should have either both features from group A (below), or one feature from group A and at least two features from group B. Examination of the patient must also rule out joint trauma within the last 6 months (by history) as well as inflammatory arthritis (diagnosed by radiographs, history, and laboratory findings).

▸ Group A: Definite osteophyte formation; full thickness cartilage loss.

▸ Group B: Subchondral marrow lesion or cyst not associated with meniscal or ligamentous attachments; meniscal subluxation, maceration, or degenerative (horizontal) tear; partial-thickness cartilage loss (without full thickness loss).

2. Patellofemoral OA requires the following features involving the patella or the anterior femur:

▸ Definite osteophyte formation.

▸ Partial- or full-thickness cartilage loss.

BRUSSELS — The use of magnetic resonance imaging may enable earlier recognition of knee osteoarthritis, and should be incorporated into recommended diagnostic criteria, a panel of 16 osteoarthritis experts concluded.

Using MRI to define knee osteoarthritis (OA) may allow detection of the disease before radiographic changes occur. But despite a growing body of literature on the role of MRI in OA, little uniformity exists for its diagnostic application, perhaps because of the absence of criteria for an MRI-based structural diagnosis of OA, the group said.

The Osteoarthritis Research Society International (OARSI) organized the 16-member panel, the OA Imaging Working Group, to develop an MRI-based definition of structural OA. The working group sought to identify structural changes on MRI that defined a structural diagnosis of knee OA, Dr. David J. Hunter and the other members of the working group wrote in a poster presented at the congress, which was organized by OARSI.

The working group began with a literature review through April 2009, a process that yielded 25 studies that met the group's inclusion criteria and evaluated MRI diagnostic performance. Through a multiphase process of discussion and voting, the group agreed on a set of nine propositions and two OA definitions based on MRI criteria. (See boxes.) These constitute “statements of preamble and context setting.” The two definitions “offer an opportunity for formal testing against other diagnostic constructs,” said Dr. Hunter of the University of Sydney and his associates in the working group.

The working group noted that the American College of Rheumatology in 1986 first released the current standard criteria for diagnosing OA, which deal only with radiographic imaging (Arthritis Rheum. 1986;29:1039–49). The European League Against Rheumatism published more current recommendations this year, but focused on a clinical diagnosis that did not involve imaging (Ann. Rheum. Dis. 2010;69:483–9).

The working group aimed to “include MRI as a means to define the disease with the intent that one may be able to identify early, pre-radiographic disease, thus enabling recruitment of study populations where structure modification (or structure maintenance) may be realistic in a more preventive manner.”

The group stressed that “the propositions have been developed for structural OA, not for a clinical diagnosis, not for early OA, and not to facilitate staging of the disease.”

An osteoarthritis specialist who was not involved with the working group cautioned that waiting for MRI structural changes that are specific for OA may still miss a truly early diagnosis, before irreversible pathology occurred.

“There are early changes [seen with MRI] that are not picked up on radiographs, but we don't yet have a standardized, validated definition of an earlier stage” on MRI, Dr. Tuhina Neogi, a rheumatologist at Boston University, said in an interview.

Dr. Hunter said that he has received research support from AstraZeneca, DJO Inc. (DonJoy), Eli Lilly & Co., Merck & Co., Pfizer Inc., Stryker Corp., and Wyeth. Eight of the other members of the working group also provided disclosures, whereas the remaining seven members said they had no disclosures. Dr. Neogi had no disclosures.

The OARSI Panel's Propositions

The following are nine propositions on MRI diagnosis of knee OA:

1. MRI changes of OA may occur in the absence of radiographic findings of OA.

2. MRI may add to the diagnosis and should be incorporated into the ACR diagnostic criteria including x-ray, clinical, and laboratory parameters.

3. MRI may be included in clinical studies according to the criteria detailed above, but should not be a primary diagnostic tool.

4. Certain MRI changes that occur in isolation are not diagnostic of OA. These include cartilage loss, change in cartilage composition, cystic change and development of bone marrow lesions, ligamentous and tendinous damage, meniscal damage, and effusion and synovitis.

5. No single finding is diagnostic of knee OA.

6. MRI findings indicative of knee OA may include abnormalities in all tissues of the joint (bone, cartilage, meniscus, synovium, ligament, and capsule).

7. Given the multiple tissue abnormalities detected by MRI in OA, diagnostic criteria are likely to involve several possible combinations of features.

8. Definite osteophyte production is indicative of OA.

9. Joint space narrowing as assessed by (nonweight-bearing) MRI cannot be used as a diagnostic criterion.

Two MRI-Based Definitions

The panel arrived at the following two definitions for MRI findings that were diagnostic of knee osteoarthritis:

1. Tibiofemoral OA should have either both features from group A (below), or one feature from group A and at least two features from group B. Examination of the patient must also rule out joint trauma within the last 6 months (by history) as well as inflammatory arthritis (diagnosed by radiographs, history, and laboratory findings).

▸ Group A: Definite osteophyte formation; full thickness cartilage loss.

▸ Group B: Subchondral marrow lesion or cyst not associated with meniscal or ligamentous attachments; meniscal subluxation, maceration, or degenerative (horizontal) tear; partial-thickness cartilage loss (without full thickness loss).

2. Patellofemoral OA requires the following features involving the patella or the anterior femur:

▸ Definite osteophyte formation.

▸ Partial- or full-thickness cartilage loss.

BRUSSELS — The use of magnetic resonance imaging may enable earlier recognition of knee osteoarthritis, and should be incorporated into recommended diagnostic criteria, a panel of 16 osteoarthritis experts concluded.

Using MRI to define knee osteoarthritis (OA) may allow detection of the disease before radiographic changes occur. But despite a growing body of literature on the role of MRI in OA, little uniformity exists for its diagnostic application, perhaps because of the absence of criteria for an MRI-based structural diagnosis of OA, the group said.

The Osteoarthritis Research Society International (OARSI) organized the 16-member panel, the OA Imaging Working Group, to develop an MRI-based definition of structural OA. The working group sought to identify structural changes on MRI that defined a structural diagnosis of knee OA, Dr. David J. Hunter and the other members of the working group wrote in a poster presented at the congress, which was organized by OARSI.

The working group began with a literature review through April 2009, a process that yielded 25 studies that met the group's inclusion criteria and evaluated MRI diagnostic performance. Through a multiphase process of discussion and voting, the group agreed on a set of nine propositions and two OA definitions based on MRI criteria. (See boxes.) These constitute “statements of preamble and context setting.” The two definitions “offer an opportunity for formal testing against other diagnostic constructs,” said Dr. Hunter of the University of Sydney and his associates in the working group.

The working group noted that the American College of Rheumatology in 1986 first released the current standard criteria for diagnosing OA, which deal only with radiographic imaging (Arthritis Rheum. 1986;29:1039–49). The European League Against Rheumatism published more current recommendations this year, but focused on a clinical diagnosis that did not involve imaging (Ann. Rheum. Dis. 2010;69:483–9).

The working group aimed to “include MRI as a means to define the disease with the intent that one may be able to identify early, pre-radiographic disease, thus enabling recruitment of study populations where structure modification (or structure maintenance) may be realistic in a more preventive manner.”

The group stressed that “the propositions have been developed for structural OA, not for a clinical diagnosis, not for early OA, and not to facilitate staging of the disease.”

An osteoarthritis specialist who was not involved with the working group cautioned that waiting for MRI structural changes that are specific for OA may still miss a truly early diagnosis, before irreversible pathology occurred.

“There are early changes [seen with MRI] that are not picked up on radiographs, but we don't yet have a standardized, validated definition of an earlier stage” on MRI, Dr. Tuhina Neogi, a rheumatologist at Boston University, said in an interview.

Dr. Hunter said that he has received research support from AstraZeneca, DJO Inc. (DonJoy), Eli Lilly & Co., Merck & Co., Pfizer Inc., Stryker Corp., and Wyeth. Eight of the other members of the working group also provided disclosures, whereas the remaining seven members said they had no disclosures. Dr. Neogi had no disclosures.

The OARSI Panel's Propositions

The following are nine propositions on MRI diagnosis of knee OA:

1. MRI changes of OA may occur in the absence of radiographic findings of OA.

2. MRI may add to the diagnosis and should be incorporated into the ACR diagnostic criteria including x-ray, clinical, and laboratory parameters.

3. MRI may be included in clinical studies according to the criteria detailed above, but should not be a primary diagnostic tool.

4. Certain MRI changes that occur in isolation are not diagnostic of OA. These include cartilage loss, change in cartilage composition, cystic change and development of bone marrow lesions, ligamentous and tendinous damage, meniscal damage, and effusion and synovitis.

5. No single finding is diagnostic of knee OA.

6. MRI findings indicative of knee OA may include abnormalities in all tissues of the joint (bone, cartilage, meniscus, synovium, ligament, and capsule).

7. Given the multiple tissue abnormalities detected by MRI in OA, diagnostic criteria are likely to involve several possible combinations of features.

8. Definite osteophyte production is indicative of OA.

9. Joint space narrowing as assessed by (nonweight-bearing) MRI cannot be used as a diagnostic criterion.

Two MRI-Based Definitions

The panel arrived at the following two definitions for MRI findings that were diagnostic of knee osteoarthritis:

1. Tibiofemoral OA should have either both features from group A (below), or one feature from group A and at least two features from group B. Examination of the patient must also rule out joint trauma within the last 6 months (by history) as well as inflammatory arthritis (diagnosed by radiographs, history, and laboratory findings).

