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Physicians Often Missing Boat on Gout Therapy
SNOWMASS, COLO. – A disturbing proportion of gout cases are mismanaged by primary care physicians, and the blame falls squarely upon rheumatologists, according to one prominent gout expert.
"As rheumatologists, gout is our disease. The cause and pathophysiology are well understood, we can make the diagnosis with absolute certainty, and we’ve got great medicines. Yet today we all see people with tophi. That’s tragic. It shouldn’t exist. One of our biggest mistakes has been not being able to educate primary care physicians that having a tophus is bad, that it’s eroding cartilage and bone, and that it’s something we can prevent if we start urate-lowering therapy soon enough," Dr. Robert L. Wortmann said at the conference.
An estimated 8.3 million Americans have gout. Yet, the pharmaceutical industry says only 3.1 million of them are prescribed urate-lowering drugs. Five different studies show that a mere 40% of those on allopurinol are prescribed a dose sufficient to drive serum uric acid below 6 mg/dL, a key tenet of gout management, noted Dr. Wortmann, professor of medicine at Dartmouth Medical School in Hanover, N.H.
Moreover, poor treatment adherence is a huge problem in gout. A study of close to 4,200 gout patients started on urate-lowering drug therapy found that 56% of them were nonadherent (Arthritis Res. Ther. 2009;11(2):R46).
"I charge you all to go back from this meeting and try to communicate with all the primary care physicians you can about the principles of managing gout. People shouldn’t suffer from this," the rheumatologist declared.
He offered these major take home points:
Don’t prescribe urate-lowering drugs for asymptomatic hyperuricemia: This practice hasn’t been shown to prevent the future development of gout, yet it exposes patients to the risk of drug toxicities.
But don’t ignore asymptomatic hyperuricemia, either: Epidemiologic studies have linked asymptomatic hyperuricemia, defined by a serum urate in excess of 6.8 mg/dL, to increased risks of hypertension, cardiovascular disease, diabetes, chronic kidney disease, and all-cause mortality. The big unanswered question is whether using medications to lower serum urate in individuals with asymptomatic hyperuricemia reduces the risk of any of these conditions. That’s the subject of ongoing large clinical trials in high-risk patients. If those studies prove positive, clinical practice will change.
While awaiting the outcome of the prevention trials, it’s worth bearing in mind that Framingham Heart Study data indicate that individuals with a serum uric acid level above 9 mg/dL have a 22% chance of developing gout within the next 5 years. The major contributors to asymptomatic hyperuricemia include obesity, metabolic syndrome, and heavy consumption of fructose-containing beverages or alcohol. Those issues should be addressed.
Losartan is the only antihypertensive agent that’s uricosuric. Fenofibrate is the sole uricosuric drug indicated for dyslipidemia. Preferential consideration could be given to the use of these drugs in hypertensive and/or hyperlipidemic patients with asymptomatic hyperuricemia.
The important thing is not which oral agent you use for treatment of acute gout, it’s to initiate therapy as early as possible, at the first hint of an attack. Colchicine, maximum-dose NSAIDs, and oral prednisone dosed at 20 mg BID until symptoms have been gone for 1 week followed by another week at 20 mg/day – they’re all effective. And since they work by different mechanisms, they can beneficially be combined in refractory patients.
The old-school colchicine dosing regimen most physicians were taught has been cast aside of late. It had a high rate of diarrhea, an inhumane side effect in gout patients hobbled by a foot too sore to walk on. The former regimen has been replaced by 1.2 mg, given in a single dose, followed by 0.6 mg 1 hour later.
"This lower dose is just as effective as the old high-dose regimen of two 0.6-mg pills given at once and then one per hour for the next 5 hours. And the lower-dose program has the same side effect profile as placebo," Dr. Wortmann said.
Get the gout patient’s serum urate below 6 mg/dL using the lowest effective dose of the urate-lowering drug you’ve selected. Physicians have traditionally started gout patients on allopurinol at the standard dose of 300 mg/day. Recently, it has been demonstrated that the risk of developing allopurinol hypersensitivity syndrome is greatly reduced by starting off at 150 mg/day, checking the urate level 2 weeks later, then increasing to 300 mg/day if the serum urate isn’t below 6 mg/dL. After 2 weeks at 300 mg/day, check the urate again, and if it still isn’t below 6 mg/dL then bump the dose to 400 mg/day. Continue testing and titrating every 2 weeks until the serum urate is less than 6 mg/dL – and preferably less than 4 mg/dL if the patient has tophi – or until the maximum approved dose of 800 mg/day is reached.
The same start-low-and-titrate strategy applies to febuxostat, with a maximum approved dose of 80 mg/day.
"We have to educate primary care physicians to check the serum urate after starting therapy, and that, if it’s not below 6 mg/dL, they need to increase the dose. And if they don’t feel comfortable with that, they need to send the patient to us," the rheumatologist said.
Fortunately, patients who have a hypersensitivity reaction to allopurinol are very unlikely to experience one with febuxostat, and vice versa.
For patients who can’t reach the target serum urate with maximum-dose therapy, take heart: Second-line agents with impressive potency are well-along in the developmental pipeline.
Many labs now list the upper limit of normal for serum urate as 8 mg/dL or 8.5 mg/dL. Ignore that. This raised ceiling is simply the result of the changing demographics among the increasingly obese U.S. population in the last several decades. The definition of asymptomatic hyperuricemia remains unchanged: a serum urate greater than 6.8 mg/dL. And the target in patients with gout is still a serum urate less than 6 mg/dL. Merely dropping a gout patient’s urate from 10 to 8 or even 6.6 mg/dL isn’t doing any favors; the disease will continue to progress if the urate is above 6 mg/dL.
All gout is tophaceous. Even if tophi aren’t apparent on clinical examination, often they are radiographically. "This is a message that has to get out," Dr. Wortmann insisted.
Proposed American College of Rheumatology gout management guidelines call for starting urate-lowering drug therapy when a patient is experiencing three attacks per year. Dr. Wortmann takes issue with that.
"I would argue that once you’ve had a third attack of gout, period, you should be treated. Maybe even sooner. We need to prevent the erosion and bony destruction that occur with tophi," he said.
One audience member complained that his gout patients with comorbid renal insufficiency and/or cardiovascular disease often get caught in a revolving door. He titrates their allopurinol to an effective dose, but when they are later admitted to the hospital because of their comorbid condition the hospitalists, nephrologists, and/or cardiologists are shocked at the allopurinol dose and either reduce it or stop it altogether. The first that the rheumatologist learns of it is when patients reappear in his office with active gout. He then resumes their allopurinol at the previous dose, and they remain well controlled until the next hospitalization, when the same thing happens.
Dr. Wortmann responded that the solution requires convincing the nonrheumatologists in one-on-one conversation that urate-lowering therapy is not a one-size-fits-all matter. They need to understand that to get rid of gout, it’s necessary to drive the serum urate to the target of less than 6 mg/dL, and it helps to reassure them that that this will be accomplished using the lowest effective dose.
He reported serving as a consultant to Savient, Takeda, URL Pharmaceuticals, Novartis, and Ardea Biosciences.
SNOWMASS, COLO. – A disturbing proportion of gout cases are mismanaged by primary care physicians, and the blame falls squarely upon rheumatologists, according to one prominent gout expert.
"As rheumatologists, gout is our disease. The cause and pathophysiology are well understood, we can make the diagnosis with absolute certainty, and we’ve got great medicines. Yet today we all see people with tophi. That’s tragic. It shouldn’t exist. One of our biggest mistakes has been not being able to educate primary care physicians that having a tophus is bad, that it’s eroding cartilage and bone, and that it’s something we can prevent if we start urate-lowering therapy soon enough," Dr. Robert L. Wortmann said at the conference.
An estimated 8.3 million Americans have gout. Yet, the pharmaceutical industry says only 3.1 million of them are prescribed urate-lowering drugs. Five different studies show that a mere 40% of those on allopurinol are prescribed a dose sufficient to drive serum uric acid below 6 mg/dL, a key tenet of gout management, noted Dr. Wortmann, professor of medicine at Dartmouth Medical School in Hanover, N.H.
Moreover, poor treatment adherence is a huge problem in gout. A study of close to 4,200 gout patients started on urate-lowering drug therapy found that 56% of them were nonadherent (Arthritis Res. Ther. 2009;11(2):R46).
"I charge you all to go back from this meeting and try to communicate with all the primary care physicians you can about the principles of managing gout. People shouldn’t suffer from this," the rheumatologist declared.
He offered these major take home points:
Don’t prescribe urate-lowering drugs for asymptomatic hyperuricemia: This practice hasn’t been shown to prevent the future development of gout, yet it exposes patients to the risk of drug toxicities.
But don’t ignore asymptomatic hyperuricemia, either: Epidemiologic studies have linked asymptomatic hyperuricemia, defined by a serum urate in excess of 6.8 mg/dL, to increased risks of hypertension, cardiovascular disease, diabetes, chronic kidney disease, and all-cause mortality. The big unanswered question is whether using medications to lower serum urate in individuals with asymptomatic hyperuricemia reduces the risk of any of these conditions. That’s the subject of ongoing large clinical trials in high-risk patients. If those studies prove positive, clinical practice will change.
While awaiting the outcome of the prevention trials, it’s worth bearing in mind that Framingham Heart Study data indicate that individuals with a serum uric acid level above 9 mg/dL have a 22% chance of developing gout within the next 5 years. The major contributors to asymptomatic hyperuricemia include obesity, metabolic syndrome, and heavy consumption of fructose-containing beverages or alcohol. Those issues should be addressed.
Losartan is the only antihypertensive agent that’s uricosuric. Fenofibrate is the sole uricosuric drug indicated for dyslipidemia. Preferential consideration could be given to the use of these drugs in hypertensive and/or hyperlipidemic patients with asymptomatic hyperuricemia.
The important thing is not which oral agent you use for treatment of acute gout, it’s to initiate therapy as early as possible, at the first hint of an attack. Colchicine, maximum-dose NSAIDs, and oral prednisone dosed at 20 mg BID until symptoms have been gone for 1 week followed by another week at 20 mg/day – they’re all effective. And since they work by different mechanisms, they can beneficially be combined in refractory patients.
The old-school colchicine dosing regimen most physicians were taught has been cast aside of late. It had a high rate of diarrhea, an inhumane side effect in gout patients hobbled by a foot too sore to walk on. The former regimen has been replaced by 1.2 mg, given in a single dose, followed by 0.6 mg 1 hour later.
"This lower dose is just as effective as the old high-dose regimen of two 0.6-mg pills given at once and then one per hour for the next 5 hours. And the lower-dose program has the same side effect profile as placebo," Dr. Wortmann said.
Get the gout patient’s serum urate below 6 mg/dL using the lowest effective dose of the urate-lowering drug you’ve selected. Physicians have traditionally started gout patients on allopurinol at the standard dose of 300 mg/day. Recently, it has been demonstrated that the risk of developing allopurinol hypersensitivity syndrome is greatly reduced by starting off at 150 mg/day, checking the urate level 2 weeks later, then increasing to 300 mg/day if the serum urate isn’t below 6 mg/dL. After 2 weeks at 300 mg/day, check the urate again, and if it still isn’t below 6 mg/dL then bump the dose to 400 mg/day. Continue testing and titrating every 2 weeks until the serum urate is less than 6 mg/dL – and preferably less than 4 mg/dL if the patient has tophi – or until the maximum approved dose of 800 mg/day is reached.
The same start-low-and-titrate strategy applies to febuxostat, with a maximum approved dose of 80 mg/day.
"We have to educate primary care physicians to check the serum urate after starting therapy, and that, if it’s not below 6 mg/dL, they need to increase the dose. And if they don’t feel comfortable with that, they need to send the patient to us," the rheumatologist said.
Fortunately, patients who have a hypersensitivity reaction to allopurinol are very unlikely to experience one with febuxostat, and vice versa.
For patients who can’t reach the target serum urate with maximum-dose therapy, take heart: Second-line agents with impressive potency are well-along in the developmental pipeline.
Many labs now list the upper limit of normal for serum urate as 8 mg/dL or 8.5 mg/dL. Ignore that. This raised ceiling is simply the result of the changing demographics among the increasingly obese U.S. population in the last several decades. The definition of asymptomatic hyperuricemia remains unchanged: a serum urate greater than 6.8 mg/dL. And the target in patients with gout is still a serum urate less than 6 mg/dL. Merely dropping a gout patient’s urate from 10 to 8 or even 6.6 mg/dL isn’t doing any favors; the disease will continue to progress if the urate is above 6 mg/dL.
All gout is tophaceous. Even if tophi aren’t apparent on clinical examination, often they are radiographically. "This is a message that has to get out," Dr. Wortmann insisted.
Proposed American College of Rheumatology gout management guidelines call for starting urate-lowering drug therapy when a patient is experiencing three attacks per year. Dr. Wortmann takes issue with that.
"I would argue that once you’ve had a third attack of gout, period, you should be treated. Maybe even sooner. We need to prevent the erosion and bony destruction that occur with tophi," he said.
One audience member complained that his gout patients with comorbid renal insufficiency and/or cardiovascular disease often get caught in a revolving door. He titrates their allopurinol to an effective dose, but when they are later admitted to the hospital because of their comorbid condition the hospitalists, nephrologists, and/or cardiologists are shocked at the allopurinol dose and either reduce it or stop it altogether. The first that the rheumatologist learns of it is when patients reappear in his office with active gout. He then resumes their allopurinol at the previous dose, and they remain well controlled until the next hospitalization, when the same thing happens.
Dr. Wortmann responded that the solution requires convincing the nonrheumatologists in one-on-one conversation that urate-lowering therapy is not a one-size-fits-all matter. They need to understand that to get rid of gout, it’s necessary to drive the serum urate to the target of less than 6 mg/dL, and it helps to reassure them that that this will be accomplished using the lowest effective dose.
He reported serving as a consultant to Savient, Takeda, URL Pharmaceuticals, Novartis, and Ardea Biosciences.
