Gout

Identification of monosodium urate crystals, either in a joint fluid sample or in a tophi aspirate, should be performed for a definite diagnosis of gout, according to new multinational evidence-based recommendations on the diagnosis and management of the disease.

When identification of monosodium urate (MSU) crystals is not possible, the diagnosis can be supported by classical clinical features such as podagra, tophi, or rapid response to colchicine, or by characteristic imaging findings, Dr. Francisca Sivera of Hospital General Universitario de Elda (Spain) and her colleagues reported on behalf of the 2011 3e (Evidence, Expertise, Exchange) Initiative. The initiative is a multinational collaboration tasked with promoting evidence-based practice in rheumatology through the development of practical recommendations that address relevant clinical issues.

The MSU identification recommendation is one of 10 recommendations developed by 474 rheumatologists from 14 countries who participated in the 2011 3e Initiative. In keeping with 3e protocol, a panel of 78 experts representing the 14 countries developed 10 key clinical questions pertinent to the diagnosis and management of gout, each of which was investigated via extensive literature review. Recommendations for each of the questions were then formulated, debated, and voted on by Initiative participants, and each recommendation was graded based on the level of evidence.

In addition to diagnosis, the gout recommendations address comorbidity screening, acute gout treatment, lifestyle counseling, urate-lowering therapy, flare prophylaxis, the effect of comorbidities on drug selection, patient monitoring, tophi treatment, and management of asymptomatic hyperuricemia (Ann. Rheum. Dis. 2013 July 18 [doi: 10.1136/annrheumdis-2013-203325]).

Specifically, with a high level of agreement that ranged from a mean of 8.1 to 9.2 on a 1-10 scale, the 3e Initiative participants recommended:

• Assessing renal function and cardiovascular risk factors in patients with gout and/or hyperuricemia.

• Treating acute gout with low-dose colchicine, nonsteroidal anti-inflammatory drugs, and/or glucocorticoids, depending on comorbidities and the risk of adverse effects.

• Advising patients about health lifestyle choices.

• Using allopurinol first-line as urate-lowering therapy, and considering uricosurics as alternatives when necessary.

• Educating patients on the risk and management of flares – and using prophylaxis – when introducing urate-lowering therapy.

• Using allopurinol with close monitoring, and starting at a low dose with slow titration, in patients with mild to moderate renal impairment.

• Setting the treatment target for serum urate at below 0.36 mmol/L (6 mg/dL) with eventual absence of gout attacks and resolution of tophi.

• Treating tophi medically by achieving a sustained reduction in serum uric acid, preferably below 0.30 mmol/L (5 mg/dL) and reserving surgery for select cases, such as those involving nerve compression, mechanical impingement, or infection.

• Forgoing pharmacological treatment of asymptomatic hyperuricemia.

The ultimate goal of these recommendations, which were based on 1a-5 evidence levels, and which received recommendation grades ranging from B to D, is to improve patient care, Dr. Sivera said in an interview. The level of evidence and grade of recommendation were made according to the Oxford Centre for Evidence-Based Medicine levels of evidence.

Gout affects up to 2% of men in Western countries, and is associated with morbidity, disability, and poorer quality of life. Despite the availability of a number of guidelines and recommendations, management of the condition is often suboptimal, she said.

"Gout is a curable disease, but evidence shows that many patients are mismanaged with regard to both treatment and diagnosis. Even in a rheumatology clinic, only about a quarter of the patients have a diagnosis of gout established by MSU crystal identification, and in a U.K. study, only one in three patients with a diagnosis of gout were taking urate-lowering therapy," she said.

Research shows that when guidelines are implemented, they improve the quality of care. Educational outreach has an effect on implementation, she said, noting that "both dissemination and education – in both gout and in evidence-based medicine – are an integral part of the 3e Initiative, so these multinational recommendations have the potential to positively influence the standard of care."

The 3e recommendations follow those published in 2012 on behalf of the American College of Rheumatology, which centered on the treatment and prophylaxis of acute gout flares and the appropriate use of urate-lowering therapy.

"Some of the recommendations provided are similar, such as treating to a target serum uric acid level, and the ‘start low, go slow’ approach to allopurinol therapy. This highlights the general consensus on many aspects of the optimal standard of gout management," Dr. Sivera said.

Where the 3e recommendation and the ACR guidelines overlap, there is, indeed, general agreement, Dr. John FitzGerald of the University of California, Los Angeles, said in an interview.