▸ Group A: Definite osteophyte formation; full thickness cartilage loss.

▸ Group B: Subchondral marrow lesion or cyst not associated with meniscal or ligamentous attachments; meniscal subluxation, maceration, or degenerative (horizontal) tear; partial-thickness cartilage loss (without full thickness loss).

2. Patellofemoral OA requires the following features involving the patella or the anterior femur:

▸ Definite osteophyte formation.

▸ Partial- or full-thickness cartilage loss.

SANTA MONICA, CALIF. — Advances in biomarker research and imaging may eventually make earlier diagnosis of osteoarthritis a reality. Unfortunately, such technologies remain prohibitively expensive for routine use.

And there's another problem: nothing to offer patients by way of an effective early therapy for knee OA.

“So at the present time, when such treatments are not available, the benefit of early diagnosis is really to identify individuals at an early stage when an investigational therapy might be of use, and such individuals can be enrolled in clinical trials,” Dr. Amanda E. Nelson noted.

“In the absence of specific disease-modifying treatments, the extra expense of an MRI for diagnosis is not warranted in daily practice at this time,” advised Dr. Nelson of the University of North Carolina at Chapel Hill.

What has stymied the development of effective drugs for altering the course of knee OA?

The progress is slow for a few reasons, according to Dr. Nelson. Among them are lack of sensitive, cost-effective early diagnostics to best identify candidates for treatment, medicine's as-yet poor understanding of the causes of progression in OA, and its inability to identify which patients will progress to knee OA. This disease has a very long natural history: An injury in one's 20s may not lead to OA until after age 40 years. These things make trials difficult to conduct and to fund.

Current treatment is directed toward late-stage disease, and by and large these therapies focus on easing pain, not on modifying the course of the disease, Dr. Nelson said at a meeting sponsored by Skin Disease Education Foundation and the University of Louisville.

Corticosteroids have no effect on function, but they do relieve pain for 1–3 weeks. The administration of intra-articular hyaluronans eases pain and preserves or improves function for 5–13 weeks, judging from a systematic review (Cochrane Database Syst. Rev. 2006 [doi:10.1002/14651858.CD005328.pub2]).

On the investigational front, at least one phase III trial of the cyclooxygenase/lipoxygenase (COX/LOX) agent licofelone has been completed.

This investigational agent is an anti-inflammatory agent without the adverse effects of COX inhibition. Findings from a trial of 355 patients with knee OA showed that licofelone given in a 200-mg dose twice daily preserved the volume of knee cartilage as well as did naproxen given in a 500-mg dose twice daily, with less GI toxicity (Ann. Rheum. Dis. 2009;68:938–47).

Another category of symptomatic treatment that has gone through a phase III trial is COX-inhibiting nitric oxide donators (CINODs). These agents have anti-inflammatory properties similar to those of NSAIDs, but – unlike NSAIDs – CINODS protect the gastric mucosa and act as both a vasodilator and an inhibitor of platelet aggregation, thereby preventing vascular damage (J. Pharm. Pharm. Sci. 2008; Sep 20;11:81s-110s).

Findings from research using intra-articular injection of the cytokine inhibitor IL-1Ra in humans has been disappointing. The drug did not ease pain at 12 weeks but did provide more short-term pain relief.

Some investigators were keeping a close eye on trials of tanezumab, a monoclonal antibody against nerve growth factor that showed early efficacy in OA pain.

Although Pfizer Inc. has halted the trials because of increased progression and higher numbers of joint replacement, it is unclear whether that was related to the drug or to increased activity by the study subjects who experienced pain relief.

SDEF and

A video interview with Dr. Amanda E. Nelson is available at

Source Sally Kubetin/Elsevier Global Medical Newshttp://www.rheumatologynews.com/

SANTA MONICA, CALIF. — Advances in biomarker research and imaging may eventually make earlier diagnosis of osteoarthritis a reality. Unfortunately, such technologies remain prohibitively expensive for routine use.

And there's another problem: nothing to offer patients by way of an effective early therapy for knee OA.

“So at the present time, when such treatments are not available, the benefit of early diagnosis is really to identify individuals at an early stage when an investigational therapy might be of use, and such individuals can be enrolled in clinical trials,” Dr. Amanda E. Nelson noted.

“In the absence of specific disease-modifying treatments, the extra expense of an MRI for diagnosis is not warranted in daily practice at this time,” advised Dr. Nelson of the University of North Carolina at Chapel Hill.

What has stymied the development of effective drugs for altering the course of knee OA?

The progress is slow for a few reasons, according to Dr. Nelson. Among them are lack of sensitive, cost-effective early diagnostics to best identify candidates for treatment, medicine's as-yet poor understanding of the causes of progression in OA, and its inability to identify which patients will progress to knee OA. This disease has a very long natural history: An injury in one's 20s may not lead to OA until after age 40 years. These things make trials difficult to conduct and to fund.

Current treatment is directed toward late-stage disease, and by and large these therapies focus on easing pain, not on modifying the course of the disease, Dr. Nelson said at a meeting sponsored by Skin Disease Education Foundation and the University of Louisville.

Corticosteroids have no effect on function, but they do relieve pain for 1–3 weeks. The administration of intra-articular hyaluronans eases pain and preserves or improves function for 5–13 weeks, judging from a systematic review (Cochrane Database Syst. Rev. 2006 [doi:10.1002/14651858.CD005328.pub2]).

On the investigational front, at least one phase III trial of the cyclooxygenase/lipoxygenase (COX/LOX) agent licofelone has been completed.

This investigational agent is an anti-inflammatory agent without the adverse effects of COX inhibition. Findings from a trial of 355 patients with knee OA showed that licofelone given in a 200-mg dose twice daily preserved the volume of knee cartilage as well as did naproxen given in a 500-mg dose twice daily, with less GI toxicity (Ann. Rheum. Dis. 2009;68:938–47).

Another category of symptomatic treatment that has gone through a phase III trial is COX-inhibiting nitric oxide donators (CINODs). These agents have anti-inflammatory properties similar to those of NSAIDs, but – unlike NSAIDs – CINODS protect the gastric mucosa and act as both a vasodilator and an inhibitor of platelet aggregation, thereby preventing vascular damage (J. Pharm. Pharm. Sci. 2008; Sep 20;11:81s-110s).

Findings from research using intra-articular injection of the cytokine inhibitor IL-1Ra in humans has been disappointing. The drug did not ease pain at 12 weeks but did provide more short-term pain relief.

Some investigators were keeping a close eye on trials of tanezumab, a monoclonal antibody against nerve growth factor that showed early efficacy in OA pain.

Although Pfizer Inc. has halted the trials because of increased progression and higher numbers of joint replacement, it is unclear whether that was related to the drug or to increased activity by the study subjects who experienced pain relief.

SDEF and

A video interview with Dr. Amanda E. Nelson is available at

Source Sally Kubetin/Elsevier Global Medical Newshttp://www.rheumatologynews.com/

SANTA MONICA, CALIF. — Advances in biomarker research and imaging may eventually make earlier diagnosis of osteoarthritis a reality. Unfortunately, such technologies remain prohibitively expensive for routine use.

And there's another problem: nothing to offer patients by way of an effective early therapy for knee OA.

“So at the present time, when such treatments are not available, the benefit of early diagnosis is really to identify individuals at an early stage when an investigational therapy might be of use, and such individuals can be enrolled in clinical trials,” Dr. Amanda E. Nelson noted.

“In the absence of specific disease-modifying treatments, the extra expense of an MRI for diagnosis is not warranted in daily practice at this time,” advised Dr. Nelson of the University of North Carolina at Chapel Hill.

What has stymied the development of effective drugs for altering the course of knee OA?

The progress is slow for a few reasons, according to Dr. Nelson. Among them are lack of sensitive, cost-effective early diagnostics to best identify candidates for treatment, medicine's as-yet poor understanding of the causes of progression in OA, and its inability to identify which patients will progress to knee OA. This disease has a very long natural history: An injury in one's 20s may not lead to OA until after age 40 years. These things make trials difficult to conduct and to fund.

Current treatment is directed toward late-stage disease, and by and large these therapies focus on easing pain, not on modifying the course of the disease, Dr. Nelson said at a meeting sponsored by Skin Disease Education Foundation and the University of Louisville.

Corticosteroids have no effect on function, but they do relieve pain for 1–3 weeks. The administration of intra-articular hyaluronans eases pain and preserves or improves function for 5–13 weeks, judging from a systematic review (Cochrane Database Syst. Rev. 2006 [doi:10.1002/14651858.CD005328.pub2]).

On the investigational front, at least one phase III trial of the cyclooxygenase/lipoxygenase (COX/LOX) agent licofelone has been completed.

This investigational agent is an anti-inflammatory agent without the adverse effects of COX inhibition. Findings from a trial of 355 patients with knee OA showed that licofelone given in a 200-mg dose twice daily preserved the volume of knee cartilage as well as did naproxen given in a 500-mg dose twice daily, with less GI toxicity (Ann. Rheum. Dis. 2009;68:938–47).

Another category of symptomatic treatment that has gone through a phase III trial is COX-inhibiting nitric oxide donators (CINODs). These agents have anti-inflammatory properties similar to those of NSAIDs, but – unlike NSAIDs – CINODS protect the gastric mucosa and act as both a vasodilator and an inhibitor of platelet aggregation, thereby preventing vascular damage (J. Pharm. Pharm. Sci. 2008; Sep 20;11:81s-110s).