SNOWMASS, COLO. – A disturbing proportion of gout cases are mismanaged by primary care physicians, and the blame falls squarely upon rheumatologists, according to one prominent gout expert.
"As rheumatologists, gout is our disease. The cause and pathophysiology are well understood, we can make the diagnosis with absolute certainty, and we’ve got great medicines. Yet today we all see people with tophi. That’s tragic. It shouldn’t exist. One of our biggest mistakes has been not being able to educate primary care physicians that having a tophus is bad, that it’s eroding cartilage and bone, and that it’s something we can prevent if we start urate-lowering therapy soon enough," Dr. Robert L. Wortmann said at the conference.
An estimated 8.3 million Americans have gout. Yet, the pharmaceutical industry says only 3.1 million of them are prescribed urate-lowering drugs. Five different studies show that a mere 40% of those on allopurinol are prescribed a dose sufficient to drive serum uric acid below 6 mg/dL, a key tenet of gout management, noted Dr. Wortmann, professor of medicine at Dartmouth Medical School in Hanover, N.H.
Moreover, poor treatment adherence is a huge problem in gout. A study of close to 4,200 gout patients started on urate-lowering drug therapy found that 56% of them were nonadherent (Arthritis Res. Ther. 2009;11(2):R46).
"I charge you all to go back from this meeting and try to communicate with all the primary care physicians you can about the principles of managing gout. People shouldn’t suffer from this," the rheumatologist declared.
He offered these major take home points:
Don’t prescribe urate-lowering drugs for asymptomatic hyperuricemia: This practice hasn’t been shown to prevent the future development of gout, yet it exposes patients to the risk of drug toxicities.
But don’t ignore asymptomatic hyperuricemia, either: Epidemiologic studies have linked asymptomatic hyperuricemia, defined by a serum urate in excess of 6.8 mg/dL, to increased risks of hypertension, cardiovascular disease, diabetes, chronic kidney disease, and all-cause mortality. The big unanswered question is whether using medications to lower serum urate in individuals with asymptomatic hyperuricemia reduces the risk of any of these conditions. That’s the subject of ongoing large clinical trials in high-risk patients. If those studies prove positive, clinical practice will change.
While awaiting the outcome of the prevention trials, it’s worth bearing in mind that Framingham Heart Study data indicate that individuals with a serum uric acid level above 9 mg/dL have a 22% chance of developing gout within the next 5 years. The major contributors to asymptomatic hyperuricemia include obesity, metabolic syndrome, and heavy consumption of fructose-containing beverages or alcohol. Those issues should be addressed.
Losartan is the only antihypertensive agent that’s uricosuric. Fenofibrate is the sole uricosuric drug indicated for dyslipidemia. Preferential consideration could be given to the use of these drugs in hypertensive and/or hyperlipidemic patients with asymptomatic hyperuricemia.
The important thing is not which oral agent you use for treatment of acute gout, it’s to initiate therapy as early as possible, at the first hint of an attack. Colchicine, maximum-dose NSAIDs, and oral prednisone dosed at 20 mg BID until symptoms have been gone for 1 week followed by another week at 20 mg/day – they’re all effective. And since they work by different mechanisms, they can beneficially be combined in refractory patients.
The old-school colchicine dosing regimen most physicians were taught has been cast aside of late. It had a high rate of diarrhea, an inhumane side effect in gout patients hobbled by a foot too sore to walk on. The former regimen has been replaced by 1.2 mg, given in a single dose, followed by 0.6 mg 1 hour later.
"This lower dose is just as effective as the old high-dose regimen of two 0.6-mg pills given at once and then one per hour for the next 5 hours. And the lower-dose program has the same side effect profile as placebo," Dr. Wortmann said.
Get the gout patient’s serum urate below 6 mg/dL using the lowest effective dose of the urate-lowering drug you’ve selected. Physicians have traditionally started gout patients on allopurinol at the standard dose of 300 mg/day. Recently, it has been demonstrated that the risk of developing allopurinol hypersensitivity syndrome is greatly reduced by starting off at 150 mg/day, checking the urate level 2 weeks later, then increasing to 300 mg/day if the serum urate isn’t below 6 mg/dL. After 2 weeks at 300 mg/day, check the urate again, and if it still isn’t below 6 mg/dL then bump the dose to 400 mg/day. Continue testing and titrating every 2 weeks until the serum urate is less than 6 mg/dL – and preferably less than 4 mg/dL if the patient has tophi – or until the maximum approved dose of 800 mg/day is reached.
The same start-low-and-titrate strategy applies to febuxostat, with a maximum approved dose of 80 mg/day.
"We have to educate primary care physicians to check the serum urate after starting therapy, and that, if it’s not below 6 mg/dL, they need to increase the dose. And if they don’t feel comfortable with that, they need to send the patient to us," the rheumatologist said.
Fortunately, patients who have a hypersensitivity reaction to allopurinol are very unlikely to experience one with febuxostat, and vice versa.
For patients who can’t reach the target serum urate with maximum-dose therapy, take heart: Second-line agents with impressive potency are well-along in the developmental pipeline.
Many labs now list the upper limit of normal for serum urate as 8 mg/dL or 8.5 mg/dL. Ignore that. This raised ceiling is simply the result of the changing demographics among the increasingly obese U.S. population in the last several decades. The definition of asymptomatic hyperuricemia remains unchanged: a serum urate greater than 6.8 mg/dL. And the target in patients with gout is still a serum urate less than 6 mg/dL. Merely dropping a gout patient’s urate from 10 to 8 or even 6.6 mg/dL isn’t doing any favors; the disease will continue to progress if the urate is above 6 mg/dL.
All gout is tophaceous. Even if tophi aren’t apparent on clinical examination, often they are radiographically. "This is a message that has to get out," Dr. Wortmann insisted.
Proposed American College of Rheumatology gout management guidelines call for starting urate-lowering drug therapy when a patient is experiencing three attacks per year. Dr. Wortmann takes issue with that.
"I would argue that once you’ve had a third attack of gout, period, you should be treated. Maybe even sooner. We need to prevent the erosion and bony destruction that occur with tophi," he said.
One audience member complained that his gout patients with comorbid renal insufficiency and/or cardiovascular disease often get caught in a revolving door. He titrates their allopurinol to an effective dose, but when they are later admitted to the hospital because of their comorbid condition the hospitalists, nephrologists, and/or cardiologists are shocked at the allopurinol dose and either reduce it or stop it altogether. The first that the rheumatologist learns of it is when patients reappear in his office with active gout. He then resumes their allopurinol at the previous dose, and they remain well controlled until the next hospitalization, when the same thing happens.
Dr. Wortmann responded that the solution requires convincing the nonrheumatologists in one-on-one conversation that urate-lowering therapy is not a one-size-fits-all matter. They need to understand that to get rid of gout, it’s necessary to drive the serum urate to the target of less than 6 mg/dL, and it helps to reassure them that that this will be accomplished using the lowest effective dose.
He reported serving as a consultant to Savient, Takeda, URL Pharmaceuticals, Novartis, and Ardea Biosciences.
EXPERT ANALYSIS FROM A SYMPOSIUM SPONSORED BY THE AMERICAN COLLEGE OF RHEUMATOLOGY
Obesity Epidemic Is Skewing Face of Gout
SNOWMASS, COLO. – The epidemiology of gout has changed considerably in the past several decades, rendering treatment more challenging.
For example, today fully 21.4% of all U.S. adults are hyperuricemic as defined by a serum uric acid in excess of 6.8 mg/dL.
"When I was a fellow it was 5%. There’s a lot more uric acid in the world today," Dr. Robert L. Wortmann observed at the symposium.
Major contributing factors include metabolic syndrome, the obesity epidemic, increased consumption of high-fructose drinks and processed foods, and alcohol. Liquor has a twofold stronger urate-boosting effect than does wine, and beer’s impact is fourfold greater than wine, according to Dr. Wortmann, professor of medicine at Dartmouth Medical School in Hanover, N.H.
"When I was in training uric acids above 9 mg/dL weren’t common; now, when I see a newly diagnosed gout patient with a uric acid level below 9, it’s exceptional. Gout patients today have uric acids of 10, 11, and 12 mg/dL as opposed to 7.5, 8, and 9 in decades past," he said.
Since 1964 the standard dose of allopurinol has been 300 mg/day. Back then, that was sufficient to reach the serum uric acid target of less than 6.0 mg/dL in about 90% of gout patients. Today, 300 mg/day gets only about 40% of patients to target, as has been shown in numerous studies.
Dr. Wortmann reported serving as a consultant to Ardea Biosciences, Novartis, Savient, Takeda, and URL Pharmaceuticals.
SNOWMASS, COLO. – The epidemiology of gout has changed considerably in the past several decades, rendering treatment more challenging.
For example, today fully 21.4% of all U.S. adults are hyperuricemic as defined by a serum uric acid in excess of 6.8 mg/dL.
"When I was a fellow it was 5%. There’s a lot more uric acid in the world today," Dr. Robert L. Wortmann observed at the symposium.
Major contributing factors include metabolic syndrome, the obesity epidemic, increased consumption of high-fructose drinks and processed foods, and alcohol. Liquor has a twofold stronger urate-boosting effect than does wine, and beer’s impact is fourfold greater than wine, according to Dr. Wortmann, professor of medicine at Dartmouth Medical School in Hanover, N.H.
"When I was in training uric acids above 9 mg/dL weren’t common; now, when I see a newly diagnosed gout patient with a uric acid level below 9, it’s exceptional. Gout patients today have uric acids of 10, 11, and 12 mg/dL as opposed to 7.5, 8, and 9 in decades past," he said.
Since 1964 the standard dose of allopurinol has been 300 mg/day. Back then, that was sufficient to reach the serum uric acid target of less than 6.0 mg/dL in about 90% of gout patients. Today, 300 mg/day gets only about 40% of patients to target, as has been shown in numerous studies.
Dr. Wortmann reported serving as a consultant to Ardea Biosciences, Novartis, Savient, Takeda, and URL Pharmaceuticals.
SNOWMASS, COLO. – The epidemiology of gout has changed considerably in the past several decades, rendering treatment more challenging.
For example, today fully 21.4% of all U.S. adults are hyperuricemic as defined by a serum uric acid in excess of 6.8 mg/dL.
"When I was a fellow it was 5%. There’s a lot more uric acid in the world today," Dr. Robert L. Wortmann observed at the symposium.
Major contributing factors include metabolic syndrome, the obesity epidemic, increased consumption of high-fructose drinks and processed foods, and alcohol. Liquor has a twofold stronger urate-boosting effect than does wine, and beer’s impact is fourfold greater than wine, according to Dr. Wortmann, professor of medicine at Dartmouth Medical School in Hanover, N.H.
"When I was in training uric acids above 9 mg/dL weren’t common; now, when I see a newly diagnosed gout patient with a uric acid level below 9, it’s exceptional. Gout patients today have uric acids of 10, 11, and 12 mg/dL as opposed to 7.5, 8, and 9 in decades past," he said.
Since 1964 the standard dose of allopurinol has been 300 mg/day. Back then, that was sufficient to reach the serum uric acid target of less than 6.0 mg/dL in about 90% of gout patients. Today, 300 mg/day gets only about 40% of patients to target, as has been shown in numerous studies.
Dr. Wortmann reported serving as a consultant to Ardea Biosciences, Novartis, Savient, Takeda, and URL Pharmaceuticals.
EXPERT ANALYSIS FROM A SYMPOSIUM SPONSORED BY THE AMERICAN COLLEGE OF RHEUMATOLOGY
Novel Gout Treatment Boosts Response in Allopurinol Nonresponders
CHICAGO – Combined treatment with allopurinol and the novel purine nucleoside phosphorylase inhibitor BCX4208 significantly lowered serum uric acid levels in gout patients who had failed to respond to allopurinol alone, according to findings from a randomized placebo-controlled trial involving 278 adults.
Between 33% and 49% of patients who received 12 weeks of combined treatment with BCX4208 at doses ranging from 5 to 40 mg/day plus allopurinol at 300 mg/day achieved the goal serum uric acid level of less than 6.0 mg/dL, compared with only 18% of those receiving placebo and allopurinol, Dr. William P. Sheridan reported during a late-breaking abstract session at the annual meeting of the American College of Rheumatology.
The response rates differed by BCX4208 dose, with 45%, 33%, 39%, and 49% of those receiving 5, 10, 20, and 40 mg, respectively, achieving goal serum uric acid levels. The differences between the 5, 20, and 40 mg groups and the placebo arm were statistically significant, said Dr. Sheridan of BioCryst Pharmaceuticals, Durham, N.C., which is the maker of BCX4208 and the sponsor of the study.
Gout flares occurred in 5%-11% of patient in each BCX4208 arm and in 5% of patient in the placebo group, and both the severity and frequency of adverse events were evenly distributed across dose groups. No opportunistic infections occurred.
Also, dose-related reductions in lymphocytes and lymphocyte subsets occurred during drug administration, but these appeared to plateau within 12 weeks, Dr. Sheridan said.
Discontinuations occurred in both the 20- and 40-mg groups because of confirmed CD4+ cell counts less than 350 cells/mm3. No patients in the other groups discontinued because of low CD4+ cell counts, he said.
Study participants were adults with a mean age of 49 years with a gout diagnosis and serum uric acid levels of 6.0 mg/dL or less who had not responded sufficiently after treatment with at least 2 weeks of allopurinol at 300 mg/day. All patients received colchicine or naproxen as prophylaxis for gout flares.
The participants had a high mean body mass index of 36 kg/m2, and comorbidities were common; 58% had hypertension, 16% had diabetes, and 39% had hypercholesterolemia.
The findings suggest that BCX4208 is generally safe and well tolerated when combined with allopurinol, and that the combination improves the likelihood that gout patient will reach goal serum uric acid levels, Dr. Sheridan said, noting that the findings are important given that few alternatives have existed for patients who fail to reach serum uric acid goal range with a xanthine oxidase inhibitor alone.
BCX4208 appears shows promise for those patients, and an extension phase of the study is underway, he said.