Both processes benefited from Delphi consensus methodologies and systematic literature reviews to inform decision making. However, the two diverge with respect to other aspects of the methodology and presentation, he noted.

"The RAND/UCLA methodology used by ACR resulted in guidelines that were evidence based to be the most efficacious recommendations. As noted, the RAND/UCLA methodology excludes cost of therapy (as typically there are insufficient head-to-head therapeutic cost-efficacy studies on which to base recommendations). The ACR guidelines therefore leave it to the practitioner to use the efficacy-based recommendations, along with their clinical and practical knowledge, to then provide recommendations for specific patients. As an example, allopurinol and febuxostat have relatively similar efficacy but significant cost differences," said Dr. FitzGerald, who co-led the ACR guidelines development project.

"The 3e approach incorporates that next step in decision making to provide evidence-based and practical recommendations to the practitioner," he said.

The ACR effort addressed four specific domains of gout management: treatment of acute gouty attacks, management of urate-lowering therapy, management of chronic tophaceous gout, and prophylaxis of acute gouty attacks. Although the 3e effort focused on 10 specific, clinically relevant questions, it is valuable for other reasons as well, such as the inclusion of diagnosis as part of the recommendations, and the fact that asymptomatic hyperuricemia is addressed, he said, noting that neither of these was addressed by the ACR guidelines.

The 3e recommendations also address the use of benzbromarone, a uricosuric agent that is not available in the United States.

While the 3e effort lacks the extent of detail included in the ACR guidelines, such as the inclusion of specific information on allopurinol dosing, the 3e group is to be commended for the size of the effort, Dr. FitzGerald said, stressing the value of the input from nearly 500 rheumatologists from 14 countries.

Indeed, the extensive effort by "a large group of practicing rheumatologists from many different countries in Europe, South America, and Australasia resulted in the recommendations addressing those aspects [of gout diagnosis and management] that rheumatologists found most clinically relevant," Dr. Sivera said.

She and her colleagues concluded that "the high level of agreement with the final recommendations and the multinational participation increase their utility and will hopefully facilitate their dissemination and implementation worldwide."

The 3e Gout Program was sponsored by AbbVie. Dr. Sivera reported receiving fees from Menarini for preparing educational presentations, and other authors reported receiving lecture or consulting fees and/or research grants from many companies, including AbbVie. Dr. FitzGerald reported receiving honoraria and grant support from the ACR.

Identification of monosodium urate crystals, either in a joint fluid sample or in a tophi aspirate, should be performed for a definite diagnosis of gout, according to new multinational evidence-based recommendations on the diagnosis and management of the disease.

When identification of monosodium urate (MSU) crystals is not possible, the diagnosis can be supported by classical clinical features such as podagra, tophi, or rapid response to colchicine, or by characteristic imaging findings, Dr. Francisca Sivera of Hospital General Universitario de Elda (Spain) and her colleagues reported on behalf of the 2011 3e (Evidence, Expertise, Exchange) Initiative. The initiative is a multinational collaboration tasked with promoting evidence-based practice in rheumatology through the development of practical recommendations that address relevant clinical issues.

The MSU identification recommendation is one of 10 recommendations developed by 474 rheumatologists from 14 countries who participated in the 2011 3e Initiative. In keeping with 3e protocol, a panel of 78 experts representing the 14 countries developed 10 key clinical questions pertinent to the diagnosis and management of gout, each of which was investigated via extensive literature review. Recommendations for each of the questions were then formulated, debated, and voted on by Initiative participants, and each recommendation was graded based on the level of evidence.

In addition to diagnosis, the gout recommendations address comorbidity screening, acute gout treatment, lifestyle counseling, urate-lowering therapy, flare prophylaxis, the effect of comorbidities on drug selection, patient monitoring, tophi treatment, and management of asymptomatic hyperuricemia (Ann. Rheum. Dis. 2013 July 18 [doi: 10.1136/annrheumdis-2013-203325]).

Specifically, with a high level of agreement that ranged from a mean of 8.1 to 9.2 on a 1-10 scale, the 3e Initiative participants recommended:

• Assessing renal function and cardiovascular risk factors in patients with gout and/or hyperuricemia.

• Treating acute gout with low-dose colchicine, nonsteroidal anti-inflammatory drugs, and/or glucocorticoids, depending on comorbidities and the risk of adverse effects.

• Advising patients about health lifestyle choices.

• Using allopurinol first-line as urate-lowering therapy, and considering uricosurics as alternatives when necessary.

• Educating patients on the risk and management of flares – and using prophylaxis – when introducing urate-lowering therapy.