Findings from research using intra-articular injection of the cytokine inhibitor IL-1Ra in humans has been disappointing. The drug did not ease pain at 12 weeks but did provide more short-term pain relief.

Some investigators were keeping a close eye on trials of tanezumab, a monoclonal antibody against nerve growth factor that showed early efficacy in OA pain.

Although Pfizer Inc. has halted the trials because of increased progression and higher numbers of joint replacement, it is unclear whether that was related to the drug or to increased activity by the study subjects who experienced pain relief.

SDEF and

A video interview with Dr. Amanda E. Nelson is available at

Source Sally Kubetin/Elsevier Global Medical Newshttp://www.rheumatologynews.com/

The European Commission and the European League Against Rheumatism have joined forces in an ambitious 3-year project that is designed to optimize the care of patients with musculoskeletal conditions all across Europe.

The new European Musculoskeletal Conditions Surveillance and Information Network (www.eumusc.net

The eumusc.net project is funded by a grant of nearly 1 million euros from the European Commission along with 300,000 euros from EULAR. After the project ends in 2013, EULAR will take it over, according to Dr. Woolf, professor of rheumatology at the Institute of Health Care Research of Peninsula College of Medicine and Dentistry, Plymouth, England.

“The goal is to improve quality of care [and] to harmonize care so there is more equity across countries and within countries,” the rheumatologist said. “Wherever you're being treated, you should have the same chance of doing well or going into remission.”

“We're not going to come up with new guidelines because we already have excellent guidelines for the management of osteoarthritis and rheumatoid arthritis from EULAR. It's time to get them implemented,” he continued.

The eumusc.net project was granted funding by the European Union Health Program in a competitive bidding process. EU health officials were persuaded to make improved care for musculoskeletal conditions a high priority, in part on the strength of data showing that osteoarthritis is tied with disorders related to alcohol abuse for fourth place on the top-10 list of causes of years lived with disability in high-income countries.

Only unipolar depression, dementias, and adult-onset hearing loss ranked higher. Osteoarthritis was rated higher than cerebrovascular disease, chronic obstructive pulmonary disease, diabetes, and other major chronic diseases. These are the sorts of data that grab the attention of social security and health department officials.

In the United Kingdom, “musculoskeletal conditions are the No. 3 reason for general practitioner consultations. One can put a price on that, and it's very impressive,” Dr. Woolf said.

Although mortality may not be the best indicator of the societal impact of musculoskeletal disorders, Dr. Josef S. Smolen said it's a factor that should not be underestimated.

“If a woman breaks a hip, she has the same life expectancy as a metastasized breast cancer patient, and that's not sufficiently appreciated,” observed Dr. Smolen, professor and chairman of rheumatology at the Medical University of Vienna, 1 of 23 European medical centers and patient organizations serving as partners in eumusc.net.

Dr. Alan J. Silman sounded a note of skepticism regarding eumusc.net, saying that the project sounds like an effort to “harmonize toward the mediocre.”

“We should be encouraging diversity and variability.” Harmonization as a goal “won't work” and “is not something we should ascribe to,” argued Dr. Silman, professor of rheumatic disease epidemiology at the University of Manchester (England).

He observed that virtually all discussion of the eumusc.net project has focused on developing and monitoring standards of care and process measurement. Yet what constitutes good outcomes for patients with many rheumatic diseases hasn't been well established.

“I'm concerned that we're going to get lost in terms of process, numbers of people on drugs, or waiting times for [dual-energy x-ray absorptiometry] scans, or how quickly people go onto [anti–tumor necrosis factor] drugs in the south of Sweden,” he said. “I just wonder if we're deluding ourselves if we think that if we have so many patients on biologics, that's the end of the story.”

In the United Kingdom, “we've got the British Society of Rheumatology Biologics Registry, and we know from that [that] there's a substantial proportion of patients being maintained on biologic agents who've not had a clinical response. We can say, 'Look how wonderful it is that the number of patients on biologics is increasing,' but surely we're failing those patients who aren't having a clinical response, and we're not doing anything further, Dr. Silman said.”

Disclosures: Dr. Woolf, Dr. Smolen, and Dr. Silman had no financial conflicts of interest that were relevant to the report.

'If a woman breaks a hip, she has the same life expectancy as a metastasized breast cancer patient.'

Source DR. SMOLEN

The European Commission and the European League Against Rheumatism have joined forces in an ambitious 3-year project that is designed to optimize the care of patients with musculoskeletal conditions all across Europe.

The new European Musculoskeletal Conditions Surveillance and Information Network (www.eumusc.net

The eumusc.net project is funded by a grant of nearly 1 million euros from the European Commission along with 300,000 euros from EULAR. After the project ends in 2013, EULAR will take it over, according to Dr. Woolf, professor of rheumatology at the Institute of Health Care Research of Peninsula College of Medicine and Dentistry, Plymouth, England.

“The goal is to improve quality of care [and] to harmonize care so there is more equity across countries and within countries,” the rheumatologist said. “Wherever you're being treated, you should have the same chance of doing well or going into remission.”

“We're not going to come up with new guidelines because we already have excellent guidelines for the management of osteoarthritis and rheumatoid arthritis from EULAR. It's time to get them implemented,” he continued.

The eumusc.net project was granted funding by the European Union Health Program in a competitive bidding process. EU health officials were persuaded to make improved care for musculoskeletal conditions a high priority, in part on the strength of data showing that osteoarthritis is tied with disorders related to alcohol abuse for fourth place on the top-10 list of causes of years lived with disability in high-income countries.

Only unipolar depression, dementias, and adult-onset hearing loss ranked higher. Osteoarthritis was rated higher than cerebrovascular disease, chronic obstructive pulmonary disease, diabetes, and other major chronic diseases. These are the sorts of data that grab the attention of social security and health department officials.

In the United Kingdom, “musculoskeletal conditions are the No. 3 reason for general practitioner consultations. One can put a price on that, and it's very impressive,” Dr. Woolf said.

Although mortality may not be the best indicator of the societal impact of musculoskeletal disorders, Dr. Josef S. Smolen said it's a factor that should not be underestimated.

“If a woman breaks a hip, she has the same life expectancy as a metastasized breast cancer patient, and that's not sufficiently appreciated,” observed Dr. Smolen, professor and chairman of rheumatology at the Medical University of Vienna, 1 of 23 European medical centers and patient organizations serving as partners in eumusc.net.

Dr. Alan J. Silman sounded a note of skepticism regarding eumusc.net, saying that the project sounds like an effort to “harmonize toward the mediocre.”

“We should be encouraging diversity and variability.” Harmonization as a goal “won't work” and “is not something we should ascribe to,” argued Dr. Silman, professor of rheumatic disease epidemiology at the University of Manchester (England).

He observed that virtually all discussion of the eumusc.net project has focused on developing and monitoring standards of care and process measurement. Yet what constitutes good outcomes for patients with many rheumatic diseases hasn't been well established.

“I'm concerned that we're going to get lost in terms of process, numbers of people on drugs, or waiting times for [dual-energy x-ray absorptiometry] scans, or how quickly people go onto [anti–tumor necrosis factor] drugs in the south of Sweden,” he said. “I just wonder if we're deluding ourselves if we think that if we have so many patients on biologics, that's the end of the story.”

In the United Kingdom, “we've got the British Society of Rheumatology Biologics Registry, and we know from that [that] there's a substantial proportion of patients being maintained on biologic agents who've not had a clinical response. We can say, 'Look how wonderful it is that the number of patients on biologics is increasing,' but surely we're failing those patients who aren't having a clinical response, and we're not doing anything further, Dr. Silman said.”

Disclosures: Dr. Woolf, Dr. Smolen, and Dr. Silman had no financial conflicts of interest that were relevant to the report.

'If a woman breaks a hip, she has the same life expectancy as a metastasized breast cancer patient.'

Source DR. SMOLEN

The European Commission and the European League Against Rheumatism have joined forces in an ambitious 3-year project that is designed to optimize the care of patients with musculoskeletal conditions all across Europe.

The new European Musculoskeletal Conditions Surveillance and Information Network (www.eumusc.net

The eumusc.net project is funded by a grant of nearly 1 million euros from the European Commission along with 300,000 euros from EULAR. After the project ends in 2013, EULAR will take it over, according to Dr. Woolf, professor of rheumatology at the Institute of Health Care Research of Peninsula College of Medicine and Dentistry, Plymouth, England.

“The goal is to improve quality of care [and] to harmonize care so there is more equity across countries and within countries,” the rheumatologist said. “Wherever you're being treated, you should have the same chance of doing well or going into remission.”

“We're not going to come up with new guidelines because we already have excellent guidelines for the management of osteoarthritis and rheumatoid arthritis from EULAR. It's time to get them implemented,” he continued.

The eumusc.net project was granted funding by the European Union Health Program in a competitive bidding process. EU health officials were persuaded to make improved care for musculoskeletal conditions a high priority, in part on the strength of data showing that osteoarthritis is tied with disorders related to alcohol abuse for fourth place on the top-10 list of causes of years lived with disability in high-income countries.

Only unipolar depression, dementias, and adult-onset hearing loss ranked higher. Osteoarthritis was rated higher than cerebrovascular disease, chronic obstructive pulmonary disease, diabetes, and other major chronic diseases. These are the sorts of data that grab the attention of social security and health department officials.

In the United Kingdom, “musculoskeletal conditions are the No. 3 reason for general practitioner consultations. One can put a price on that, and it's very impressive,” Dr. Woolf said.