"The safety and tolerability profile on BCX4208 was quite satisfactory and certainly adequate for consideration of further clinical research," he concluded, noting that phase III studies are in development.
Dr. Sheridan disclosed that he is employed by BioCryst Pharmaceuticals, which is the maker of BCX4208 and the sponsor of this study.
CHICAGO – Combined treatment with allopurinol and the novel purine nucleoside phosphorylase inhibitor BCX4208 significantly lowered serum uric acid levels in gout patients who had failed to respond to allopurinol alone, according to findings from a randomized placebo-controlled trial involving 278 adults.
Between 33% and 49% of patients who received 12 weeks of combined treatment with BCX4208 at doses ranging from 5 to 40 mg/day plus allopurinol at 300 mg/day achieved the goal serum uric acid level of less than 6.0 mg/dL, compared with only 18% of those receiving placebo and allopurinol, Dr. William P. Sheridan reported during a late-breaking abstract session at the annual meeting of the American College of Rheumatology.
The response rates differed by BCX4208 dose, with 45%, 33%, 39%, and 49% of those receiving 5, 10, 20, and 40 mg, respectively, achieving goal serum uric acid levels. The differences between the 5, 20, and 40 mg groups and the placebo arm were statistically significant, said Dr. Sheridan of BioCryst Pharmaceuticals, Durham, N.C., which is the maker of BCX4208 and the sponsor of the study.
Gout flares occurred in 5%-11% of patient in each BCX4208 arm and in 5% of patient in the placebo group, and both the severity and frequency of adverse events were evenly distributed across dose groups. No opportunistic infections occurred.
Also, dose-related reductions in lymphocytes and lymphocyte subsets occurred during drug administration, but these appeared to plateau within 12 weeks, Dr. Sheridan said.
Discontinuations occurred in both the 20- and 40-mg groups because of confirmed CD4+ cell counts less than 350 cells/mm3. No patients in the other groups discontinued because of low CD4+ cell counts, he said.
Study participants were adults with a mean age of 49 years with a gout diagnosis and serum uric acid levels of 6.0 mg/dL or less who had not responded sufficiently after treatment with at least 2 weeks of allopurinol at 300 mg/day. All patients received colchicine or naproxen as prophylaxis for gout flares.
The participants had a high mean body mass index of 36 kg/m2, and comorbidities were common; 58% had hypertension, 16% had diabetes, and 39% had hypercholesterolemia.
The findings suggest that BCX4208 is generally safe and well tolerated when combined with allopurinol, and that the combination improves the likelihood that gout patient will reach goal serum uric acid levels, Dr. Sheridan said, noting that the findings are important given that few alternatives have existed for patients who fail to reach serum uric acid goal range with a xanthine oxidase inhibitor alone.
BCX4208 appears shows promise for those patients, and an extension phase of the study is underway, he said.
"The safety and tolerability profile on BCX4208 was quite satisfactory and certainly adequate for consideration of further clinical research," he concluded, noting that phase III studies are in development.
Dr. Sheridan disclosed that he is employed by BioCryst Pharmaceuticals, which is the maker of BCX4208 and the sponsor of this study.
CHICAGO – Combined treatment with allopurinol and the novel purine nucleoside phosphorylase inhibitor BCX4208 significantly lowered serum uric acid levels in gout patients who had failed to respond to allopurinol alone, according to findings from a randomized placebo-controlled trial involving 278 adults.
Between 33% and 49% of patients who received 12 weeks of combined treatment with BCX4208 at doses ranging from 5 to 40 mg/day plus allopurinol at 300 mg/day achieved the goal serum uric acid level of less than 6.0 mg/dL, compared with only 18% of those receiving placebo and allopurinol, Dr. William P. Sheridan reported during a late-breaking abstract session at the annual meeting of the American College of Rheumatology.
The response rates differed by BCX4208 dose, with 45%, 33%, 39%, and 49% of those receiving 5, 10, 20, and 40 mg, respectively, achieving goal serum uric acid levels. The differences between the 5, 20, and 40 mg groups and the placebo arm were statistically significant, said Dr. Sheridan of BioCryst Pharmaceuticals, Durham, N.C., which is the maker of BCX4208 and the sponsor of the study.
Gout flares occurred in 5%-11% of patient in each BCX4208 arm and in 5% of patient in the placebo group, and both the severity and frequency of adverse events were evenly distributed across dose groups. No opportunistic infections occurred.
Also, dose-related reductions in lymphocytes and lymphocyte subsets occurred during drug administration, but these appeared to plateau within 12 weeks, Dr. Sheridan said.
Discontinuations occurred in both the 20- and 40-mg groups because of confirmed CD4+ cell counts less than 350 cells/mm3. No patients in the other groups discontinued because of low CD4+ cell counts, he said.
Study participants were adults with a mean age of 49 years with a gout diagnosis and serum uric acid levels of 6.0 mg/dL or less who had not responded sufficiently after treatment with at least 2 weeks of allopurinol at 300 mg/day. All patients received colchicine or naproxen as prophylaxis for gout flares.
The participants had a high mean body mass index of 36 kg/m2, and comorbidities were common; 58% had hypertension, 16% had diabetes, and 39% had hypercholesterolemia.
The findings suggest that BCX4208 is generally safe and well tolerated when combined with allopurinol, and that the combination improves the likelihood that gout patient will reach goal serum uric acid levels, Dr. Sheridan said, noting that the findings are important given that few alternatives have existed for patients who fail to reach serum uric acid goal range with a xanthine oxidase inhibitor alone.
BCX4208 appears shows promise for those patients, and an extension phase of the study is underway, he said.
"The safety and tolerability profile on BCX4208 was quite satisfactory and certainly adequate for consideration of further clinical research," he concluded, noting that phase III studies are in development.
Dr. Sheridan disclosed that he is employed by BioCryst Pharmaceuticals, which is the maker of BCX4208 and the sponsor of this study.
FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF RHEUMATOLOGY
Major Finding: Between 33% and 49% of patients who received 12 weeks of combined treatment with BCX4208 at doses ranging from 5 to 40 mg/day plus allopurinol at 300 mg/day achieved the goal serum uric acid level of less than 6.0 mg/dL, compared with only 18% of those receiving placebo and allopurinol.
Data Source: A randomized placebo-controlled study.
Disclosures: Dr. Sheridan disclosed that he is employed by BioCryst Pharmaceuticals, which is the maker of BCX4208 and the sponsor of this study.
Gout Prevalence on the Upswing, MDs on the Downswing
The prevalence of gout has been skyrocketing and there are not enough physicians including rheumatologists around to manage the patients.
An estimated 8.3 million American adults are diagnosed with gout, reflecting a 1.2% rise in the prevalence of the disease in the past 2 decades, according to the analyses of national data by researchers at Boston University (Arthritis Rheum. 2011 [doi: 10.1002/art.30520]).
What adds to the burden of this disease are the growing aging population and physician shortage. Studies have shown that there is a shortages of rheumatologists, whose numbers continue to decline as they age out of the system. And some worry that primary care physicians, who are also in short supply and care for more than 90% of gout patients, need more education.
Speaking of the increased gout prevalence, one of the study authors, Dr. Hyon K. Choi, said "To me, it’s substantial. Four percent of the population having gout is not ignorable."
Western diets, sedentary lifestyle, hypertension, the obesity epidemic, and increased use of diuretics and aspirin have been among the culprits for this increase, Dr. Choi and his colleagues reported.
"We're not surprised by the [findings]," said Dr. Christopher M. Burns, a rheumatologist at Dartmouth Medical School, Lebanon, N.H., who was not involved in the study. "The trend has been going on for quite some time now. It's more of a national health issue, because it correlates well with the obesity epidemic."
Studies have suggested that gout is strongly associated with the metabolic syndrome and may lead to myocardial infarction, diabetes, and premature death, the authors noted.
Findings from some studies have shown the incidence of gout is also increasing worldwide. This has occurred despite stepped up prevention efforts: findings from other studies have shown there was an 80% increase in the use of serum urate-lowering or other gout medications during the 1990s (J. Rheumatol. 2004;31:1582-7).
As for the physician shortage, "the relative loss of rheumatologists may make the overall care of gout patients worse unless we do a better job of educating our primary care colleagues about new diagnostic and therapeutic guidelines," said Dr. N. Lawrence Edwards, professor of medicine at the University of Florida, Gainesville.
Previous analyses of national data have documented the steady rise in the prevalence of gout since the 1960s. (Arthritis Rheum. 2008;58:26-35). Researchers suspected a continued rise since the most recent gout estimates from the 1988-1994 National Health and Nutrition Examination Survey III (Am. J. Kidney Dis. 2002;40:37-42).
To estimate the prevalence in the new millennium, they analyzed data from the Centers for Disease Control and Prevention’s 2007-2008 NHANES. They compared data from the 18,825 participants in NHANES III with 5,707 participants in NHANES, all of whom were at least 20 years old. They also analyzed the prevalence of hyperuricemia and the serum urate levels. The average age of participants was 47 years old, made up of 48% men and 69% women.
Results showed that the prevalence of gout, hyperuricemia, and high serum urate levels all significantly increased during the past 2 decades.
The prevalence of gout increased from 2.7% in NHANES III to 3.9% in NHANES (a 44% relative risk increase). The prevalence of hyperuricemia increased by 3.2%, affecting 43.3 million (21.4%) adults. (For more hyperuricemia and serum urate levels, see sidebar.)
Gout prevalence also increased by age, with people aged 20-29 years at 0.4% and those in the population aged 80 years and older at 12.6%. Prevalence among the Medicare population (65 years and older) was 9.8%.
To calculate the impact of risk factors, researcher conducted stepwise adjustments for body mass index and hypertension, which reduced the odds ratio to 1.21, and additional adjustment for diuretic use and alcohol further attenuated the association.
"Most of the [prevalence] increase falls out when you correct for BMI and hypertension," said Dr. Burns. "It's a major health issue in the country. And it’s not just gout, but also hyperuricemia."
The rising prevalence of gout in the elderly population is also of particular concern, said Dr. Choi. The study estimates that 1 in 10 men and 1 in 20 women 60 years and older have gout.
Dr. John W. Rachow, a geriatrician and rheumatologist who works with nursing home patients, said that in his 30-year career, he has seen a steady rise in the number of gout patients. "Morbid obesity in nursing homes is higher than when I started," said Dr. Rachow of the University of Iowa, Iowa City.
Given the rising rates of obesity and hypertension, Dr. Choi and other rheumatologists stressed the importance of taking a holistic approach to treating patients with gout and hyperuricemia, starting with preventive measures.
Dr. Edwards said that "Physicians should all be more aggressive in how we coach patients on weight reduction and other lifestyle modifications including exercise. We should be routinely monitoring serum urates in at-risk patients so that we can review the nonpharmacologic approaches to urate lowering and management of their comorbid diseases."
Dr. Choi and his associates recommend avoidance of heavy drinking, "while moderate drinking, sweet fruits, and seafood intake (particularly oily fish) should be tailored to the individual, considering their anticipated health benefits against cardiovascular disease." They added that coffee and vitamin C supplementation may be long-term preventive measures that can lower urate levels and reduce the risk of gout and associated comorbidities.
There remain unmet challenges.
Dr. Burns noted that "It’s easy to treat people for what they come to you for. The problem is getting people to change their lifestyle," especially for those who have arthritis for whom exercising is not easy.
Meanwhile, the increase in the number of gout patients, majority of whom are cared for by primary care physicians, raises some concerns among rheumatologists.
Dr. Maria Saurez-Almazor noted that the challenge for primary care is the management of more complex patients, particularly with the advent of new therapies with which they may not be familiar," said, head of rheumatology at the University of Texas M.D. Anderson Cancer Center. The solution? "Education, education, education," she said. "For physicians to treat hyperuricemia to target, often this goal is not pursued aggressively. For patients, understanding the role of lifestyle modifications, and the importance of adherence to therapy (non-adherence is very high in this population) is crucial."
The study has some limitations, Dr. Choi and his colleagues reported.
"Unlike estimates of serum urate levels that are based on objective measures, gout prevalence estimates in the NHANES studies are based on self-reports and are thus likely inflated, similar to other condition estimates based on the NHANES. On the other hand, we cannot rule out the possibility that the survey might have missed gout cases that have not been diagnosed by health care professionals," the authors wrote.
Dr. Choi predicted that the prevalence of gout has been rising since the NHANES data was collected. The next step, he said, "is to work on preventive strategies that now have been shown to be effective by multiple studies. So manipulation of these factors should be more aggressively implemented rather than ignored. Improvement in managing these factors can help slow down the escalation."
Dr. Choi has received research funding for other projects from Takeda Pharmaceuticals and has served on advisory boards for Takeda. The study was supported by Takeda Pharmaceuticals International Inc. Other physicians quoted had no relevant disclosures.
The prevalence of gout has been skyrocketing and there are not enough physicians including rheumatologists around to manage the patients.
An estimated 8.3 million American adults are diagnosed with gout, reflecting a 1.2% rise in the prevalence of the disease in the past 2 decades, according to the analyses of national data by researchers at Boston University (Arthritis Rheum. 2011 [doi: 10.1002/art.30520]).
What adds to the burden of this disease are the growing aging population and physician shortage. Studies have shown that there is a shortages of rheumatologists, whose numbers continue to decline as they age out of the system. And some worry that primary care physicians, who are also in short supply and care for more than 90% of gout patients, need more education.
Speaking of the increased gout prevalence, one of the study authors, Dr. Hyon K. Choi, said "To me, it’s substantial. Four percent of the population having gout is not ignorable."
Western diets, sedentary lifestyle, hypertension, the obesity epidemic, and increased use of diuretics and aspirin have been among the culprits for this increase, Dr. Choi and his colleagues reported.
"We're not surprised by the [findings]," said Dr. Christopher M. Burns, a rheumatologist at Dartmouth Medical School, Lebanon, N.H., who was not involved in the study. "The trend has been going on for quite some time now. It's more of a national health issue, because it correlates well with the obesity epidemic."
Studies have suggested that gout is strongly associated with the metabolic syndrome and may lead to myocardial infarction, diabetes, and premature death, the authors noted.