• Using allopurinol with close monitoring, and starting at a low dose with slow titration, in patients with mild to moderate renal impairment.

• Setting the treatment target for serum urate at below 0.36 mmol/L (6 mg/dL) with eventual absence of gout attacks and resolution of tophi.

• Treating tophi medically by achieving a sustained reduction in serum uric acid, preferably below 0.30 mmol/L (5 mg/dL) and reserving surgery for select cases, such as those involving nerve compression, mechanical impingement, or infection.

• Forgoing pharmacological treatment of asymptomatic hyperuricemia.

The ultimate goal of these recommendations, which were based on 1a-5 evidence levels, and which received recommendation grades ranging from B to D, is to improve patient care, Dr. Sivera said in an interview. The level of evidence and grade of recommendation were made according to the Oxford Centre for Evidence-Based Medicine levels of evidence.

Gout affects up to 2% of men in Western countries, and is associated with morbidity, disability, and poorer quality of life. Despite the availability of a number of guidelines and recommendations, management of the condition is often suboptimal, she said.

"Gout is a curable disease, but evidence shows that many patients are mismanaged with regard to both treatment and diagnosis. Even in a rheumatology clinic, only about a quarter of the patients have a diagnosis of gout established by MSU crystal identification, and in a U.K. study, only one in three patients with a diagnosis of gout were taking urate-lowering therapy," she said.

Research shows that when guidelines are implemented, they improve the quality of care. Educational outreach has an effect on implementation, she said, noting that "both dissemination and education – in both gout and in evidence-based medicine – are an integral part of the 3e Initiative, so these multinational recommendations have the potential to positively influence the standard of care."

The 3e recommendations follow those published in 2012 on behalf of the American College of Rheumatology, which centered on the treatment and prophylaxis of acute gout flares and the appropriate use of urate-lowering therapy.

"Some of the recommendations provided are similar, such as treating to a target serum uric acid level, and the ‘start low, go slow’ approach to allopurinol therapy. This highlights the general consensus on many aspects of the optimal standard of gout management," Dr. Sivera said.

Where the 3e recommendation and the ACR guidelines overlap, there is, indeed, general agreement, Dr. John FitzGerald of the University of California, Los Angeles, said in an interview.

Both processes benefited from Delphi consensus methodologies and systematic literature reviews to inform decision making. However, the two diverge with respect to other aspects of the methodology and presentation, he noted.

"The RAND/UCLA methodology used by ACR resulted in guidelines that were evidence based to be the most efficacious recommendations. As noted, the RAND/UCLA methodology excludes cost of therapy (as typically there are insufficient head-to-head therapeutic cost-efficacy studies on which to base recommendations). The ACR guidelines therefore leave it to the practitioner to use the efficacy-based recommendations, along with their clinical and practical knowledge, to then provide recommendations for specific patients. As an example, allopurinol and febuxostat have relatively similar efficacy but significant cost differences," said Dr. FitzGerald, who co-led the ACR guidelines development project.

"The 3e approach incorporates that next step in decision making to provide evidence-based and practical recommendations to the practitioner," he said.

The ACR effort addressed four specific domains of gout management: treatment of acute gouty attacks, management of urate-lowering therapy, management of chronic tophaceous gout, and prophylaxis of acute gouty attacks. Although the 3e effort focused on 10 specific, clinically relevant questions, it is valuable for other reasons as well, such as the inclusion of diagnosis as part of the recommendations, and the fact that asymptomatic hyperuricemia is addressed, he said, noting that neither of these was addressed by the ACR guidelines.

The 3e recommendations also address the use of benzbromarone, a uricosuric agent that is not available in the United States.

While the 3e effort lacks the extent of detail included in the ACR guidelines, such as the inclusion of specific information on allopurinol dosing, the 3e group is to be commended for the size of the effort, Dr. FitzGerald said, stressing the value of the input from nearly 500 rheumatologists from 14 countries.

Indeed, the extensive effort by "a large group of practicing rheumatologists from many different countries in Europe, South America, and Australasia resulted in the recommendations addressing those aspects [of gout diagnosis and management] that rheumatologists found most clinically relevant," Dr. Sivera said.

She and her colleagues concluded that "the high level of agreement with the final recommendations and the multinational participation increase their utility and will hopefully facilitate their dissemination and implementation worldwide."

The 3e Gout Program was sponsored by AbbVie. Dr. Sivera reported receiving fees from Menarini for preparing educational presentations, and other authors reported receiving lecture or consulting fees and/or research grants from many companies, including AbbVie. Dr. FitzGerald reported receiving honoraria and grant support from the ACR.