Although mortality may not be the best indicator of the societal impact of musculoskeletal disorders, Dr. Josef S. Smolen said it's a factor that should not be underestimated.

“If a woman breaks a hip, she has the same life expectancy as a metastasized breast cancer patient, and that's not sufficiently appreciated,” observed Dr. Smolen, professor and chairman of rheumatology at the Medical University of Vienna, 1 of 23 European medical centers and patient organizations serving as partners in eumusc.net.

Dr. Alan J. Silman sounded a note of skepticism regarding eumusc.net, saying that the project sounds like an effort to “harmonize toward the mediocre.”

“We should be encouraging diversity and variability.” Harmonization as a goal “won't work” and “is not something we should ascribe to,” argued Dr. Silman, professor of rheumatic disease epidemiology at the University of Manchester (England).

He observed that virtually all discussion of the eumusc.net project has focused on developing and monitoring standards of care and process measurement. Yet what constitutes good outcomes for patients with many rheumatic diseases hasn't been well established.

“I'm concerned that we're going to get lost in terms of process, numbers of people on drugs, or waiting times for [dual-energy x-ray absorptiometry] scans, or how quickly people go onto [anti–tumor necrosis factor] drugs in the south of Sweden,” he said. “I just wonder if we're deluding ourselves if we think that if we have so many patients on biologics, that's the end of the story.”

In the United Kingdom, “we've got the British Society of Rheumatology Biologics Registry, and we know from that [that] there's a substantial proportion of patients being maintained on biologic agents who've not had a clinical response. We can say, 'Look how wonderful it is that the number of patients on biologics is increasing,' but surely we're failing those patients who aren't having a clinical response, and we're not doing anything further, Dr. Silman said.”

Disclosures: Dr. Woolf, Dr. Smolen, and Dr. Silman had no financial conflicts of interest that were relevant to the report.

'If a woman breaks a hip, she has the same life expectancy as a metastasized breast cancer patient.'

Source DR. SMOLEN

Major Finding: The estimated incidence rate of hospitalization for shingles in the rheumatic population was 32 cases per 100,000 patient-years, compared with an expected rate of 3.4 in the general population. The estimated incidence of hospitalization for chickenpox in the rheumatic patients was 26 per 100,000, compared with 1.9 in the general population. The absolute incidence of varicella-related hospitalizations remains low, at about 3 cases per 10,000 person-years of exposure.

Data Source: A secondary analysis of data from two large databases.

Disclosures: Various authors on the study reported serving on the advisory board for and/or receiving lecture fees or honoraria from Wyeth, Abbott, Schering-Plough, Roche, and/or Bristol-Myers Squibb.

Rheumatic disease patients who are exposed to tumor necrosis factor antagonists have a 10-fold increased risk of hospitalization for varicella zoster virus infections, compared with the general population, according to a secondary analysis of two large databases.

Nonetheless, the absolute incidence of varicella-related hospitalizations remains low at about three cases per 10,000 person-years of exposure, and the risks of using vaccination for prevention likely outweigh the benefits, Dr. Ignacio Garcia-Doval of Complexo Hospitalario de Pontevedra (Spain) and colleagues reported.

The estimated incidence rate of hospitalization for shingles in the rheumatic population was 32 cases per 100,000 patient-years, compared with an expected rate of 3.4 in the general population, and the estimated incidence of hospitalization for chickenpox in the rheumatic patients was 26 per 100,000, compared with 1.9 in the general population.

This finding is based on analysis of data from a national registry of rheumatic disease patients who were treated with TNF agents (BIOBADASER database) and from a database of all hospital admissions in public centers in Spain (Conjunto Minimo Basico de Datos al Alta Hospitalaria, or CMBD), which together represent more than 114 million patient-years.

The estimated age- and sex-standardized incidence rate per 100,000 person-years, and the estimated standardized incidence difference were 9 and 26, respectively, for shingles, and 19 and 33, respectively, for chickenpox, they said (Ann. Rheum. Dis. 2010;69:1751-5).

TNF antagonists are associated with an increased risk of tuberculosis in particular and of opportunistic infections in general. There is a biological basis for an increased risk of viral infections, the investigators said, noting that although some studies have shown an increased rate of viral infection in TNF antagonist–treated patients, the clinical relevance of the increase is uncertain. The current study does not allow differentiation of the causes for the increased risk, but it does show that the absolute rate is low.

The researchers said it is unlikely that the cohorts received systematic vaccination against varicella zoster virus because the general health mandate in Spain was given in 2005 and only for children aged 11-14 years. “Standard guidelines for chickenpox vaccination probably apply to the population included in our study,” they wrote.

However, shingles vaccine (an attenuated vaccine with a higher dose of antigen) could potentially lead to more side effects in an immunosuppressed population, they said.

For example, in a randomized trial of adults older than age 60 years, shingles vaccine was associated with 7 cases of severe adverse events and 14 cases of vaccine-related adverse events per 10,000 vaccinations, they noted.

“These vaccination-associated risks are similar in rate and severity to the risks of hospitalized infections in our study. Hence, shingles vaccination before starting a TNF antagonist may not be warranted at present,” they wrote.

The investigators concluded that although vaccination in healthy children is warranted, it is not warranted in adults with “immunosuppression secondary to the baseline inflammatory disease and its complications.”

View on The News

Vaccinate Prior to Anti-TNF Therapy

The rationale for zoster vaccination goes beyond the goal of simply preventing hospitalized herpes zoster. Vaccination in RA patients who are at least 60 years of age should be the standard of care before initiation of anti-TNF or other long-term immunosuppressive therapy.

Prospective data on the efficacy of herpes zoster vaccination, particularly in patients with RA, are lacking. But there is strong evidence for the protective effects of vaccination in adults aged 60 years and older.

Given that patients with rheumatoid arthritis are at increased risk for herpes zoster and that vaccination with live viruses is contraindicated while biological therapies are used, it would make sense to target this group for vaccination before anti-TNF therapy is initiated.

The purpose of vaccination is not only to lower the risk of rare, serious manifestations of herpes zoster, but also to lower the risk of uncomplicated herpes zoster, which causes considerable morbidity.

Future studies should look at the potential benefits of vaccinating those younger than age 60 and those receiving other types of immunosuppressive therapy.

DR. FURST

The opinions above are excerpted from an editorial accompanying the research report (Ann. Rheum. Dis. 2010;69:1735-7). KEVIN L. WINTHROP, M.D., is in the department of infectious diseases at the Oregon Health and Science University, Portland. DANIEL E. FURST, M.D., is Carl M. Pearson Professor of Rheumatology at the University of California, Los Angeles. Dr. Winthrop reported receiving funding from the Agency for Healthcare Research and Quality for work on the manuscript, and receiving a grant from UCB Pharmaceuticals, as well as consulting fees from Amgen, Wyeth, and Genentech. Dr. Furst reported receiving research support for studies of abatacept, adalimumab, certolizumab, etanercept, infliximab, rituximab, and tocilizumab, and consulting with Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genentech, and UCB.

Major Finding: The estimated incidence rate of hospitalization for shingles in the rheumatic population was 32 cases per 100,000 patient-years, compared with an expected rate of 3.4 in the general population. The estimated incidence of hospitalization for chickenpox in the rheumatic patients was 26 per 100,000, compared with 1.9 in the general population. The absolute incidence of varicella-related hospitalizations remains low, at about 3 cases per 10,000 person-years of exposure.

Data Source: A secondary analysis of data from two large databases.

Disclosures: Various authors on the study reported serving on the advisory board for and/or receiving lecture fees or honoraria from Wyeth, Abbott, Schering-Plough, Roche, and/or Bristol-Myers Squibb.

Rheumatic disease patients who are exposed to tumor necrosis factor antagonists have a 10-fold increased risk of hospitalization for varicella zoster virus infections, compared with the general population, according to a secondary analysis of two large databases.

Nonetheless, the absolute incidence of varicella-related hospitalizations remains low at about three cases per 10,000 person-years of exposure, and the risks of using vaccination for prevention likely outweigh the benefits, Dr. Ignacio Garcia-Doval of Complexo Hospitalario de Pontevedra (Spain) and colleagues reported.

The estimated incidence rate of hospitalization for shingles in the rheumatic population was 32 cases per 100,000 patient-years, compared with an expected rate of 3.4 in the general population, and the estimated incidence of hospitalization for chickenpox in the rheumatic patients was 26 per 100,000, compared with 1.9 in the general population.

This finding is based on analysis of data from a national registry of rheumatic disease patients who were treated with TNF agents (BIOBADASER database) and from a database of all hospital admissions in public centers in Spain (Conjunto Minimo Basico de Datos al Alta Hospitalaria, or CMBD), which together represent more than 114 million patient-years.

The estimated age- and sex-standardized incidence rate per 100,000 person-years, and the estimated standardized incidence difference were 9 and 26, respectively, for shingles, and 19 and 33, respectively, for chickenpox, they said (Ann. Rheum. Dis. 2010;69:1751-5).

TNF antagonists are associated with an increased risk of tuberculosis in particular and of opportunistic infections in general. There is a biological basis for an increased risk of viral infections, the investigators said, noting that although some studies have shown an increased rate of viral infection in TNF antagonist–treated patients, the clinical relevance of the increase is uncertain. The current study does not allow differentiation of the causes for the increased risk, but it does show that the absolute rate is low.

The researchers said it is unlikely that the cohorts received systematic vaccination against varicella zoster virus because the general health mandate in Spain was given in 2005 and only for children aged 11-14 years. “Standard guidelines for chickenpox vaccination probably apply to the population included in our study,” they wrote.