Findings from some studies have shown the incidence of gout is also increasing worldwide. This has occurred despite stepped up prevention efforts: findings from other studies have shown there was an 80% increase in the use of serum urate-lowering or other gout medications during the 1990s (J. Rheumatol. 2004;31:1582-7).
As for the physician shortage, "the relative loss of rheumatologists may make the overall care of gout patients worse unless we do a better job of educating our primary care colleagues about new diagnostic and therapeutic guidelines," said Dr. N. Lawrence Edwards, professor of medicine at the University of Florida, Gainesville.
Previous analyses of national data have documented the steady rise in the prevalence of gout since the 1960s. (Arthritis Rheum. 2008;58:26-35). Researchers suspected a continued rise since the most recent gout estimates from the 1988-1994 National Health and Nutrition Examination Survey III (Am. J. Kidney Dis. 2002;40:37-42).
To estimate the prevalence in the new millennium, they analyzed data from the Centers for Disease Control and Prevention’s 2007-2008 NHANES. They compared data from the 18,825 participants in NHANES III with 5,707 participants in NHANES, all of whom were at least 20 years old. They also analyzed the prevalence of hyperuricemia and the serum urate levels. The average age of participants was 47 years old, made up of 48% men and 69% women.
Results showed that the prevalence of gout, hyperuricemia, and high serum urate levels all significantly increased during the past 2 decades.
The prevalence of gout increased from 2.7% in NHANES III to 3.9% in NHANES (a 44% relative risk increase). The prevalence of hyperuricemia increased by 3.2%, affecting 43.3 million (21.4%) adults. (For more hyperuricemia and serum urate levels, see sidebar.)
Gout prevalence also increased by age, with people aged 20-29 years at 0.4% and those in the population aged 80 years and older at 12.6%. Prevalence among the Medicare population (65 years and older) was 9.8%.
To calculate the impact of risk factors, researcher conducted stepwise adjustments for body mass index and hypertension, which reduced the odds ratio to 1.21, and additional adjustment for diuretic use and alcohol further attenuated the association.
"Most of the [prevalence] increase falls out when you correct for BMI and hypertension," said Dr. Burns. "It's a major health issue in the country. And it’s not just gout, but also hyperuricemia."
The rising prevalence of gout in the elderly population is also of particular concern, said Dr. Choi. The study estimates that 1 in 10 men and 1 in 20 women 60 years and older have gout.
Dr. John W. Rachow, a geriatrician and rheumatologist who works with nursing home patients, said that in his 30-year career, he has seen a steady rise in the number of gout patients. "Morbid obesity in nursing homes is higher than when I started," said Dr. Rachow of the University of Iowa, Iowa City.
Given the rising rates of obesity and hypertension, Dr. Choi and other rheumatologists stressed the importance of taking a holistic approach to treating patients with gout and hyperuricemia, starting with preventive measures.
Dr. Edwards said that "Physicians should all be more aggressive in how we coach patients on weight reduction and other lifestyle modifications including exercise. We should be routinely monitoring serum urates in at-risk patients so that we can review the nonpharmacologic approaches to urate lowering and management of their comorbid diseases."
Dr. Choi and his associates recommend avoidance of heavy drinking, "while moderate drinking, sweet fruits, and seafood intake (particularly oily fish) should be tailored to the individual, considering their anticipated health benefits against cardiovascular disease." They added that coffee and vitamin C supplementation may be long-term preventive measures that can lower urate levels and reduce the risk of gout and associated comorbidities.
There remain unmet challenges.
Dr. Burns noted that "It’s easy to treat people for what they come to you for. The problem is getting people to change their lifestyle," especially for those who have arthritis for whom exercising is not easy.
Meanwhile, the increase in the number of gout patients, majority of whom are cared for by primary care physicians, raises some concerns among rheumatologists.
Dr. Maria Saurez-Almazor noted that the challenge for primary care is the management of more complex patients, particularly with the advent of new therapies with which they may not be familiar," said, head of rheumatology at the University of Texas M.D. Anderson Cancer Center. The solution? "Education, education, education," she said. "For physicians to treat hyperuricemia to target, often this goal is not pursued aggressively. For patients, understanding the role of lifestyle modifications, and the importance of adherence to therapy (non-adherence is very high in this population) is crucial."
The study has some limitations, Dr. Choi and his colleagues reported.
"Unlike estimates of serum urate levels that are based on objective measures, gout prevalence estimates in the NHANES studies are based on self-reports and are thus likely inflated, similar to other condition estimates based on the NHANES. On the other hand, we cannot rule out the possibility that the survey might have missed gout cases that have not been diagnosed by health care professionals," the authors wrote.
Dr. Choi predicted that the prevalence of gout has been rising since the NHANES data was collected. The next step, he said, "is to work on preventive strategies that now have been shown to be effective by multiple studies. So manipulation of these factors should be more aggressively implemented rather than ignored. Improvement in managing these factors can help slow down the escalation."
Dr. Choi has received research funding for other projects from Takeda Pharmaceuticals and has served on advisory boards for Takeda. The study was supported by Takeda Pharmaceuticals International Inc. Other physicians quoted had no relevant disclosures.
The prevalence of gout has been skyrocketing and there are not enough physicians including rheumatologists around to manage the patients.
An estimated 8.3 million American adults are diagnosed with gout, reflecting a 1.2% rise in the prevalence of the disease in the past 2 decades, according to the analyses of national data by researchers at Boston University (Arthritis Rheum. 2011 [doi: 10.1002/art.30520]).
What adds to the burden of this disease are the growing aging population and physician shortage. Studies have shown that there is a shortages of rheumatologists, whose numbers continue to decline as they age out of the system. And some worry that primary care physicians, who are also in short supply and care for more than 90% of gout patients, need more education.
Speaking of the increased gout prevalence, one of the study authors, Dr. Hyon K. Choi, said "To me, it’s substantial. Four percent of the population having gout is not ignorable."
Western diets, sedentary lifestyle, hypertension, the obesity epidemic, and increased use of diuretics and aspirin have been among the culprits for this increase, Dr. Choi and his colleagues reported.
"We're not surprised by the [findings]," said Dr. Christopher M. Burns, a rheumatologist at Dartmouth Medical School, Lebanon, N.H., who was not involved in the study. "The trend has been going on for quite some time now. It's more of a national health issue, because it correlates well with the obesity epidemic."
Studies have suggested that gout is strongly associated with the metabolic syndrome and may lead to myocardial infarction, diabetes, and premature death, the authors noted.
Findings from some studies have shown the incidence of gout is also increasing worldwide. This has occurred despite stepped up prevention efforts: findings from other studies have shown there was an 80% increase in the use of serum urate-lowering or other gout medications during the 1990s (J. Rheumatol. 2004;31:1582-7).
As for the physician shortage, "the relative loss of rheumatologists may make the overall care of gout patients worse unless we do a better job of educating our primary care colleagues about new diagnostic and therapeutic guidelines," said Dr. N. Lawrence Edwards, professor of medicine at the University of Florida, Gainesville.
Previous analyses of national data have documented the steady rise in the prevalence of gout since the 1960s. (Arthritis Rheum. 2008;58:26-35). Researchers suspected a continued rise since the most recent gout estimates from the 1988-1994 National Health and Nutrition Examination Survey III (Am. J. Kidney Dis. 2002;40:37-42).
To estimate the prevalence in the new millennium, they analyzed data from the Centers for Disease Control and Prevention’s 2007-2008 NHANES. They compared data from the 18,825 participants in NHANES III with 5,707 participants in NHANES, all of whom were at least 20 years old. They also analyzed the prevalence of hyperuricemia and the serum urate levels. The average age of participants was 47 years old, made up of 48% men and 69% women.
Results showed that the prevalence of gout, hyperuricemia, and high serum urate levels all significantly increased during the past 2 decades.
The prevalence of gout increased from 2.7% in NHANES III to 3.9% in NHANES (a 44% relative risk increase). The prevalence of hyperuricemia increased by 3.2%, affecting 43.3 million (21.4%) adults. (For more hyperuricemia and serum urate levels, see sidebar.)
Gout prevalence also increased by age, with people aged 20-29 years at 0.4% and those in the population aged 80 years and older at 12.6%. Prevalence among the Medicare population (65 years and older) was 9.8%.
To calculate the impact of risk factors, researcher conducted stepwise adjustments for body mass index and hypertension, which reduced the odds ratio to 1.21, and additional adjustment for diuretic use and alcohol further attenuated the association.
"Most of the [prevalence] increase falls out when you correct for BMI and hypertension," said Dr. Burns. "It's a major health issue in the country. And it’s not just gout, but also hyperuricemia."
The rising prevalence of gout in the elderly population is also of particular concern, said Dr. Choi. The study estimates that 1 in 10 men and 1 in 20 women 60 years and older have gout.
Dr. John W. Rachow, a geriatrician and rheumatologist who works with nursing home patients, said that in his 30-year career, he has seen a steady rise in the number of gout patients. "Morbid obesity in nursing homes is higher than when I started," said Dr. Rachow of the University of Iowa, Iowa City.
Given the rising rates of obesity and hypertension, Dr. Choi and other rheumatologists stressed the importance of taking a holistic approach to treating patients with gout and hyperuricemia, starting with preventive measures.
Dr. Edwards said that "Physicians should all be more aggressive in how we coach patients on weight reduction and other lifestyle modifications including exercise. We should be routinely monitoring serum urates in at-risk patients so that we can review the nonpharmacologic approaches to urate lowering and management of their comorbid diseases."
Dr. Choi and his associates recommend avoidance of heavy drinking, "while moderate drinking, sweet fruits, and seafood intake (particularly oily fish) should be tailored to the individual, considering their anticipated health benefits against cardiovascular disease." They added that coffee and vitamin C supplementation may be long-term preventive measures that can lower urate levels and reduce the risk of gout and associated comorbidities.
There remain unmet challenges.
Dr. Burns noted that "It’s easy to treat people for what they come to you for. The problem is getting people to change their lifestyle," especially for those who have arthritis for whom exercising is not easy.
Meanwhile, the increase in the number of gout patients, majority of whom are cared for by primary care physicians, raises some concerns among rheumatologists.
Dr. Maria Saurez-Almazor noted that the challenge for primary care is the management of more complex patients, particularly with the advent of new therapies with which they may not be familiar," said, head of rheumatology at the University of Texas M.D. Anderson Cancer Center. The solution? "Education, education, education," she said. "For physicians to treat hyperuricemia to target, often this goal is not pursued aggressively. For patients, understanding the role of lifestyle modifications, and the importance of adherence to therapy (non-adherence is very high in this population) is crucial."
The study has some limitations, Dr. Choi and his colleagues reported.
"Unlike estimates of serum urate levels that are based on objective measures, gout prevalence estimates in the NHANES studies are based on self-reports and are thus likely inflated, similar to other condition estimates based on the NHANES. On the other hand, we cannot rule out the possibility that the survey might have missed gout cases that have not been diagnosed by health care professionals," the authors wrote.
Dr. Choi predicted that the prevalence of gout has been rising since the NHANES data was collected. The next step, he said, "is to work on preventive strategies that now have been shown to be effective by multiple studies. So manipulation of these factors should be more aggressively implemented rather than ignored. Improvement in managing these factors can help slow down the escalation."
Dr. Choi has received research funding for other projects from Takeda Pharmaceuticals and has served on advisory boards for Takeda. The study was supported by Takeda Pharmaceuticals International Inc. Other physicians quoted had no relevant disclosures.
FROM ARTHRITIS & RHEUMATISM
Major Finding: An estimated 8.3 million American adults are diagnosed with gout, reflecting a 1.2% rise in the prevalence of the disease in the past two decades.
Data Source: Researchers analyzed data from the Centers for Disease Control and Prevention’s 2007 -2008 National Health and Nutrition Examination Survey, including 5,707 participants. They compared the findings with results from analysis of NHANES III, which included data from 1988 to 1994.
Disclosures: Dr. Choi has received research funding for other projects from Takeda Pharmaceuticals and has served on advisory boards for Takeda Pharmaceuticals. The study was supported by Takeda Pharmaceuticals International, Inc. Other physicians quoted had no relevant disclosures.
Gout by the Numbers
Gout
Total Prevalence: 3.9% (8.3 million)
Prevalence in Men: 5.9% (6.1 million)
Prevalence in Women: 2.0% (2.2 million)
Hyperuricemia
Total Prevalence: 21.4% (43.3 million)
Prevalence in Men: 21.2% (20.7 million)
Prevalence in Women: 21.6% (22.6 million)
Serum Urate Level
> 7 mg/dL Regardless of Gender: 13.2% (26.6 million)
> 6 mg/dL Regardless of Gender: 32.8% (66.3 million)
Overall Mean Urate Level: 5.48 mg/dL
Comparison of NHANES & NHANES III
Increase in prevalence of gout: 1.2% (2.7% to 3.9%)
Increase in prevalence of hyperuricemia: 3.2% (18.2% to 21.4%)
Increase in mean serum urate level: 0.15 mg/dL (5.33 mg/dL to 5.48 mg/dL)
Source: Prevalence of Gout and Hyperuricemia in the U.S. General Population; NHANES 2007-2008
Gout
Total Prevalence: 3.9% (8.3 million)
Prevalence in Men: 5.9% (6.1 million)
Prevalence in Women: 2.0% (2.2 million)
Hyperuricemia
Total Prevalence: 21.4% (43.3 million)
Prevalence in Men: 21.2% (20.7 million)
Prevalence in Women: 21.6% (22.6 million)
Serum Urate Level
> 7 mg/dL Regardless of Gender: 13.2% (26.6 million)
> 6 mg/dL Regardless of Gender: 32.8% (66.3 million)
Overall Mean Urate Level: 5.48 mg/dL
Comparison of NHANES & NHANES III
Increase in prevalence of gout: 1.2% (2.7% to 3.9%)
Increase in prevalence of hyperuricemia: 3.2% (18.2% to 21.4%)
Increase in mean serum urate level: 0.15 mg/dL (5.33 mg/dL to 5.48 mg/dL)
Source: Prevalence of Gout and Hyperuricemia in the U.S. General Population; NHANES 2007-2008
Gout
Total Prevalence: 3.9% (8.3 million)
Prevalence in Men: 5.9% (6.1 million)
Prevalence in Women: 2.0% (2.2 million)
Hyperuricemia
Total Prevalence: 21.4% (43.3 million)
Prevalence in Men: 21.2% (20.7 million)
Prevalence in Women: 21.6% (22.6 million)
Serum Urate Level
> 7 mg/dL Regardless of Gender: 13.2% (26.6 million)
> 6 mg/dL Regardless of Gender: 32.8% (66.3 million)
Overall Mean Urate Level: 5.48 mg/dL
Comparison of NHANES & NHANES III
Increase in prevalence of gout: 1.2% (2.7% to 3.9%)
Increase in prevalence of hyperuricemia: 3.2% (18.2% to 21.4%)
Increase in mean serum urate level: 0.15 mg/dL (5.33 mg/dL to 5.48 mg/dL)
Source: Prevalence of Gout and Hyperuricemia in the U.S. General Population; NHANES 2007-2008
To Reverse Metabolic Syndrome, Take Gout by the Horns
Patients presenting with hyperuricemia or gout should be evaluated for metabolic syndrome, and any recommendations regarding dietary changes and medical treatment for gout should take into consideration the potential benefits of urate reduction, according to Dr. N. Lawrence Edwards.