Identification of monosodium urate crystals, either in a joint fluid sample or in a tophi aspirate, should be performed for a definite diagnosis of gout, according to new multinational evidence-based recommendations on the diagnosis and management of the disease.

When identification of monosodium urate (MSU) crystals is not possible, the diagnosis can be supported by classical clinical features such as podagra, tophi, or rapid response to colchicine, or by characteristic imaging findings, Dr. Francisca Sivera of Hospital General Universitario de Elda (Spain) and her colleagues reported on behalf of the 2011 3e (Evidence, Expertise, Exchange) Initiative. The initiative is a multinational collaboration tasked with promoting evidence-based practice in rheumatology through the development of practical recommendations that address relevant clinical issues.

The MSU identification recommendation is one of 10 recommendations developed by 474 rheumatologists from 14 countries who participated in the 2011 3e Initiative. In keeping with 3e protocol, a panel of 78 experts representing the 14 countries developed 10 key clinical questions pertinent to the diagnosis and management of gout, each of which was investigated via extensive literature review. Recommendations for each of the questions were then formulated, debated, and voted on by Initiative participants, and each recommendation was graded based on the level of evidence.

In addition to diagnosis, the gout recommendations address comorbidity screening, acute gout treatment, lifestyle counseling, urate-lowering therapy, flare prophylaxis, the effect of comorbidities on drug selection, patient monitoring, tophi treatment, and management of asymptomatic hyperuricemia (Ann. Rheum. Dis. 2013 July 18 [doi: 10.1136/annrheumdis-2013-203325]).

Specifically, with a high level of agreement that ranged from a mean of 8.1 to 9.2 on a 1-10 scale, the 3e Initiative participants recommended:

• Assessing renal function and cardiovascular risk factors in patients with gout and/or hyperuricemia.

• Treating acute gout with low-dose colchicine, nonsteroidal anti-inflammatory drugs, and/or glucocorticoids, depending on comorbidities and the risk of adverse effects.

• Advising patients about health lifestyle choices.

• Using allopurinol first-line as urate-lowering therapy, and considering uricosurics as alternatives when necessary.

• Educating patients on the risk and management of flares – and using prophylaxis – when introducing urate-lowering therapy.

• Using allopurinol with close monitoring, and starting at a low dose with slow titration, in patients with mild to moderate renal impairment.

• Setting the treatment target for serum urate at below 0.36 mmol/L (6 mg/dL) with eventual absence of gout attacks and resolution of tophi.

• Treating tophi medically by achieving a sustained reduction in serum uric acid, preferably below 0.30 mmol/L (5 mg/dL) and reserving surgery for select cases, such as those involving nerve compression, mechanical impingement, or infection.

• Forgoing pharmacological treatment of asymptomatic hyperuricemia.

The ultimate goal of these recommendations, which were based on 1a-5 evidence levels, and which received recommendation grades ranging from B to D, is to improve patient care, Dr. Sivera said in an interview. The level of evidence and grade of recommendation were made according to the Oxford Centre for Evidence-Based Medicine levels of evidence.

Gout affects up to 2% of men in Western countries, and is associated with morbidity, disability, and poorer quality of life. Despite the availability of a number of guidelines and recommendations, management of the condition is often suboptimal, she said.

"Gout is a curable disease, but evidence shows that many patients are mismanaged with regard to both treatment and diagnosis. Even in a rheumatology clinic, only about a quarter of the patients have a diagnosis of gout established by MSU crystal identification, and in a U.K. study, only one in three patients with a diagnosis of gout were taking urate-lowering therapy," she said.

Research shows that when guidelines are implemented, they improve the quality of care. Educational outreach has an effect on implementation, she said, noting that "both dissemination and education – in both gout and in evidence-based medicine – are an integral part of the 3e Initiative, so these multinational recommendations have the potential to positively influence the standard of care."

The 3e recommendations follow those published in 2012 on behalf of the American College of Rheumatology, which centered on the treatment and prophylaxis of acute gout flares and the appropriate use of urate-lowering therapy.

"Some of the recommendations provided are similar, such as treating to a target serum uric acid level, and the ‘start low, go slow’ approach to allopurinol therapy. This highlights the general consensus on many aspects of the optimal standard of gout management," Dr. Sivera said.

Where the 3e recommendation and the ACR guidelines overlap, there is, indeed, general agreement, Dr. John FitzGerald of the University of California, Los Angeles, said in an interview.