However, shingles vaccine (an attenuated vaccine with a higher dose of antigen) could potentially lead to more side effects in an immunosuppressed population, they said.

For example, in a randomized trial of adults older than age 60 years, shingles vaccine was associated with 7 cases of severe adverse events and 14 cases of vaccine-related adverse events per 10,000 vaccinations, they noted.

“These vaccination-associated risks are similar in rate and severity to the risks of hospitalized infections in our study. Hence, shingles vaccination before starting a TNF antagonist may not be warranted at present,” they wrote.

The investigators concluded that although vaccination in healthy children is warranted, it is not warranted in adults with “immunosuppression secondary to the baseline inflammatory disease and its complications.”

View on The News

Vaccinate Prior to Anti-TNF Therapy

The rationale for zoster vaccination goes beyond the goal of simply preventing hospitalized herpes zoster. Vaccination in RA patients who are at least 60 years of age should be the standard of care before initiation of anti-TNF or other long-term immunosuppressive therapy.

Prospective data on the efficacy of herpes zoster vaccination, particularly in patients with RA, are lacking. But there is strong evidence for the protective effects of vaccination in adults aged 60 years and older.

Given that patients with rheumatoid arthritis are at increased risk for herpes zoster and that vaccination with live viruses is contraindicated while biological therapies are used, it would make sense to target this group for vaccination before anti-TNF therapy is initiated.

The purpose of vaccination is not only to lower the risk of rare, serious manifestations of herpes zoster, but also to lower the risk of uncomplicated herpes zoster, which causes considerable morbidity.

Future studies should look at the potential benefits of vaccinating those younger than age 60 and those receiving other types of immunosuppressive therapy.

DR. FURST

The opinions above are excerpted from an editorial accompanying the research report (Ann. Rheum. Dis. 2010;69:1735-7). KEVIN L. WINTHROP, M.D., is in the department of infectious diseases at the Oregon Health and Science University, Portland. DANIEL E. FURST, M.D., is Carl M. Pearson Professor of Rheumatology at the University of California, Los Angeles. Dr. Winthrop reported receiving funding from the Agency for Healthcare Research and Quality for work on the manuscript, and receiving a grant from UCB Pharmaceuticals, as well as consulting fees from Amgen, Wyeth, and Genentech. Dr. Furst reported receiving research support for studies of abatacept, adalimumab, certolizumab, etanercept, infliximab, rituximab, and tocilizumab, and consulting with Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genentech, and UCB.

Major Finding: The estimated incidence rate of hospitalization for shingles in the rheumatic population was 32 cases per 100,000 patient-years, compared with an expected rate of 3.4 in the general population. The estimated incidence of hospitalization for chickenpox in the rheumatic patients was 26 per 100,000, compared with 1.9 in the general population. The absolute incidence of varicella-related hospitalizations remains low, at about 3 cases per 10,000 person-years of exposure.

Data Source: A secondary analysis of data from two large databases.

Disclosures: Various authors on the study reported serving on the advisory board for and/or receiving lecture fees or honoraria from Wyeth, Abbott, Schering-Plough, Roche, and/or Bristol-Myers Squibb.

Rheumatic disease patients who are exposed to tumor necrosis factor antagonists have a 10-fold increased risk of hospitalization for varicella zoster virus infections, compared with the general population, according to a secondary analysis of two large databases.

Nonetheless, the absolute incidence of varicella-related hospitalizations remains low at about three cases per 10,000 person-years of exposure, and the risks of using vaccination for prevention likely outweigh the benefits, Dr. Ignacio Garcia-Doval of Complexo Hospitalario de Pontevedra (Spain) and colleagues reported.

The estimated incidence rate of hospitalization for shingles in the rheumatic population was 32 cases per 100,000 patient-years, compared with an expected rate of 3.4 in the general population, and the estimated incidence of hospitalization for chickenpox in the rheumatic patients was 26 per 100,000, compared with 1.9 in the general population.

This finding is based on analysis of data from a national registry of rheumatic disease patients who were treated with TNF agents (BIOBADASER database) and from a database of all hospital admissions in public centers in Spain (Conjunto Minimo Basico de Datos al Alta Hospitalaria, or CMBD), which together represent more than 114 million patient-years.

The estimated age- and sex-standardized incidence rate per 100,000 person-years, and the estimated standardized incidence difference were 9 and 26, respectively, for shingles, and 19 and 33, respectively, for chickenpox, they said (Ann. Rheum. Dis. 2010;69:1751-5).

TNF antagonists are associated with an increased risk of tuberculosis in particular and of opportunistic infections in general. There is a biological basis for an increased risk of viral infections, the investigators said, noting that although some studies have shown an increased rate of viral infection in TNF antagonist–treated patients, the clinical relevance of the increase is uncertain. The current study does not allow differentiation of the causes for the increased risk, but it does show that the absolute rate is low.

The researchers said it is unlikely that the cohorts received systematic vaccination against varicella zoster virus because the general health mandate in Spain was given in 2005 and only for children aged 11-14 years. “Standard guidelines for chickenpox vaccination probably apply to the population included in our study,” they wrote.

However, shingles vaccine (an attenuated vaccine with a higher dose of antigen) could potentially lead to more side effects in an immunosuppressed population, they said.

For example, in a randomized trial of adults older than age 60 years, shingles vaccine was associated with 7 cases of severe adverse events and 14 cases of vaccine-related adverse events per 10,000 vaccinations, they noted.

“These vaccination-associated risks are similar in rate and severity to the risks of hospitalized infections in our study. Hence, shingles vaccination before starting a TNF antagonist may not be warranted at present,” they wrote.

The investigators concluded that although vaccination in healthy children is warranted, it is not warranted in adults with “immunosuppression secondary to the baseline inflammatory disease and its complications.”

View on The News

Vaccinate Prior to Anti-TNF Therapy

The rationale for zoster vaccination goes beyond the goal of simply preventing hospitalized herpes zoster. Vaccination in RA patients who are at least 60 years of age should be the standard of care before initiation of anti-TNF or other long-term immunosuppressive therapy.

Prospective data on the efficacy of herpes zoster vaccination, particularly in patients with RA, are lacking. But there is strong evidence for the protective effects of vaccination in adults aged 60 years and older.

Given that patients with rheumatoid arthritis are at increased risk for herpes zoster and that vaccination with live viruses is contraindicated while biological therapies are used, it would make sense to target this group for vaccination before anti-TNF therapy is initiated.

The purpose of vaccination is not only to lower the risk of rare, serious manifestations of herpes zoster, but also to lower the risk of uncomplicated herpes zoster, which causes considerable morbidity.

Future studies should look at the potential benefits of vaccinating those younger than age 60 and those receiving other types of immunosuppressive therapy.

DR. FURST

The opinions above are excerpted from an editorial accompanying the research report (Ann. Rheum. Dis. 2010;69:1735-7). KEVIN L. WINTHROP, M.D., is in the department of infectious diseases at the Oregon Health and Science University, Portland. DANIEL E. FURST, M.D., is Carl M. Pearson Professor of Rheumatology at the University of California, Los Angeles. Dr. Winthrop reported receiving funding from the Agency for Healthcare Research and Quality for work on the manuscript, and receiving a grant from UCB Pharmaceuticals, as well as consulting fees from Amgen, Wyeth, and Genentech. Dr. Furst reported receiving research support for studies of abatacept, adalimumab, certolizumab, etanercept, infliximab, rituximab, and tocilizumab, and consulting with Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genentech, and UCB.

Major Finding: Treatment with some anti–tumor necrosis factor agents increase the risk of L. pneumophila infection as much as 22-fold.

Data Source: Incidence and risk analysis of data from a prospective French database on L. pneumophila associated with tumor necrosis factor–alpha antagonists; analysis of postmarketing adverse events from FDA Adverse Event Reporting System.

Disclosures: Dr. Lanternier disclosed no conflicts of interests. Coinvestigator Dr. Dominique Salmon disclosed research relationships with Schering, Wyeth, and Abbott. Dr. Sorbello disclosed no financial conflicts.

BOSTON – The risk of Legionnaires' disease associated with tumor necrosis factor–alpha antagonist therapy is greatest during the first year of treatment and is significantly higher for patients receiving adalimumab or infliximab compared with etanercept, according to findings from a study reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

Using data from the prospective French RATIO (Research Axed on Tolerance of Biotherapies) registry, which was designed to collect information on opportunistic and severe bacterial infections and lymphoma in patients treated with anti–tumor necrosis factor–alpha (anti-TNF-alpha) agents, Dr. Fanny Lanternier of the Necker Hospital for Sick Children in Paris and colleagues conducted an incidence and risk factor study to investigate the relationship between the three drugs included in the registry – adalimumab, infliximab, and etanercept – and Legionella pneumophila infection, which they previously reported in patients receiving anti-TNF-alpha treatment.

The researchers used the French population as the reference for the incidence analysis and they conducted a case control study – with four anti-TNF-alpha–treated controls per case – to investigate the risk of newly diagnosed cases of L. pneumophila infection.

The mean age of participating patients 53 years.

From Feb. 1, 2004, to Jan.1, 2007, the RATIO registry received reports of 27 cases of laboratory-confirmed L. pneumophila infection.

“The overall annual incidence rate of infection for patients on anti-TNF-alpha therapy, adjusted for age and sex, was 47/100,000 patients per year, which represents a 13-fold increased risk, compared with the reference population,” Dr. Lanternier reported.