Both hyperuricemia and gout are independent risk factors for metabolic syndrome and its individual components, said Dr. Edwards, professor of medicine at the University of Florida, Gainesville.
In a 2007 study looking at the prevalence of metabolic syndrome in nearly 8,700 patients with hyperuricemia from the NHANES (National Health and Nutrition Examination Survey) III database, the prevalence of metabolic syndrome increased in tandem with increasing levels of serum urate, and the increase persisted across subgroups stratified by age, sex, alcohol intake, body mass index, hypertension, and diabetes (Am. J. Med. 2007;120:442-7).
The investigators found that the prevalence of metabolic syndrome (defined using both original and revised National Cholesterol Education Program Adult Treatment Panel III criteria) was 19% in those with uric acid levels less than 6 mg/dL, 36% in those with 8.0-8.9 mg/dL, 62% for 9.0-9.9 mg/dL, and 71% for levels of 10 mg/dL or greater.
Physicians should recognize that metabolic syndrome occurs frequently in patients with hyperuricemia, and should be treated to prevent serious complications, they concluded.
In a related study, the prevalence of metabolic syndrome in patients with doctor-diagnosed gout from the same NHANES population was high (nearly 63%), compared with 25% in those without a gout diagnosis. The prevalence was even higher (83%) among those with a more stringently defined gout diagnosis (specifically, those on urate-lowering therapy), Dr. Edwards noted (Arthritis Rheum. 2007;57:109-15).
As with hyperuricemia, the investigators concluded that the prevalence of metabolic syndrome is high in individuals with gout, and that, given the serious complications that can be associated with metabolic syndrome, the condition should be recognized and taken into account when clinicians plan the long-term treatment of patients with gout.
The findings of these two studies support a pathogenic overlap between metabolic syndrome and gout, and underscore the importance of evaluating gout patients for the syndrome, Dr. Edwards said.
“You see a lot of patients coming in, and they haven't had fasting glucoses performed, blood pressures may be a little out of control, and weight is certainly out of control,” he noted.
“We need to look at these patients much more seriously than if they only have gout; they need a full-court press on all of their metabolic problems and not just their uric acid.”
Dietary recommendations that consist of the standard advice to avoid foods high in purines are not sufficient. Patients will often cut out meat and shellfish, but replace those with foods high in carbohydrates and fat, which can increase insulin resistance. Therefore, it is important to advise patients to reduce intake of high-purine foods, but also to avoid high-fat foods and the wrong kinds of carbohydrates.
About 40% of their diet should be complex carbohydrates, no more than 30% should be proteins, and no more than 30% should be mono- or polyunsaturated fats, he said.
As for medical treatment considerations, it is important to keep in mind the mechanisms of hyperuricemia as it relates to insulin resistance, he added.
In patients who are hypertriglyceridemic, for example, niacin is a commonly used drug.
However, niacin can elevate uric acid levels “by quite a margin” of 1.5-2.5 mg/dL. Conversely, fenofibrate can also be used to treat hypertriglyceridemia, and can lower the levels by a similar margin.
“So just making that switch might make a pretty substantial difference,” Dr. Edwards said.
In patients who are being treated for hypertension, keep in mind that hydrochlorothiazide is associated with elevated uric acid levels, and consider switching to the angiotensin receptor blocker losartan in those in whom hydrochlorathiazide is used solely for hypertension control and not for fluid control, as losartan has uric acid lowering effects, he said.
Dr. Edwards had no disclosures relevant to his presentation.
Patients presenting with hyperuricemia or gout should be evaluated for metabolic syndrome, and any recommendations regarding dietary changes and medical treatment for gout should take into consideration the potential benefits of urate reduction, according to Dr. N. Lawrence Edwards.
Both hyperuricemia and gout are independent risk factors for metabolic syndrome and its individual components, said Dr. Edwards, professor of medicine at the University of Florida, Gainesville.
In a 2007 study looking at the prevalence of metabolic syndrome in nearly 8,700 patients with hyperuricemia from the NHANES (National Health and Nutrition Examination Survey) III database, the prevalence of metabolic syndrome increased in tandem with increasing levels of serum urate, and the increase persisted across subgroups stratified by age, sex, alcohol intake, body mass index, hypertension, and diabetes (Am. J. Med. 2007;120:442-7).
The investigators found that the prevalence of metabolic syndrome (defined using both original and revised National Cholesterol Education Program Adult Treatment Panel III criteria) was 19% in those with uric acid levels less than 6 mg/dL, 36% in those with 8.0-8.9 mg/dL, 62% for 9.0-9.9 mg/dL, and 71% for levels of 10 mg/dL or greater.
Physicians should recognize that metabolic syndrome occurs frequently in patients with hyperuricemia, and should be treated to prevent serious complications, they concluded.
In a related study, the prevalence of metabolic syndrome in patients with doctor-diagnosed gout from the same NHANES population was high (nearly 63%), compared with 25% in those without a gout diagnosis. The prevalence was even higher (83%) among those with a more stringently defined gout diagnosis (specifically, those on urate-lowering therapy), Dr. Edwards noted (Arthritis Rheum. 2007;57:109-15).
As with hyperuricemia, the investigators concluded that the prevalence of metabolic syndrome is high in individuals with gout, and that, given the serious complications that can be associated with metabolic syndrome, the condition should be recognized and taken into account when clinicians plan the long-term treatment of patients with gout.
The findings of these two studies support a pathogenic overlap between metabolic syndrome and gout, and underscore the importance of evaluating gout patients for the syndrome, Dr. Edwards said.
“You see a lot of patients coming in, and they haven't had fasting glucoses performed, blood pressures may be a little out of control, and weight is certainly out of control,” he noted.
“We need to look at these patients much more seriously than if they only have gout; they need a full-court press on all of their metabolic problems and not just their uric acid.”
Dietary recommendations that consist of the standard advice to avoid foods high in purines are not sufficient. Patients will often cut out meat and shellfish, but replace those with foods high in carbohydrates and fat, which can increase insulin resistance. Therefore, it is important to advise patients to reduce intake of high-purine foods, but also to avoid high-fat foods and the wrong kinds of carbohydrates.
About 40% of their diet should be complex carbohydrates, no more than 30% should be proteins, and no more than 30% should be mono- or polyunsaturated fats, he said.
As for medical treatment considerations, it is important to keep in mind the mechanisms of hyperuricemia as it relates to insulin resistance, he added.
In patients who are hypertriglyceridemic, for example, niacin is a commonly used drug.
However, niacin can elevate uric acid levels “by quite a margin” of 1.5-2.5 mg/dL. Conversely, fenofibrate can also be used to treat hypertriglyceridemia, and can lower the levels by a similar margin.
“So just making that switch might make a pretty substantial difference,” Dr. Edwards said.
In patients who are being treated for hypertension, keep in mind that hydrochlorothiazide is associated with elevated uric acid levels, and consider switching to the angiotensin receptor blocker losartan in those in whom hydrochlorathiazide is used solely for hypertension control and not for fluid control, as losartan has uric acid lowering effects, he said.
Dr. Edwards had no disclosures relevant to his presentation.
Patients presenting with hyperuricemia or gout should be evaluated for metabolic syndrome, and any recommendations regarding dietary changes and medical treatment for gout should take into consideration the potential benefits of urate reduction, according to Dr. N. Lawrence Edwards.
Both hyperuricemia and gout are independent risk factors for metabolic syndrome and its individual components, said Dr. Edwards, professor of medicine at the University of Florida, Gainesville.
In a 2007 study looking at the prevalence of metabolic syndrome in nearly 8,700 patients with hyperuricemia from the NHANES (National Health and Nutrition Examination Survey) III database, the prevalence of metabolic syndrome increased in tandem with increasing levels of serum urate, and the increase persisted across subgroups stratified by age, sex, alcohol intake, body mass index, hypertension, and diabetes (Am. J. Med. 2007;120:442-7).
The investigators found that the prevalence of metabolic syndrome (defined using both original and revised National Cholesterol Education Program Adult Treatment Panel III criteria) was 19% in those with uric acid levels less than 6 mg/dL, 36% in those with 8.0-8.9 mg/dL, 62% for 9.0-9.9 mg/dL, and 71% for levels of 10 mg/dL or greater.
Physicians should recognize that metabolic syndrome occurs frequently in patients with hyperuricemia, and should be treated to prevent serious complications, they concluded.
In a related study, the prevalence of metabolic syndrome in patients with doctor-diagnosed gout from the same NHANES population was high (nearly 63%), compared with 25% in those without a gout diagnosis. The prevalence was even higher (83%) among those with a more stringently defined gout diagnosis (specifically, those on urate-lowering therapy), Dr. Edwards noted (Arthritis Rheum. 2007;57:109-15).
As with hyperuricemia, the investigators concluded that the prevalence of metabolic syndrome is high in individuals with gout, and that, given the serious complications that can be associated with metabolic syndrome, the condition should be recognized and taken into account when clinicians plan the long-term treatment of patients with gout.
The findings of these two studies support a pathogenic overlap between metabolic syndrome and gout, and underscore the importance of evaluating gout patients for the syndrome, Dr. Edwards said.
“You see a lot of patients coming in, and they haven't had fasting glucoses performed, blood pressures may be a little out of control, and weight is certainly out of control,” he noted.
“We need to look at these patients much more seriously than if they only have gout; they need a full-court press on all of their metabolic problems and not just their uric acid.”
Dietary recommendations that consist of the standard advice to avoid foods high in purines are not sufficient. Patients will often cut out meat and shellfish, but replace those with foods high in carbohydrates and fat, which can increase insulin resistance. Therefore, it is important to advise patients to reduce intake of high-purine foods, but also to avoid high-fat foods and the wrong kinds of carbohydrates.
About 40% of their diet should be complex carbohydrates, no more than 30% should be proteins, and no more than 30% should be mono- or polyunsaturated fats, he said.
As for medical treatment considerations, it is important to keep in mind the mechanisms of hyperuricemia as it relates to insulin resistance, he added.
In patients who are hypertriglyceridemic, for example, niacin is a commonly used drug.
However, niacin can elevate uric acid levels “by quite a margin” of 1.5-2.5 mg/dL. Conversely, fenofibrate can also be used to treat hypertriglyceridemia, and can lower the levels by a similar margin.
“So just making that switch might make a pretty substantial difference,” Dr. Edwards said.
In patients who are being treated for hypertension, keep in mind that hydrochlorothiazide is associated with elevated uric acid levels, and consider switching to the angiotensin receptor blocker losartan in those in whom hydrochlorathiazide is used solely for hypertension control and not for fluid control, as losartan has uric acid lowering effects, he said.
Dr. Edwards had no disclosures relevant to his presentation.
Lesinurad Cuts Uric Acid in Refractory Gout : Ninety percent of patients who remained on treatment for 28 weeks met the study's target level.
Major Finding: After 4 weeks of treatment with a combination of 200-600 mg/day lesinurad plus allopurinol and colchicine, 71%-87% of patients had serum uric acid levels lower than 6 mg/dL, compared with 28% of patients who were treated with allopurinol, colchicine, and placebo.
Data Source: A randomized, phase II study with 208 patients who were diagnosed with gout and whose serum uric acid levels remained above 6 mg/dL despite at least 6 weeks on steady treatment with 200-600 mg/day of allo-purinol.
Disclosures: The study was funded by Ardea Biosciences, which is developing lesinurad. Dr. Perez-Ruiz said that he has had financial relationships with Ardea, Menarini, and Novartis. Dr. Dougados said he has been a consultant for and received research support from Roche.
LONDON – An investigational drug that boosts uric acid secretion led to significant cuts in serum uric acid levels during 4 weeks of treatment in a phase II study of 208 patients with allopurinol-refractory gout.
In addition, among 30 patients who remained on the uricosuric agent lesinurad for 28 weeks in an extension phase, 27 patients (90%) reached the study's target level of serum uric acid (lower than 6 mg/dL), according to Dr. Fernando Perez-Ruiz.
Treatment with dosages of 200-600 mg/day of lesinurad also appeared safe, with no adverse effects or other safety concerns seen during the limited treatment period reported, said Dr. Perez-Ruiz, a rheumatologist at Hospital de Cruces in Barakaldo, Spain.
The drug worked equally well in patients with normal renal function (a glomerular filtration rate of at least 90 mL/min per 1.73 m
Phase III Trial to Start This Year
Based on these promising early results, a phase III trial of lesinurad will start before the end of this year, said Barry D. Quart, Pharm.D., president of Ardea Biosciences, the San Diego–based company that is developing the drug.
The phase III study will likely focus on the 200-mg and 400-mg/day dosages, as over time most patients appeared to respond to these lower dosages.