When evaluated by agent, the standardized incidence risk was significantly higher, at 22.3, for patients taking infliximab or adalimumab – both anti-TNF-alpha monoclonal antibody agents – compared with 3.0 for patients taking etanercept, which is a soluble TNF-alpha receptor therapy, she said at the meeting, which was sponsored by the American Society for Microbiology.

Similarly, findings from the case-control analysis show that exposure to adalimumab or infliximab vs. etanercept was an independent risk factor for L. pneumophila infection, as was the first year of anti-TNF-alpha treatment, according to Dr. Lanternier.

Compared with patients with L. pneumophila infection in the French population, anti-TNF-alpha–treated patients with the infection were younger and had a markedly lower infection-related mortality rate at 3.7% vs. the 10%-20% observed in the population not treated with anti-TNF-alpha drugs, said Dr. Lanternier, attributing the difference to the probability that the immunosuppressed patients are more closely monitored.

In a separate study, Dr. Alfred F. Sorbello, medical officer for the U.S. Food and Drug Administration reported an association between L. pneumophila infection-related mortality and onset of the infection within 90 days of initiating anti-TNF-alpha therapy in patients of younger mean age receiving concomitant steroids or methotrexate.

This finding was based on a review of postmarketing adverse event reports for 21 of 80 patients from the FDA Adverse Event Reporting System between 1999 and 2010.

Although the results are limited by the small number of patients included in the analysis because of missing data, lack of randomization, and underreporting, they do suggest a key role for TNF-alpha in host defense against L. pneumophila, and they point to the need for clinical vigilance with appropriate diagnostic testing and treatment in these patients, he stressed.

From Feb. 1, 2004, to Jan.1, 2007, the Research Axed on Tolerance of Biotherapies (RATIO) registry received reports of 27 cases of laboratory-confirmed Legionella pneumophila infection.

Source Courtesy Janice Haney Carr/CDC

Major Finding: Treatment with some anti–tumor necrosis factor agents increase the risk of L. pneumophila infection as much as 22-fold.

Data Source: Incidence and risk analysis of data from a prospective French database on L. pneumophila associated with tumor necrosis factor–alpha antagonists; analysis of postmarketing adverse events from FDA Adverse Event Reporting System.

Disclosures: Dr. Lanternier disclosed no conflicts of interests. Coinvestigator Dr. Dominique Salmon disclosed research relationships with Schering, Wyeth, and Abbott. Dr. Sorbello disclosed no financial conflicts.

BOSTON – The risk of Legionnaires' disease associated with tumor necrosis factor–alpha antagonist therapy is greatest during the first year of treatment and is significantly higher for patients receiving adalimumab or infliximab compared with etanercept, according to findings from a study reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

Using data from the prospective French RATIO (Research Axed on Tolerance of Biotherapies) registry, which was designed to collect information on opportunistic and severe bacterial infections and lymphoma in patients treated with anti–tumor necrosis factor–alpha (anti-TNF-alpha) agents, Dr. Fanny Lanternier of the Necker Hospital for Sick Children in Paris and colleagues conducted an incidence and risk factor study to investigate the relationship between the three drugs included in the registry – adalimumab, infliximab, and etanercept – and Legionella pneumophila infection, which they previously reported in patients receiving anti-TNF-alpha treatment.

The researchers used the French population as the reference for the incidence analysis and they conducted a case control study – with four anti-TNF-alpha–treated controls per case – to investigate the risk of newly diagnosed cases of L. pneumophila infection.

The mean age of participating patients 53 years.

From Feb. 1, 2004, to Jan.1, 2007, the RATIO registry received reports of 27 cases of laboratory-confirmed L. pneumophila infection.

“The overall annual incidence rate of infection for patients on anti-TNF-alpha therapy, adjusted for age and sex, was 47/100,000 patients per year, which represents a 13-fold increased risk, compared with the reference population,” Dr. Lanternier reported.

When evaluated by agent, the standardized incidence risk was significantly higher, at 22.3, for patients taking infliximab or adalimumab – both anti-TNF-alpha monoclonal antibody agents – compared with 3.0 for patients taking etanercept, which is a soluble TNF-alpha receptor therapy, she said at the meeting, which was sponsored by the American Society for Microbiology.

Similarly, findings from the case-control analysis show that exposure to adalimumab or infliximab vs. etanercept was an independent risk factor for L. pneumophila infection, as was the first year of anti-TNF-alpha treatment, according to Dr. Lanternier.

Compared with patients with L. pneumophila infection in the French population, anti-TNF-alpha–treated patients with the infection were younger and had a markedly lower infection-related mortality rate at 3.7% vs. the 10%-20% observed in the population not treated with anti-TNF-alpha drugs, said Dr. Lanternier, attributing the difference to the probability that the immunosuppressed patients are more closely monitored.

In a separate study, Dr. Alfred F. Sorbello, medical officer for the U.S. Food and Drug Administration reported an association between L. pneumophila infection-related mortality and onset of the infection within 90 days of initiating anti-TNF-alpha therapy in patients of younger mean age receiving concomitant steroids or methotrexate.

This finding was based on a review of postmarketing adverse event reports for 21 of 80 patients from the FDA Adverse Event Reporting System between 1999 and 2010.

Although the results are limited by the small number of patients included in the analysis because of missing data, lack of randomization, and underreporting, they do suggest a key role for TNF-alpha in host defense against L. pneumophila, and they point to the need for clinical vigilance with appropriate diagnostic testing and treatment in these patients, he stressed.

From Feb. 1, 2004, to Jan.1, 2007, the Research Axed on Tolerance of Biotherapies (RATIO) registry received reports of 27 cases of laboratory-confirmed Legionella pneumophila infection.

Source Courtesy Janice Haney Carr/CDC

Major Finding: Treatment with some anti–tumor necrosis factor agents increase the risk of L. pneumophila infection as much as 22-fold.

Data Source: Incidence and risk analysis of data from a prospective French database on L. pneumophila associated with tumor necrosis factor–alpha antagonists; analysis of postmarketing adverse events from FDA Adverse Event Reporting System.

Disclosures: Dr. Lanternier disclosed no conflicts of interests. Coinvestigator Dr. Dominique Salmon disclosed research relationships with Schering, Wyeth, and Abbott. Dr. Sorbello disclosed no financial conflicts.

BOSTON – The risk of Legionnaires' disease associated with tumor necrosis factor–alpha antagonist therapy is greatest during the first year of treatment and is significantly higher for patients receiving adalimumab or infliximab compared with etanercept, according to findings from a study reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

Using data from the prospective French RATIO (Research Axed on Tolerance of Biotherapies) registry, which was designed to collect information on opportunistic and severe bacterial infections and lymphoma in patients treated with anti–tumor necrosis factor–alpha (anti-TNF-alpha) agents, Dr. Fanny Lanternier of the Necker Hospital for Sick Children in Paris and colleagues conducted an incidence and risk factor study to investigate the relationship between the three drugs included in the registry – adalimumab, infliximab, and etanercept – and Legionella pneumophila infection, which they previously reported in patients receiving anti-TNF-alpha treatment.

The researchers used the French population as the reference for the incidence analysis and they conducted a case control study – with four anti-TNF-alpha–treated controls per case – to investigate the risk of newly diagnosed cases of L. pneumophila infection.

The mean age of participating patients 53 years.

From Feb. 1, 2004, to Jan.1, 2007, the RATIO registry received reports of 27 cases of laboratory-confirmed L. pneumophila infection.

“The overall annual incidence rate of infection for patients on anti-TNF-alpha therapy, adjusted for age and sex, was 47/100,000 patients per year, which represents a 13-fold increased risk, compared with the reference population,” Dr. Lanternier reported.

When evaluated by agent, the standardized incidence risk was significantly higher, at 22.3, for patients taking infliximab or adalimumab – both anti-TNF-alpha monoclonal antibody agents – compared with 3.0 for patients taking etanercept, which is a soluble TNF-alpha receptor therapy, she said at the meeting, which was sponsored by the American Society for Microbiology.

Similarly, findings from the case-control analysis show that exposure to adalimumab or infliximab vs. etanercept was an independent risk factor for L. pneumophila infection, as was the first year of anti-TNF-alpha treatment, according to Dr. Lanternier.

Compared with patients with L. pneumophila infection in the French population, anti-TNF-alpha–treated patients with the infection were younger and had a markedly lower infection-related mortality rate at 3.7% vs. the 10%-20% observed in the population not treated with anti-TNF-alpha drugs, said Dr. Lanternier, attributing the difference to the probability that the immunosuppressed patients are more closely monitored.

In a separate study, Dr. Alfred F. Sorbello, medical officer for the U.S. Food and Drug Administration reported an association between L. pneumophila infection-related mortality and onset of the infection within 90 days of initiating anti-TNF-alpha therapy in patients of younger mean age receiving concomitant steroids or methotrexate.

This finding was based on a review of postmarketing adverse event reports for 21 of 80 patients from the FDA Adverse Event Reporting System between 1999 and 2010.

Although the results are limited by the small number of patients included in the analysis because of missing data, lack of randomization, and underreporting, they do suggest a key role for TNF-alpha in host defense against L. pneumophila, and they point to the need for clinical vigilance with appropriate diagnostic testing and treatment in these patients, he stressed.

From Feb. 1, 2004, to Jan.1, 2007, the Research Axed on Tolerance of Biotherapies (RATIO) registry received reports of 27 cases of laboratory-confirmed Legionella pneumophila infection.