“Almost no one needs 600 mg/day to get a response,” Dr. Quart said in an interview.
Although the current study used patients' serum uric acid levels of lower than 6 mg/dL as the end point and did not assess clinical features of gout, this end point is highly meaningful, said Dr. Maxime Dougados, professor of rheumatology at René Descartes University in Paris.
Gout treatment guidelines developed by the European League Against Rheumatism (EULAR) emphasize “the importance of treating patients to a target serum uric acid of less than 6 mg/dL,” commented Dr. Dougados.
New Drugs Increase Excretion
“Until now, we have drugs that decrease uric acid synthesis, but we have not recently had any drugs to increase excretion,” Dr. Dougados observed, adding that “Now we have a new drug to increase excretion, and that is very important because allopurinol is often not sufficient to achieve the target serum uric acid level.”
Lesinurad works by inhibiting URAT1, a uric acid transporter molecule in the kidney that takes uric acid out of urine and places it back into the blood.
The study led by Dr. Perez-Ruiz enrolled patients who met the 1977 gout diagnosis criteria of the American Rheumatism Association (now the American College of Rheumatology) and who had a serum uric acid level greater than 6 mg/dL despite being on a stable dose of 200-600 mg allopurinol for at least 6 weeks.
Patients were randomized to daily treatment with 200 mg, 400 mg, or 600 mg of oral lesinurad or placebo.
All patients also received a 0.5-mg or 0.6-mg daily dose of colchicine, and they all also remained on the dosage of allopurinol that they were taking at entry into the study.
After 4 weeks on treatment, the percentage of patients whose serum uric acid level had fallen below 6 mg/dL was 28% in the 72 placebo patients, and 71%, 76%, and 87% in the three lesinurad treatment groups, which each contained 42-48 patients.
The difference in the percentage of responding patients in each of the three treatment arms was statistically significant, compared with the placebo group.
“Lesinurad produced rapid and sustained reductions in uric acid levels when added on to allopurinol in patients who were not adequately responding to allopurinol alone,” Dr. Perez-Ruiz concluded.
Major Finding: After 4 weeks of treatment with a combination of 200-600 mg/day lesinurad plus allopurinol and colchicine, 71%-87% of patients had serum uric acid levels lower than 6 mg/dL, compared with 28% of patients who were treated with allopurinol, colchicine, and placebo.
Data Source: A randomized, phase II study with 208 patients who were diagnosed with gout and whose serum uric acid levels remained above 6 mg/dL despite at least 6 weeks on steady treatment with 200-600 mg/day of allo-purinol.
Disclosures: The study was funded by Ardea Biosciences, which is developing lesinurad. Dr. Perez-Ruiz said that he has had financial relationships with Ardea, Menarini, and Novartis. Dr. Dougados said he has been a consultant for and received research support from Roche.
LONDON – An investigational drug that boosts uric acid secretion led to significant cuts in serum uric acid levels during 4 weeks of treatment in a phase II study of 208 patients with allopurinol-refractory gout.
In addition, among 30 patients who remained on the uricosuric agent lesinurad for 28 weeks in an extension phase, 27 patients (90%) reached the study's target level of serum uric acid (lower than 6 mg/dL), according to Dr. Fernando Perez-Ruiz.
Treatment with dosages of 200-600 mg/day of lesinurad also appeared safe, with no adverse effects or other safety concerns seen during the limited treatment period reported, said Dr. Perez-Ruiz, a rheumatologist at Hospital de Cruces in Barakaldo, Spain.
The drug worked equally well in patients with normal renal function (a glomerular filtration rate of at least 90 mL/min per 1.73 m
Phase III Trial to Start This Year
Based on these promising early results, a phase III trial of lesinurad will start before the end of this year, said Barry D. Quart, Pharm.D., president of Ardea Biosciences, the San Diego–based company that is developing the drug.
The phase III study will likely focus on the 200-mg and 400-mg/day dosages, as over time most patients appeared to respond to these lower dosages.
“Almost no one needs 600 mg/day to get a response,” Dr. Quart said in an interview.
Although the current study used patients' serum uric acid levels of lower than 6 mg/dL as the end point and did not assess clinical features of gout, this end point is highly meaningful, said Dr. Maxime Dougados, professor of rheumatology at René Descartes University in Paris.
Gout treatment guidelines developed by the European League Against Rheumatism (EULAR) emphasize “the importance of treating patients to a target serum uric acid of less than 6 mg/dL,” commented Dr. Dougados.
New Drugs Increase Excretion
“Until now, we have drugs that decrease uric acid synthesis, but we have not recently had any drugs to increase excretion,” Dr. Dougados observed, adding that “Now we have a new drug to increase excretion, and that is very important because allopurinol is often not sufficient to achieve the target serum uric acid level.”
Lesinurad works by inhibiting URAT1, a uric acid transporter molecule in the kidney that takes uric acid out of urine and places it back into the blood.
The study led by Dr. Perez-Ruiz enrolled patients who met the 1977 gout diagnosis criteria of the American Rheumatism Association (now the American College of Rheumatology) and who had a serum uric acid level greater than 6 mg/dL despite being on a stable dose of 200-600 mg allopurinol for at least 6 weeks.
Patients were randomized to daily treatment with 200 mg, 400 mg, or 600 mg of oral lesinurad or placebo.
All patients also received a 0.5-mg or 0.6-mg daily dose of colchicine, and they all also remained on the dosage of allopurinol that they were taking at entry into the study.
After 4 weeks on treatment, the percentage of patients whose serum uric acid level had fallen below 6 mg/dL was 28% in the 72 placebo patients, and 71%, 76%, and 87% in the three lesinurad treatment groups, which each contained 42-48 patients.
The difference in the percentage of responding patients in each of the three treatment arms was statistically significant, compared with the placebo group.
“Lesinurad produced rapid and sustained reductions in uric acid levels when added on to allopurinol in patients who were not adequately responding to allopurinol alone,” Dr. Perez-Ruiz concluded.
Major Finding: After 4 weeks of treatment with a combination of 200-600 mg/day lesinurad plus allopurinol and colchicine, 71%-87% of patients had serum uric acid levels lower than 6 mg/dL, compared with 28% of patients who were treated with allopurinol, colchicine, and placebo.
Data Source: A randomized, phase II study with 208 patients who were diagnosed with gout and whose serum uric acid levels remained above 6 mg/dL despite at least 6 weeks on steady treatment with 200-600 mg/day of allo-purinol.
Disclosures: The study was funded by Ardea Biosciences, which is developing lesinurad. Dr. Perez-Ruiz said that he has had financial relationships with Ardea, Menarini, and Novartis. Dr. Dougados said he has been a consultant for and received research support from Roche.
LONDON – An investigational drug that boosts uric acid secretion led to significant cuts in serum uric acid levels during 4 weeks of treatment in a phase II study of 208 patients with allopurinol-refractory gout.
In addition, among 30 patients who remained on the uricosuric agent lesinurad for 28 weeks in an extension phase, 27 patients (90%) reached the study's target level of serum uric acid (lower than 6 mg/dL), according to Dr. Fernando Perez-Ruiz.
Treatment with dosages of 200-600 mg/day of lesinurad also appeared safe, with no adverse effects or other safety concerns seen during the limited treatment period reported, said Dr. Perez-Ruiz, a rheumatologist at Hospital de Cruces in Barakaldo, Spain.
The drug worked equally well in patients with normal renal function (a glomerular filtration rate of at least 90 mL/min per 1.73 m
Phase III Trial to Start This Year
Based on these promising early results, a phase III trial of lesinurad will start before the end of this year, said Barry D. Quart, Pharm.D., president of Ardea Biosciences, the San Diego–based company that is developing the drug.
The phase III study will likely focus on the 200-mg and 400-mg/day dosages, as over time most patients appeared to respond to these lower dosages.
“Almost no one needs 600 mg/day to get a response,” Dr. Quart said in an interview.
Although the current study used patients' serum uric acid levels of lower than 6 mg/dL as the end point and did not assess clinical features of gout, this end point is highly meaningful, said Dr. Maxime Dougados, professor of rheumatology at René Descartes University in Paris.
Gout treatment guidelines developed by the European League Against Rheumatism (EULAR) emphasize “the importance of treating patients to a target serum uric acid of less than 6 mg/dL,” commented Dr. Dougados.
New Drugs Increase Excretion
“Until now, we have drugs that decrease uric acid synthesis, but we have not recently had any drugs to increase excretion,” Dr. Dougados observed, adding that “Now we have a new drug to increase excretion, and that is very important because allopurinol is often not sufficient to achieve the target serum uric acid level.”
Lesinurad works by inhibiting URAT1, a uric acid transporter molecule in the kidney that takes uric acid out of urine and places it back into the blood.
The study led by Dr. Perez-Ruiz enrolled patients who met the 1977 gout diagnosis criteria of the American Rheumatism Association (now the American College of Rheumatology) and who had a serum uric acid level greater than 6 mg/dL despite being on a stable dose of 200-600 mg allopurinol for at least 6 weeks.
Patients were randomized to daily treatment with 200 mg, 400 mg, or 600 mg of oral lesinurad or placebo.
All patients also received a 0.5-mg or 0.6-mg daily dose of colchicine, and they all also remained on the dosage of allopurinol that they were taking at entry into the study.
After 4 weeks on treatment, the percentage of patients whose serum uric acid level had fallen below 6 mg/dL was 28% in the 72 placebo patients, and 71%, 76%, and 87% in the three lesinurad treatment groups, which each contained 42-48 patients.
The difference in the percentage of responding patients in each of the three treatment arms was statistically significant, compared with the placebo group.
“Lesinurad produced rapid and sustained reductions in uric acid levels when added on to allopurinol in patients who were not adequately responding to allopurinol alone,” Dr. Perez-Ruiz concluded.
Hyperuricemia Boosts Risk of Hypertension in Young Adults
Young adults with hyperuricemia faced a significantly increased risk for later developing hypertension, based on follow-up of more than 4,900 Americans.
This link between hyperuricemia and the later appearance of hypertension did not involve a confounding role by metabolic syndrome.
And although the analysis could not establish a causal link between hyperuricemia and hypertension, the results indicated that an elevated serum level of uric acid marks people with an increased risk for later having hypertension, according to Dr. Eswar Krishnan.
Dr. Krishnan and his associates conducted a multivariate analysis that adjusted for baseline differences in subject age, gender, race, serum creatinine clearance, and waist circumferences.
The investigators found that people in the highest quartile of serum uric acid level at baseline had a significant, 76% increased risk for later developing hypertension, compared with the quartile of people with the lowest baseline serum uric acid level, reported Dr. Krishnan, a rheumatologist at Stanford (Calif.) University.
The study used data from the 5,115 people enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA), which entered people between the ages of 18-33 years at four U.S. sites in 1986.
The investigators followed them for up to 20 years.
Excluding people who at baseline had hypertension or any other component of metabolic syndrome (abdominal obesity, elevated triglycerides, depressed high-density lipoprotein cholesterol, elevated fasting glucose) left 4,918 people for the analysis.
The researchers used serum uric acid levels as the basis for dividing the study group into quartile.
They found that in men serum uric acid levels ranged from 0.4-5.3 mg/dL uric acid in the lowest quartile to 6.8 mg/dL or greater in the highest quartile, and in women ranged from 0.6-3.7 mg/dL in the lowest quartile to 5.0 mg/dL or greater in the highest quartile.
During the 20 years of follow-up, 7% of the men in the lowest quartile for serum uric acid developed incident hypertension. In contrast, 16% of the men in the highest uric acid quartile developed new-onset hypertension. The difference was statistically significant, Dr. Krishnan and his associates reported at the annual European Congress of Rheumatology in London.
When the researchers subdivided the CARDIA subjects by race and sex, elevated serum uric acid levels linked with a significantly increased risk of later developing hypertension among black men and women and among white men.
The link did not reach statistical significance among white women because of the small number of incident cases of hypertension during follow-up.
The analysis was sponsored by Takeda, which markets febuxostat (Uloric), a drug approved to lower serum uric acid levels in patients with gout.
Dr. Krishnan said that he has been a consultant to Takeda, Savient, and Ardea. Three coauthors on the study are Takeda employees.
Young adults with hyperuricemia faced a significantly increased risk for later developing hypertension, based on follow-up of more than 4,900 Americans.
This link between hyperuricemia and the later appearance of hypertension did not involve a confounding role by metabolic syndrome.
And although the analysis could not establish a causal link between hyperuricemia and hypertension, the results indicated that an elevated serum level of uric acid marks people with an increased risk for later having hypertension, according to Dr. Eswar Krishnan.
Dr. Krishnan and his associates conducted a multivariate analysis that adjusted for baseline differences in subject age, gender, race, serum creatinine clearance, and waist circumferences.
The investigators found that people in the highest quartile of serum uric acid level at baseline had a significant, 76% increased risk for later developing hypertension, compared with the quartile of people with the lowest baseline serum uric acid level, reported Dr. Krishnan, a rheumatologist at Stanford (Calif.) University.
The study used data from the 5,115 people enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA), which entered people between the ages of 18-33 years at four U.S. sites in 1986.
The investigators followed them for up to 20 years.
Excluding people who at baseline had hypertension or any other component of metabolic syndrome (abdominal obesity, elevated triglycerides, depressed high-density lipoprotein cholesterol, elevated fasting glucose) left 4,918 people for the analysis.
The researchers used serum uric acid levels as the basis for dividing the study group into quartile.
They found that in men serum uric acid levels ranged from 0.4-5.3 mg/dL uric acid in the lowest quartile to 6.8 mg/dL or greater in the highest quartile, and in women ranged from 0.6-3.7 mg/dL in the lowest quartile to 5.0 mg/dL or greater in the highest quartile.
During the 20 years of follow-up, 7% of the men in the lowest quartile for serum uric acid developed incident hypertension. In contrast, 16% of the men in the highest uric acid quartile developed new-onset hypertension. The difference was statistically significant, Dr. Krishnan and his associates reported at the annual European Congress of Rheumatology in London.