Source Courtesy Janice Haney Carr/CDC

Investigational new drugs, including biologic drugs, will face new safety reporting requirements designed to increase timeliness as well as decrease unnecessary reporting of events not likely to be causal.

The changes bring the Food and Drug Administration's reporting policies in line with international agencies, including the World Health Organization (WHO).

The changes focus on the reporting of adverse events clearly linked to the drug that occur during animal or human testing of the agent.

Adherence to the former rule often resulted in reporting of events not likely to be associated with the drug, slowing recognition of truly causal effects, according to the draft guidance.

Under the new rule, applicants may submit only “suspected adverse reactions,” defined as events for which there is “evidence to suggest a causal relationship between the drug and the adverse event,” according to a FDA draft guidance for investigators.

Other reportable findings include data concerning bioequivalence of generic biologic drugs, compared with their name-brand counterparts — for example, differing rates of absorption into the bloodstream.

To see the full text of the final rule, visit http://tinyurl.com/36fld9u

Investigational new drugs, including biologic drugs, will face new safety reporting requirements designed to increase timeliness as well as decrease unnecessary reporting of events not likely to be causal.

The changes bring the Food and Drug Administration's reporting policies in line with international agencies, including the World Health Organization (WHO).

The changes focus on the reporting of adverse events clearly linked to the drug that occur during animal or human testing of the agent.

Adherence to the former rule often resulted in reporting of events not likely to be associated with the drug, slowing recognition of truly causal effects, according to the draft guidance.

Under the new rule, applicants may submit only “suspected adverse reactions,” defined as events for which there is “evidence to suggest a causal relationship between the drug and the adverse event,” according to a FDA draft guidance for investigators.

Other reportable findings include data concerning bioequivalence of generic biologic drugs, compared with their name-brand counterparts — for example, differing rates of absorption into the bloodstream.

To see the full text of the final rule, visit http://tinyurl.com/36fld9u

Investigational new drugs, including biologic drugs, will face new safety reporting requirements designed to increase timeliness as well as decrease unnecessary reporting of events not likely to be causal.

The changes bring the Food and Drug Administration's reporting policies in line with international agencies, including the World Health Organization (WHO).

The changes focus on the reporting of adverse events clearly linked to the drug that occur during animal or human testing of the agent.

Adherence to the former rule often resulted in reporting of events not likely to be associated with the drug, slowing recognition of truly causal effects, according to the draft guidance.

Under the new rule, applicants may submit only “suspected adverse reactions,” defined as events for which there is “evidence to suggest a causal relationship between the drug and the adverse event,” according to a FDA draft guidance for investigators.

Other reportable findings include data concerning bioequivalence of generic biologic drugs, compared with their name-brand counterparts — for example, differing rates of absorption into the bloodstream.

To see the full text of the final rule, visit http://tinyurl.com/36fld9u

ROME — Last year's approval of febuxostat as the first new gout medication in over 40 years appears to have triggered a sharp uptick in drug development for a disease many physicians consider long neglected. The recent approval of pegoticase is proof of the pudding.

Novel gout therapies in the developmental pipeline range from the high tech — a fully human monoclonal antibody to interleukin-1beta — to the low tech, as in cherry juice.

“I've got more than 100 gout patients in my practice on cherry juice concentrate,” Dr. Naomi Schlesinger said in an interview with

Her small retrospective study showed that consumption of 1 tablespoon of Brownwood Acres tart cherry juice concentrate twice daily — equivalent to eating 90-120 cherries — led to a 50% or greater reduction in acute gout attacks in 92% of treated patients, with no side effects. Prophylaxis with cherry juice concentrate is worth considering as an adjunct to urate-lowering therapy, said Dr. Schlesinger, chief of the division of rheumatology and connective tissue research at Robert Wood Johnson Medical School, New Brunswick, N.J.

Many patients over the years had told her they loved to eat cherries and thought they might be helpful. Eventually she came across a small 1950 study suggesting a preventive effect.

“I've looked at pomegranate juice, too. It didn't work,” she added.

The mechanism of benefit for cherry juice concentrate is an anti-inflammatory effect, the rheumatologist said. Her in vitro studies showed that cherry juice concentrate reduced by up to half interleukin-1-beta and tumor necrosis factor-alpha secretion by monocytes exposed to monosodium urate crystals.

In gout patients, cherry juice concentrate didn't lower serum urate levels; indeed, more than one-third of patients not on urate-lowering therapy who had averaged close to one attack per month remained attack free during 4-6 months on cherry juice concentrate despite an average serum urate level of 7.8 mg/dL.

Other novel gout therapies subjected to studies presented at the European congress included the anti-interleukin-1-beta monoclonal antibody canakinumab, a uricosuric drug known for now as RDEA594, and tranilast, which has been licensed in Japan for several decades as an oral mast cell inhibitor for treatment of asthma and allergic rhinitis.

Tranilast also has a potent serum uric acid—lowering effect, making it a potential therapy for chronic management of hyperuricemia in gout patients — one that already has a well-established track record for safety, according to Dr. Michael Kitt, executive vice president and chief medical officer at Nuon Therapeutics Inc., San Mateo, Calif.

He presented a preliminary study in which 49 healthy subjects who received 7 days of tranilast at 300, 600, or 900 mg daily showed dose-dependent 1.1- to 3.3- mg/dL reductions in serum uric acid. A phase-IIa study in hyperuricemic patients should be completed in time for presentation later this year at the American College of Rheumatology meeting, and a phase IIb study of tranilast plus allopurinol is just starting in gout patients. When commercialized, tranilast will be combined with allopurinol in a single tablet, Dr. Kitt said in an interview.

Dr. Schlesinger also presented a large phase II clinical trial in which canakinumab, the fully human anti-interleukin-1-beta monoclonal antibody, outperformed colchicine for the reduction of flares in gout patients starting allopurinol therapy.

The double-blind, multicenter, 24-week study included 432 gout patients starting allopurinol who were randomized to 16 weeks of colchicine at 0.5 mg/day, a single subcutaneous injection of canakinumab at 25, 50, 100, 200, or 300 mg, or monthly canakinumab injections at 50, 50, 25, and 25 mg.

The canakinumab regimens reduced the risk of one or more urate-lowering therapy-induced flares by 61%-80% compared with colchicine. Canakinumab also reduced the overall rate of flares by 48%-75% relative to colchicine.

Phase III studies are underway, and Novartis plans to file for marketing approval of canakinumab for the treatment and prevention of acute gout attacks by year's end. The monoclonal antibody is licensed as Ilaris for treatment of cryopyrin-associated periodic syndromes.

Dr. Fernando Perez-Ruiz presented a phase II study of RDEA594, a uricosuric drug that normalizes gout patients' underexcretion of uric acid by a novel mechanism: inhibition of reabsorption of uric acid in the proximal tubule of the kidney.

The study involved 123 hyperuricemic gout patients randomized to 4 weeks of RDEA594 at 200, 400, or 600 mg/day or placebo. All were on colchicine at 0.5-0.6 mg/day to reduce the rate of gout flares.

The primary end point — reduction of serum uric acid to less than 6 mg/dL after 4 weeks of treatment — was achieved in 45% of patients on the highest dose of RDEA594 and 0% of those on placebo. The median reduction in serum uric acid in patients on the highest dose was 38%, versus a 1% increase in the placebo arm.

Among the subset of patients with a baseline serum uric level below 10 mg/dL, as is the case for a large majority of gout patients seen in clinical practice, the response rate to the highest dose of RDEA594 was 58%. The side effect profile of RDEA594 was comparable to placebo, added Dr. Perez-Ruiz of Hospital de Cruces in Vizcaya, Spain.

Ardea Biosciences, San Diego, which is developing RDEA594, has not decided whether to take the drug into phase III trials as monotherapy or in combination with febuxostat, with which RDEA594 has shown synergistic effects, a company official said in an interview with

Disclosures: Dr. Schlesinger has received research grants from Brownwood Acres and Novartis. Dr. Kitt is employed by Nuon Therapeutics Inc. Dr. Perez-Ruiz is a consultant to Ardea Biosciences.

As a result of its anti-inflammatory effect, cherry juice concentrate halves levels of interleukin-1-beta and TNF-alpha.

Source DR. SCHLESINGER

ROME — Last year's approval of febuxostat as the first new gout medication in over 40 years appears to have triggered a sharp uptick in drug development for a disease many physicians consider long neglected. The recent approval of pegoticase is proof of the pudding.

Novel gout therapies in the developmental pipeline range from the high tech — a fully human monoclonal antibody to interleukin-1beta — to the low tech, as in cherry juice.

“I've got more than 100 gout patients in my practice on cherry juice concentrate,” Dr. Naomi Schlesinger said in an interview with

Her small retrospective study showed that consumption of 1 tablespoon of Brownwood Acres tart cherry juice concentrate twice daily — equivalent to eating 90-120 cherries — led to a 50% or greater reduction in acute gout attacks in 92% of treated patients, with no side effects. Prophylaxis with cherry juice concentrate is worth considering as an adjunct to urate-lowering therapy, said Dr. Schlesinger, chief of the division of rheumatology and connective tissue research at Robert Wood Johnson Medical School, New Brunswick, N.J.

Many patients over the years had told her they loved to eat cherries and thought they might be helpful. Eventually she came across a small 1950 study suggesting a preventive effect.

“I've looked at pomegranate juice, too. It didn't work,” she added.

The mechanism of benefit for cherry juice concentrate is an anti-inflammatory effect, the rheumatologist said. Her in vitro studies showed that cherry juice concentrate reduced by up to half interleukin-1-beta and tumor necrosis factor-alpha secretion by monocytes exposed to monosodium urate crystals.

In gout patients, cherry juice concentrate didn't lower serum urate levels; indeed, more than one-third of patients not on urate-lowering therapy who had averaged close to one attack per month remained attack free during 4-6 months on cherry juice concentrate despite an average serum urate level of 7.8 mg/dL.

Other novel gout therapies subjected to studies presented at the European congress included the anti-interleukin-1-beta monoclonal antibody canakinumab, a uricosuric drug known for now as RDEA594, and tranilast, which has been licensed in Japan for several decades as an oral mast cell inhibitor for treatment of asthma and allergic rhinitis.

Tranilast also has a potent serum uric acid—lowering effect, making it a potential therapy for chronic management of hyperuricemia in gout patients — one that already has a well-established track record for safety, according to Dr. Michael Kitt, executive vice president and chief medical officer at Nuon Therapeutics Inc., San Mateo, Calif.

He presented a preliminary study in which 49 healthy subjects who received 7 days of tranilast at 300, 600, or 900 mg daily showed dose-dependent 1.1- to 3.3- mg/dL reductions in serum uric acid. A phase-IIa study in hyperuricemic patients should be completed in time for presentation later this year at the American College of Rheumatology meeting, and a phase IIb study of tranilast plus allopurinol is just starting in gout patients. When commercialized, tranilast will be combined with allopurinol in a single tablet, Dr. Kitt said in an interview.

Dr. Schlesinger also presented a large phase II clinical trial in which canakinumab, the fully human anti-interleukin-1-beta monoclonal antibody, outperformed colchicine for the reduction of flares in gout patients starting allopurinol therapy.

The double-blind, multicenter, 24-week study included 432 gout patients starting allopurinol who were randomized to 16 weeks of colchicine at 0.5 mg/day, a single subcutaneous injection of canakinumab at 25, 50, 100, 200, or 300 mg, or monthly canakinumab injections at 50, 50, 25, and 25 mg.

The canakinumab regimens reduced the risk of one or more urate-lowering therapy-induced flares by 61%-80% compared with colchicine. Canakinumab also reduced the overall rate of flares by 48%-75% relative to colchicine.

Phase III studies are underway, and Novartis plans to file for marketing approval of canakinumab for the treatment and prevention of acute gout attacks by year's end. The monoclonal antibody is licensed as Ilaris for treatment of cryopyrin-associated periodic syndromes.

Dr. Fernando Perez-Ruiz presented a phase II study of RDEA594, a uricosuric drug that normalizes gout patients' underexcretion of uric acid by a novel mechanism: inhibition of reabsorption of uric acid in the proximal tubule of the kidney.

The study involved 123 hyperuricemic gout patients randomized to 4 weeks of RDEA594 at 200, 400, or 600 mg/day or placebo. All were on colchicine at 0.5-0.6 mg/day to reduce the rate of gout flares.

The primary end point — reduction of serum uric acid to less than 6 mg/dL after 4 weeks of treatment — was achieved in 45% of patients on the highest dose of RDEA594 and 0% of those on placebo. The median reduction in serum uric acid in patients on the highest dose was 38%, versus a 1% increase in the placebo arm.

Among the subset of patients with a baseline serum uric level below 10 mg/dL, as is the case for a large majority of gout patients seen in clinical practice, the response rate to the highest dose of RDEA594 was 58%. The side effect profile of RDEA594 was comparable to placebo, added Dr. Perez-Ruiz of Hospital de Cruces in Vizcaya, Spain.

Ardea Biosciences, San Diego, which is developing RDEA594, has not decided whether to take the drug into phase III trials as monotherapy or in combination with febuxostat, with which RDEA594 has shown synergistic effects, a company official said in an interview with

Disclosures: Dr. Schlesinger has received research grants from Brownwood Acres and Novartis. Dr. Kitt is employed by Nuon Therapeutics Inc. Dr. Perez-Ruiz is a consultant to Ardea Biosciences.

As a result of its anti-inflammatory effect, cherry juice concentrate halves levels of interleukin-1-beta and TNF-alpha.

Source DR. SCHLESINGER

ROME — Last year's approval of febuxostat as the first new gout medication in over 40 years appears to have triggered a sharp uptick in drug development for a disease many physicians consider long neglected. The recent approval of pegoticase is proof of the pudding.

Novel gout therapies in the developmental pipeline range from the high tech — a fully human monoclonal antibody to interleukin-1beta — to the low tech, as in cherry juice.

“I've got more than 100 gout patients in my practice on cherry juice concentrate,” Dr. Naomi Schlesinger said in an interview with

Her small retrospective study showed that consumption of 1 tablespoon of Brownwood Acres tart cherry juice concentrate twice daily — equivalent to eating 90-120 cherries — led to a 50% or greater reduction in acute gout attacks in 92% of treated patients, with no side effects. Prophylaxis with cherry juice concentrate is worth considering as an adjunct to urate-lowering therapy, said Dr. Schlesinger, chief of the division of rheumatology and connective tissue research at Robert Wood Johnson Medical School, New Brunswick, N.J.

Many patients over the years had told her they loved to eat cherries and thought they might be helpful. Eventually she came across a small 1950 study suggesting a preventive effect.

“I've looked at pomegranate juice, too. It didn't work,” she added.

The mechanism of benefit for cherry juice concentrate is an anti-inflammatory effect, the rheumatologist said. Her in vitro studies showed that cherry juice concentrate reduced by up to half interleukin-1-beta and tumor necrosis factor-alpha secretion by monocytes exposed to monosodium urate crystals.

In gout patients, cherry juice concentrate didn't lower serum urate levels; indeed, more than one-third of patients not on urate-lowering therapy who had averaged close to one attack per month remained attack free during 4-6 months on cherry juice concentrate despite an average serum urate level of 7.8 mg/dL.

Other novel gout therapies subjected to studies presented at the European congress included the anti-interleukin-1-beta monoclonal antibody canakinumab, a uricosuric drug known for now as RDEA594, and tranilast, which has been licensed in Japan for several decades as an oral mast cell inhibitor for treatment of asthma and allergic rhinitis.

Tranilast also has a potent serum uric acid—lowering effect, making it a potential therapy for chronic management of hyperuricemia in gout patients — one that already has a well-established track record for safety, according to Dr. Michael Kitt, executive vice president and chief medical officer at Nuon Therapeutics Inc., San Mateo, Calif.

He presented a preliminary study in which 49 healthy subjects who received 7 days of tranilast at 300, 600, or 900 mg daily showed dose-dependent 1.1- to 3.3- mg/dL reductions in serum uric acid. A phase-IIa study in hyperuricemic patients should be completed in time for presentation later this year at the American College of Rheumatology meeting, and a phase IIb study of tranilast plus allopurinol is just starting in gout patients. When commercialized, tranilast will be combined with allopurinol in a single tablet, Dr. Kitt said in an interview.

Dr. Schlesinger also presented a large phase II clinical trial in which canakinumab, the fully human anti-interleukin-1-beta monoclonal antibody, outperformed colchicine for the reduction of flares in gout patients starting allopurinol therapy.

The double-blind, multicenter, 24-week study included 432 gout patients starting allopurinol who were randomized to 16 weeks of colchicine at 0.5 mg/day, a single subcutaneous injection of canakinumab at 25, 50, 100, 200, or 300 mg, or monthly canakinumab injections at 50, 50, 25, and 25 mg.

The canakinumab regimens reduced the risk of one or more urate-lowering therapy-induced flares by 61%-80% compared with colchicine. Canakinumab also reduced the overall rate of flares by 48%-75% relative to colchicine.

Phase III studies are underway, and Novartis plans to file for marketing approval of canakinumab for the treatment and prevention of acute gout attacks by year's end. The monoclonal antibody is licensed as Ilaris for treatment of cryopyrin-associated periodic syndromes.

Dr. Fernando Perez-Ruiz presented a phase II study of RDEA594, a uricosuric drug that normalizes gout patients' underexcretion of uric acid by a novel mechanism: inhibition of reabsorption of uric acid in the proximal tubule of the kidney.

The study involved 123 hyperuricemic gout patients randomized to 4 weeks of RDEA594 at 200, 400, or 600 mg/day or placebo. All were on colchicine at 0.5-0.6 mg/day to reduce the rate of gout flares.

The primary end point — reduction of serum uric acid to less than 6 mg/dL after 4 weeks of treatment — was achieved in 45% of patients on the highest dose of RDEA594 and 0% of those on placebo. The median reduction in serum uric acid in patients on the highest dose was 38%, versus a 1% increase in the placebo arm.

Among the subset of patients with a baseline serum uric level below 10 mg/dL, as is the case for a large majority of gout patients seen in clinical practice, the response rate to the highest dose of RDEA594 was 58%. The side effect profile of RDEA594 was comparable to placebo, added Dr. Perez-Ruiz of Hospital de Cruces in Vizcaya, Spain.

Ardea Biosciences, San Diego, which is developing RDEA594, has not decided whether to take the drug into phase III trials as monotherapy or in combination with febuxostat, with which RDEA594 has shown synergistic effects, a company official said in an interview with

Disclosures: Dr. Schlesinger has received research grants from Brownwood Acres and Novartis. Dr. Kitt is employed by Nuon Therapeutics Inc. Dr. Perez-Ruiz is a consultant to Ardea Biosciences.

As a result of its anti-inflammatory effect, cherry juice concentrate halves levels of interleukin-1-beta and TNF-alpha.

Source DR. SCHLESINGER