When the researchers subdivided the CARDIA subjects by race and sex, elevated serum uric acid levels linked with a significantly increased risk of later developing hypertension among black men and women and among white men.
The link did not reach statistical significance among white women because of the small number of incident cases of hypertension during follow-up.
The analysis was sponsored by Takeda, which markets febuxostat (Uloric), a drug approved to lower serum uric acid levels in patients with gout.
Dr. Krishnan said that he has been a consultant to Takeda, Savient, and Ardea. Three coauthors on the study are Takeda employees.
Young adults with hyperuricemia faced a significantly increased risk for later developing hypertension, based on follow-up of more than 4,900 Americans.
This link between hyperuricemia and the later appearance of hypertension did not involve a confounding role by metabolic syndrome.
And although the analysis could not establish a causal link between hyperuricemia and hypertension, the results indicated that an elevated serum level of uric acid marks people with an increased risk for later having hypertension, according to Dr. Eswar Krishnan.
Dr. Krishnan and his associates conducted a multivariate analysis that adjusted for baseline differences in subject age, gender, race, serum creatinine clearance, and waist circumferences.
The investigators found that people in the highest quartile of serum uric acid level at baseline had a significant, 76% increased risk for later developing hypertension, compared with the quartile of people with the lowest baseline serum uric acid level, reported Dr. Krishnan, a rheumatologist at Stanford (Calif.) University.
The study used data from the 5,115 people enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA), which entered people between the ages of 18-33 years at four U.S. sites in 1986.
The investigators followed them for up to 20 years.
Excluding people who at baseline had hypertension or any other component of metabolic syndrome (abdominal obesity, elevated triglycerides, depressed high-density lipoprotein cholesterol, elevated fasting glucose) left 4,918 people for the analysis.
The researchers used serum uric acid levels as the basis for dividing the study group into quartile.
They found that in men serum uric acid levels ranged from 0.4-5.3 mg/dL uric acid in the lowest quartile to 6.8 mg/dL or greater in the highest quartile, and in women ranged from 0.6-3.7 mg/dL in the lowest quartile to 5.0 mg/dL or greater in the highest quartile.
During the 20 years of follow-up, 7% of the men in the lowest quartile for serum uric acid developed incident hypertension. In contrast, 16% of the men in the highest uric acid quartile developed new-onset hypertension. The difference was statistically significant, Dr. Krishnan and his associates reported at the annual European Congress of Rheumatology in London.
When the researchers subdivided the CARDIA subjects by race and sex, elevated serum uric acid levels linked with a significantly increased risk of later developing hypertension among black men and women and among white men.
The link did not reach statistical significance among white women because of the small number of incident cases of hypertension during follow-up.
The analysis was sponsored by Takeda, which markets febuxostat (Uloric), a drug approved to lower serum uric acid levels in patients with gout.
Dr. Krishnan said that he has been a consultant to Takeda, Savient, and Ardea. Three coauthors on the study are Takeda employees.
As First-Line Gout Tx, Allopurinol Is Effective, Economical
SAN DIEGO – Allopurinol should remain the first-line agent for gout prophylaxis, despite competition from a newer drug, febuxostat, according to Dr. John Pendleton.
Allopurinol is very effective, can be safely titrated for those with renal impairment, and is the most cost-effective option, he said at the meeting.
“I still recommend allopurinol as the initial treatment, because you don't need a 24-hour urine collection to give it; it's effective in both overproducers and underexcretors [of uric acid]; it can be taken just once a day; and it's safe and effective for those with mild renal insufficiency when the dose is adjusted,” said Dr. Pendleton, an internist in Roanoke, Va.
“Generic allopurinol costs about $15 per month. The brand name costs about $43 per month. But the price for febuxostat comes in at about $156 per month,” he said.
With either drug, the goal is to lower uric acid levels to below 6 mg/dL, said Dr. Pendleton, referring to a retrospective study of 276 patients with recurrent gout attacks (Arthritis Rheum. 2004; 51:321-5).
In the study, “among the 81 patients with a uric acid of less than 6 mg/dL, 88% had no recurrent attacks during the 3-year observational period,” he said.
Allopurinol has been the “standby drug” for gouty arthritis for 60 years, and still performs admirably, he noted. Most initial doses range from 50 to 300 mg/day, but “some recent studies suggest that only 25% of patients will reach the uric acid target on that regimen. For many patients, we need to increase the dose to get that level down.”
The dose should be incrementally increased every 3–4 weeks to reach the uric acid target level; doses of up to 800 mg/day are approved for this indication. “But if you're not able to achieve this desired level by pushing the dose close to 800 mg, I would consider trying febuxostat.”
Febuxostat, a xanthine oxidase inhibitor, is more selective and potent than allopurnol. “It's metabolized in the liver and very little of the active drug is excreted renally, raising the possibility that it might be safer in patients with mild to moderate renal insufficiency,” Dr. Pendleton said.
It's not easy to fully compare the two, because all three of the studies on the basis of which febuxostat was approved used a fixed-dose allopurinol regimen. “None of them allowed the total upward titration of allopurinol for a fair comparison,” Dr. Pendleton pointed out.
The studies concluded that 40 mg of febuxostat was as effective as 300 mg of allopurinol. “The higher dose [of febuxostat 80 mg] seemed to be more effective than 400 mg allopurinol, but again, the studies did not allow for an upward titration” of the comparator, he said.
Although none of the patients in those trials had a creatinine level of more than 2.5 mg/dL, “a short-term study suggests that febuxostat dosing would not need to be adjusted even with a very low creatinine clearance [of 10–29 mL/min]. But just the same I would be very careful in that setting,” Dr. Pendleton said (Am. J. Ther. 2005;12:22-34).
Dr. Pendleton said he had no disclosures.
Allopurinol effectively prevents gout crystals (above) and is a cost-effective therapy.
Source ©Elsevier Inc.
SAN DIEGO – Allopurinol should remain the first-line agent for gout prophylaxis, despite competition from a newer drug, febuxostat, according to Dr. John Pendleton.
Allopurinol is very effective, can be safely titrated for those with renal impairment, and is the most cost-effective option, he said at the meeting.
“I still recommend allopurinol as the initial treatment, because you don't need a 24-hour urine collection to give it; it's effective in both overproducers and underexcretors [of uric acid]; it can be taken just once a day; and it's safe and effective for those with mild renal insufficiency when the dose is adjusted,” said Dr. Pendleton, an internist in Roanoke, Va.
“Generic allopurinol costs about $15 per month. The brand name costs about $43 per month. But the price for febuxostat comes in at about $156 per month,” he said.
With either drug, the goal is to lower uric acid levels to below 6 mg/dL, said Dr. Pendleton, referring to a retrospective study of 276 patients with recurrent gout attacks (Arthritis Rheum. 2004; 51:321-5).
In the study, “among the 81 patients with a uric acid of less than 6 mg/dL, 88% had no recurrent attacks during the 3-year observational period,” he said.
Allopurinol has been the “standby drug” for gouty arthritis for 60 years, and still performs admirably, he noted. Most initial doses range from 50 to 300 mg/day, but “some recent studies suggest that only 25% of patients will reach the uric acid target on that regimen. For many patients, we need to increase the dose to get that level down.”
The dose should be incrementally increased every 3–4 weeks to reach the uric acid target level; doses of up to 800 mg/day are approved for this indication. “But if you're not able to achieve this desired level by pushing the dose close to 800 mg, I would consider trying febuxostat.”
Febuxostat, a xanthine oxidase inhibitor, is more selective and potent than allopurnol. “It's metabolized in the liver and very little of the active drug is excreted renally, raising the possibility that it might be safer in patients with mild to moderate renal insufficiency,” Dr. Pendleton said.
It's not easy to fully compare the two, because all three of the studies on the basis of which febuxostat was approved used a fixed-dose allopurinol regimen. “None of them allowed the total upward titration of allopurinol for a fair comparison,” Dr. Pendleton pointed out.
The studies concluded that 40 mg of febuxostat was as effective as 300 mg of allopurinol. “The higher dose [of febuxostat 80 mg] seemed to be more effective than 400 mg allopurinol, but again, the studies did not allow for an upward titration” of the comparator, he said.
Although none of the patients in those trials had a creatinine level of more than 2.5 mg/dL, “a short-term study suggests that febuxostat dosing would not need to be adjusted even with a very low creatinine clearance [of 10–29 mL/min]. But just the same I would be very careful in that setting,” Dr. Pendleton said (Am. J. Ther. 2005;12:22-34).
Dr. Pendleton said he had no disclosures.
Allopurinol effectively prevents gout crystals (above) and is a cost-effective therapy.
Source ©Elsevier Inc.
SAN DIEGO – Allopurinol should remain the first-line agent for gout prophylaxis, despite competition from a newer drug, febuxostat, according to Dr. John Pendleton.
Allopurinol is very effective, can be safely titrated for those with renal impairment, and is the most cost-effective option, he said at the meeting.
“I still recommend allopurinol as the initial treatment, because you don't need a 24-hour urine collection to give it; it's effective in both overproducers and underexcretors [of uric acid]; it can be taken just once a day; and it's safe and effective for those with mild renal insufficiency when the dose is adjusted,” said Dr. Pendleton, an internist in Roanoke, Va.
“Generic allopurinol costs about $15 per month. The brand name costs about $43 per month. But the price for febuxostat comes in at about $156 per month,” he said.
With either drug, the goal is to lower uric acid levels to below 6 mg/dL, said Dr. Pendleton, referring to a retrospective study of 276 patients with recurrent gout attacks (Arthritis Rheum. 2004; 51:321-5).
In the study, “among the 81 patients with a uric acid of less than 6 mg/dL, 88% had no recurrent attacks during the 3-year observational period,” he said.
Allopurinol has been the “standby drug” for gouty arthritis for 60 years, and still performs admirably, he noted. Most initial doses range from 50 to 300 mg/day, but “some recent studies suggest that only 25% of patients will reach the uric acid target on that regimen. For many patients, we need to increase the dose to get that level down.”
The dose should be incrementally increased every 3–4 weeks to reach the uric acid target level; doses of up to 800 mg/day are approved for this indication. “But if you're not able to achieve this desired level by pushing the dose close to 800 mg, I would consider trying febuxostat.”
Febuxostat, a xanthine oxidase inhibitor, is more selective and potent than allopurnol. “It's metabolized in the liver and very little of the active drug is excreted renally, raising the possibility that it might be safer in patients with mild to moderate renal insufficiency,” Dr. Pendleton said.
It's not easy to fully compare the two, because all three of the studies on the basis of which febuxostat was approved used a fixed-dose allopurinol regimen. “None of them allowed the total upward titration of allopurinol for a fair comparison,” Dr. Pendleton pointed out.
The studies concluded that 40 mg of febuxostat was as effective as 300 mg of allopurinol. “The higher dose [of febuxostat 80 mg] seemed to be more effective than 400 mg allopurinol, but again, the studies did not allow for an upward titration” of the comparator, he said.
Although none of the patients in those trials had a creatinine level of more than 2.5 mg/dL, “a short-term study suggests that febuxostat dosing would not need to be adjusted even with a very low creatinine clearance [of 10–29 mL/min]. But just the same I would be very careful in that setting,” Dr. Pendleton said (Am. J. Ther. 2005;12:22-34).
Dr. Pendleton said he had no disclosures.
Allopurinol effectively prevents gout crystals (above) and is a cost-effective therapy.
Source ©Elsevier Inc.
Canakinumab Effective, Safe for Gouty Arthritis
Major Finding: At 3 days after a single drug dose, gouty arthritis patients who were treated with canakinumab had a statistically significant, average reduction of 11 mm on their pain score, compared with patients who were treated with triamcinolone acetonide (on a 0- to 100-mm visual analog scale). After 12 weeks on randomized treatment, patients treated with canakinumab had a statistically significant 55%–68% relative decrease in new-flare frequency, compared with triamcinolone acetonide–treated patients.
Data Source: The Beta-RELIEVED and Beta-RELIEVED II trials, two identically designed studies that together randomized 456 patients with recent flares of gouty arthritis who were contraindicated for, intolerant of, or unresponsive to NSAIDs and colchicine to treatment with canakinumab or triamcinolone acetonide.
Disclosures: The beta-RELIEVED trials were sponsored by Novartis, which markets canakinumab (Ilaris). Dr. Schlesinger said that she is on the advisory board of Novartis, Enzyme Rx, Takeda, URL Pharma, and Savient. She is a consultant to and has received research grants from Novartis, and is on the speakers bureau of Takeda and Savient. Dr. So said that he is a consultant to Novartis, Bristol-Myers Squibb, Merck, Pfizer, and UCB Pharma. Dr. Khanna said that he is a consultant to Novartis, Takeda, Savient, and UCB Pharma.
LONDON – Use of canakinumab led to greater reductions in pain among patients with acute gouty arthritis flares after 3 days, and superior prevention of new flares during 12 weeks of follow-up, compared with triamcinolone acetonide in a pair of phase III trials that together enrolled 456 patients.
“Canakinumab is a potential new therapeutic option for acute flares in frequently flaring gouty arthritis patients with limited treatment options,” Dr. Naomi Schlesinger said at the meeting.
Canakinumab is a fully human monoclonal antibody to interleukin (IL)-1 beta that selectively binds to and inhibits the proinflammatory molecule IL-1 beta, and already has Food and Drug Administration approval for treating CAPS (cryopyrin-associated periodic syndromes).
Based in part on the efficacy and safety data from the two reported phase III trials, Novartis, the company that markets canakinumab (Ilaris), filed an application with the FDA earlier this year for a supplemental indication for treating gouty arthritis flares. The FDA's Arthritis Advisory Committee discussed this application on June 21.
In the two new gouty arthritis trials, canakinumab's safety profile during the first 12 weeks of treatment “appeared consistent with longer-term safety data from CAPS patients; there were no safety signals related to specific organ class,” said Dr. Schlesinger, chief of the division of rheumatology and connective tissue research at the Robert Wood Johnson Medical School in New Brunswick, N.J. The most notable safety observation she made from the new results centered on “a modest increase in infections, mostly mild to moderate, with no opportunistic infections reported,” she said.
Despite this promising safety and efficacy, one expert viewed canakinumab as an agent for a “niche population, patients [with gout] who flare and you can't do anything about it” using standard drugs, commented Dr. Dinesh Khanna, a rheumatologist specializing in gout at the University of California, Los Angeles.
Goutologists see a lot of patients with diabetes, kidney disease, and hypertension who can't take NSAIDs or colchicine. “You also can't give them a steroid monthly, so these patients flare because of their high uric acid level and you're stuck. These are the patients who can be treated with an anti-IL-1 beta to prevent gout attacks,” he said in an interview.
The Beta-RELIEVED (Response in Acute Flare and in Prevention of Episodes of Reflare in Gout) and Beta-RELIEVED II trials enrolled patients within 5 days of an acute flare of gouty arthritis who had at least three flares during the prior year and were contraindicated for, intolerant of, or unresponsive to NSAIDs and colchicine. All patients met the American College of Rheumatology's diagnostic criteria for gouty arthritis, and had pain intensity of at least 50 mm on a visual analog scale of 0–100 mm.
The researchers randomized patients to receive a subcutaneous injection of 150 mg canakinumab or an intramuscular injection of 40 mg triamcinolone acetonide. Patients who reflared during the subsequent 12 weeks during the first phase of the study qualified to receive an additional dose of their assigned drug with each flare.
One of the study's two primary end points was pain resolution at 72 hours after initial treatment. At that time, patients treated with canakinumab in the Beta-RELIEVED study had an average pain score that was 11 mm lower than that of patients in the comparator group, a statistically significant difference, reported Dr. Alexander So, a study coinvestigator and professor of rheumatology at the University of Lausanne (Switzerland).
Patients who were treated with canakinumab began to show significantly better pain reduction, compared with those who got triamcinolone within 12 hours after their first dose, and the advantage in pain relief continued each time the investigators measured pain during the first 7 days after treatment, Dr. So said. Neither Dr. So nor Dr. Schlesinger reported the results for this end point from the Beta-RELIEVED II trial.
The second primary end point was the percentage of patients having new flares during the first 12 weeks following their initial therapy. In the Beta-RELIEVED trial, 19% of the 115 patients who were treated with canakinumab and 37% of the 115 patients treated with triamcinolone had a new flare, a 55% relative risk reduction with canakinumab that was statistically significant. In the second trial, canakinumab use led to a 68% relative reduction in new flares, also a statistically significant difference in the study that randomized 226 patients, Dr. Schlesinger reported.
The canakinumab-treated patients also showed other signs of superior response in several secondary efficacy measures. Patients in the canakinumab group had a significant reduction in their mean number of flares, significantly less inflammation and swelling, and better suppression of inflammatory markers after 12 weeks, the researchers said.
In the safety analysis, canakinumab was associated with similar rates of all adverse events, a similar low rate of serious adverse events, and a similar low rate of adverse events leading to discontinuation, compared with patients who received triamcinolone.
Major Finding: At 3 days after a single drug dose, gouty arthritis patients who were treated with canakinumab had a statistically significant, average reduction of 11 mm on their pain score, compared with patients who were treated with triamcinolone acetonide (on a 0- to 100-mm visual analog scale). After 12 weeks on randomized treatment, patients treated with canakinumab had a statistically significant 55%–68% relative decrease in new-flare frequency, compared with triamcinolone acetonide–treated patients.
Data Source: The Beta-RELIEVED and Beta-RELIEVED II trials, two identically designed studies that together randomized 456 patients with recent flares of gouty arthritis who were contraindicated for, intolerant of, or unresponsive to NSAIDs and colchicine to treatment with canakinumab or triamcinolone acetonide.
Disclosures: The beta-RELIEVED trials were sponsored by Novartis, which markets canakinumab (Ilaris). Dr. Schlesinger said that she is on the advisory board of Novartis, Enzyme Rx, Takeda, URL Pharma, and Savient. She is a consultant to and has received research grants from Novartis, and is on the speakers bureau of Takeda and Savient. Dr. So said that he is a consultant to Novartis, Bristol-Myers Squibb, Merck, Pfizer, and UCB Pharma. Dr. Khanna said that he is a consultant to Novartis, Takeda, Savient, and UCB Pharma.
LONDON – Use of canakinumab led to greater reductions in pain among patients with acute gouty arthritis flares after 3 days, and superior prevention of new flares during 12 weeks of follow-up, compared with triamcinolone acetonide in a pair of phase III trials that together enrolled 456 patients.
“Canakinumab is a potential new therapeutic option for acute flares in frequently flaring gouty arthritis patients with limited treatment options,” Dr. Naomi Schlesinger said at the meeting.
Canakinumab is a fully human monoclonal antibody to interleukin (IL)-1 beta that selectively binds to and inhibits the proinflammatory molecule IL-1 beta, and already has Food and Drug Administration approval for treating CAPS (cryopyrin-associated periodic syndromes).
Based in part on the efficacy and safety data from the two reported phase III trials, Novartis, the company that markets canakinumab (Ilaris), filed an application with the FDA earlier this year for a supplemental indication for treating gouty arthritis flares. The FDA's Arthritis Advisory Committee discussed this application on June 21.
In the two new gouty arthritis trials, canakinumab's safety profile during the first 12 weeks of treatment “appeared consistent with longer-term safety data from CAPS patients; there were no safety signals related to specific organ class,” said Dr. Schlesinger, chief of the division of rheumatology and connective tissue research at the Robert Wood Johnson Medical School in New Brunswick, N.J. The most notable safety observation she made from the new results centered on “a modest increase in infections, mostly mild to moderate, with no opportunistic infections reported,” she said.
Despite this promising safety and efficacy, one expert viewed canakinumab as an agent for a “niche population, patients [with gout] who flare and you can't do anything about it” using standard drugs, commented Dr. Dinesh Khanna, a rheumatologist specializing in gout at the University of California, Los Angeles.
Goutologists see a lot of patients with diabetes, kidney disease, and hypertension who can't take NSAIDs or colchicine. “You also can't give them a steroid monthly, so these patients flare because of their high uric acid level and you're stuck. These are the patients who can be treated with an anti-IL-1 beta to prevent gout attacks,” he said in an interview.
The Beta-RELIEVED (Response in Acute Flare and in Prevention of Episodes of Reflare in Gout) and Beta-RELIEVED II trials enrolled patients within 5 days of an acute flare of gouty arthritis who had at least three flares during the prior year and were contraindicated for, intolerant of, or unresponsive to NSAIDs and colchicine. All patients met the American College of Rheumatology's diagnostic criteria for gouty arthritis, and had pain intensity of at least 50 mm on a visual analog scale of 0–100 mm.
The researchers randomized patients to receive a subcutaneous injection of 150 mg canakinumab or an intramuscular injection of 40 mg triamcinolone acetonide. Patients who reflared during the subsequent 12 weeks during the first phase of the study qualified to receive an additional dose of their assigned drug with each flare.
One of the study's two primary end points was pain resolution at 72 hours after initial treatment. At that time, patients treated with canakinumab in the Beta-RELIEVED study had an average pain score that was 11 mm lower than that of patients in the comparator group, a statistically significant difference, reported Dr. Alexander So, a study coinvestigator and professor of rheumatology at the University of Lausanne (Switzerland).
Patients who were treated with canakinumab began to show significantly better pain reduction, compared with those who got triamcinolone within 12 hours after their first dose, and the advantage in pain relief continued each time the investigators measured pain during the first 7 days after treatment, Dr. So said. Neither Dr. So nor Dr. Schlesinger reported the results for this end point from the Beta-RELIEVED II trial.
The second primary end point was the percentage of patients having new flares during the first 12 weeks following their initial therapy. In the Beta-RELIEVED trial, 19% of the 115 patients who were treated with canakinumab and 37% of the 115 patients treated with triamcinolone had a new flare, a 55% relative risk reduction with canakinumab that was statistically significant. In the second trial, canakinumab use led to a 68% relative reduction in new flares, also a statistically significant difference in the study that randomized 226 patients, Dr. Schlesinger reported.
The canakinumab-treated patients also showed other signs of superior response in several secondary efficacy measures. Patients in the canakinumab group had a significant reduction in their mean number of flares, significantly less inflammation and swelling, and better suppression of inflammatory markers after 12 weeks, the researchers said.
In the safety analysis, canakinumab was associated with similar rates of all adverse events, a similar low rate of serious adverse events, and a similar low rate of adverse events leading to discontinuation, compared with patients who received triamcinolone.
Major Finding: At 3 days after a single drug dose, gouty arthritis patients who were treated with canakinumab had a statistically significant, average reduction of 11 mm on their pain score, compared with patients who were treated with triamcinolone acetonide (on a 0- to 100-mm visual analog scale). After 12 weeks on randomized treatment, patients treated with canakinumab had a statistically significant 55%–68% relative decrease in new-flare frequency, compared with triamcinolone acetonide–treated patients.
Data Source: The Beta-RELIEVED and Beta-RELIEVED II trials, two identically designed studies that together randomized 456 patients with recent flares of gouty arthritis who were contraindicated for, intolerant of, or unresponsive to NSAIDs and colchicine to treatment with canakinumab or triamcinolone acetonide.
Disclosures: The beta-RELIEVED trials were sponsored by Novartis, which markets canakinumab (Ilaris). Dr. Schlesinger said that she is on the advisory board of Novartis, Enzyme Rx, Takeda, URL Pharma, and Savient. She is a consultant to and has received research grants from Novartis, and is on the speakers bureau of Takeda and Savient. Dr. So said that he is a consultant to Novartis, Bristol-Myers Squibb, Merck, Pfizer, and UCB Pharma. Dr. Khanna said that he is a consultant to Novartis, Takeda, Savient, and UCB Pharma.
LONDON – Use of canakinumab led to greater reductions in pain among patients with acute gouty arthritis flares after 3 days, and superior prevention of new flares during 12 weeks of follow-up, compared with triamcinolone acetonide in a pair of phase III trials that together enrolled 456 patients.
“Canakinumab is a potential new therapeutic option for acute flares in frequently flaring gouty arthritis patients with limited treatment options,” Dr. Naomi Schlesinger said at the meeting.
Canakinumab is a fully human monoclonal antibody to interleukin (IL)-1 beta that selectively binds to and inhibits the proinflammatory molecule IL-1 beta, and already has Food and Drug Administration approval for treating CAPS (cryopyrin-associated periodic syndromes).
Based in part on the efficacy and safety data from the two reported phase III trials, Novartis, the company that markets canakinumab (Ilaris), filed an application with the FDA earlier this year for a supplemental indication for treating gouty arthritis flares. The FDA's Arthritis Advisory Committee discussed this application on June 21.
In the two new gouty arthritis trials, canakinumab's safety profile during the first 12 weeks of treatment “appeared consistent with longer-term safety data from CAPS patients; there were no safety signals related to specific organ class,” said Dr. Schlesinger, chief of the division of rheumatology and connective tissue research at the Robert Wood Johnson Medical School in New Brunswick, N.J. The most notable safety observation she made from the new results centered on “a modest increase in infections, mostly mild to moderate, with no opportunistic infections reported,” she said.
Despite this promising safety and efficacy, one expert viewed canakinumab as an agent for a “niche population, patients [with gout] who flare and you can't do anything about it” using standard drugs, commented Dr. Dinesh Khanna, a rheumatologist specializing in gout at the University of California, Los Angeles.
Goutologists see a lot of patients with diabetes, kidney disease, and hypertension who can't take NSAIDs or colchicine. “You also can't give them a steroid monthly, so these patients flare because of their high uric acid level and you're stuck. These are the patients who can be treated with an anti-IL-1 beta to prevent gout attacks,” he said in an interview.
The Beta-RELIEVED (Response in Acute Flare and in Prevention of Episodes of Reflare in Gout) and Beta-RELIEVED II trials enrolled patients within 5 days of an acute flare of gouty arthritis who had at least three flares during the prior year and were contraindicated for, intolerant of, or unresponsive to NSAIDs and colchicine. All patients met the American College of Rheumatology's diagnostic criteria for gouty arthritis, and had pain intensity of at least 50 mm on a visual analog scale of 0–100 mm.
The researchers randomized patients to receive a subcutaneous injection of 150 mg canakinumab or an intramuscular injection of 40 mg triamcinolone acetonide. Patients who reflared during the subsequent 12 weeks during the first phase of the study qualified to receive an additional dose of their assigned drug with each flare.
One of the study's two primary end points was pain resolution at 72 hours after initial treatment. At that time, patients treated with canakinumab in the Beta-RELIEVED study had an average pain score that was 11 mm lower than that of patients in the comparator group, a statistically significant difference, reported Dr. Alexander So, a study coinvestigator and professor of rheumatology at the University of Lausanne (Switzerland).
Patients who were treated with canakinumab began to show significantly better pain reduction, compared with those who got triamcinolone within 12 hours after their first dose, and the advantage in pain relief continued each time the investigators measured pain during the first 7 days after treatment, Dr. So said. Neither Dr. So nor Dr. Schlesinger reported the results for this end point from the Beta-RELIEVED II trial.
The second primary end point was the percentage of patients having new flares during the first 12 weeks following their initial therapy. In the Beta-RELIEVED trial, 19% of the 115 patients who were treated with canakinumab and 37% of the 115 patients treated with triamcinolone had a new flare, a 55% relative risk reduction with canakinumab that was statistically significant. In the second trial, canakinumab use led to a 68% relative reduction in new flares, also a statistically significant difference in the study that randomized 226 patients, Dr. Schlesinger reported.
The canakinumab-treated patients also showed other signs of superior response in several secondary efficacy measures. Patients in the canakinumab group had a significant reduction in their mean number of flares, significantly less inflammation and swelling, and better suppression of inflammatory markers after 12 weeks, the researchers said.
In the safety analysis, canakinumab was associated with similar rates of all adverse events, a similar low rate of serious adverse events, and a similar low rate of adverse events leading to discontinuation, compared with patients who received triamcinolone.