Both processes benefited from Delphi consensus methodologies and systematic literature reviews to inform decision making. However, the two diverge with respect to other aspects of the methodology and presentation, he noted.

"The RAND/UCLA methodology used by ACR resulted in guidelines that were evidence based to be the most efficacious recommendations. As noted, the RAND/UCLA methodology excludes cost of therapy (as typically there are insufficient head-to-head therapeutic cost-efficacy studies on which to base recommendations). The ACR guidelines therefore leave it to the practitioner to use the efficacy-based recommendations, along with their clinical and practical knowledge, to then provide recommendations for specific patients. As an example, allopurinol and febuxostat have relatively similar efficacy but significant cost differences," said Dr. FitzGerald, who co-led the ACR guidelines development project.

"The 3e approach incorporates that next step in decision making to provide evidence-based and practical recommendations to the practitioner," he said.

The ACR effort addressed four specific domains of gout management: treatment of acute gouty attacks, management of urate-lowering therapy, management of chronic tophaceous gout, and prophylaxis of acute gouty attacks. Although the 3e effort focused on 10 specific, clinically relevant questions, it is valuable for other reasons as well, such as the inclusion of diagnosis as part of the recommendations, and the fact that asymptomatic hyperuricemia is addressed, he said, noting that neither of these was addressed by the ACR guidelines.

The 3e recommendations also address the use of benzbromarone, a uricosuric agent that is not available in the United States.

While the 3e effort lacks the extent of detail included in the ACR guidelines, such as the inclusion of specific information on allopurinol dosing, the 3e group is to be commended for the size of the effort, Dr. FitzGerald said, stressing the value of the input from nearly 500 rheumatologists from 14 countries.

Indeed, the extensive effort by "a large group of practicing rheumatologists from many different countries in Europe, South America, and Australasia resulted in the recommendations addressing those aspects [of gout diagnosis and management] that rheumatologists found most clinically relevant," Dr. Sivera said.

She and her colleagues concluded that "the high level of agreement with the final recommendations and the multinational participation increase their utility and will hopefully facilitate their dissemination and implementation worldwide."

The 3e Gout Program was sponsored by AbbVie. Dr. Sivera reported receiving fees from Menarini for preparing educational presentations, and other authors reported receiving lecture or consulting fees and/or research grants from many companies, including AbbVie. Dr. FitzGerald reported receiving honoraria and grant support from the ACR.

MADRID – Optimizing anti-inflammatory treatment may help to reduce the risk of heart-related problems in men with crystal-proven gout, judging from 7-year follow up data from a prospective study.

Five factors were found to increase substantially the risk for cardiovascular (CV) events in the 251-patient study: including: high levels of C-reactive protein (CRP); renal insufficiency; daily intake of more than 20 g of alcohol; current coronary heart disease (CHD); and a family history of premature CV events.

The odds ratio (OR) for any CV event was 5.71 for CRP levels greater than 5 mg/L on multivariate analysis. This increased to 10.31 and 14.26 when nonfatal and fatal CV events were considered separately.

Odds ratios for renal insufficiency, defined as a creatinine clearance of less than 60 mL/min per 1.73 m², were 4.76 for any CV event and 8.42 for fatal CV events. Respective values for a family history of CV events before the age of 55 years was 3.09 considering any CV event, but 7.53 if consideration was limited to fatal events only. Current CHD also increased the risk for any CV event (OR, 3.67) and for nonfatal events (OR, 10.41).

Alcohol intake of more than 20g/day carried an OR of 4.23 for any CV event.

"We have a cardiologist in our team to ensure the reliability of the cardiovascular outcomes," said Dr. Victoria Barskova of the Research Institute of Rheumatology in Moscow, who presented the findings at the annual European Congress of Rheumatology (Ann. Rheum. Dis. 2013;72[suppl. 3]:95). She explained that the study was designed to prospectively determine baseline factors that might influence the development of CV events in male patients with crystal-proven gout.

Between 2003 and 2006, a total of 407 men were screened and 301 deemed eligible for the study. Of these, 251 had follow-up data to 2010-2012. Data collected at baseline and at follow-up included patient demographics, including family history of gout and early CV disease, smoking history, and alcohol consumption. Comorbidities and gout characteristics were also assessed and all patients had an ECG and echocardiogram.

Comparing baseline clinical features with follow-up visit data, Dr. Barskova noted that the number of allopurinol users increased from 16% to 57% (P = .00001), although regular allopurinol use was not found to decrease the risk for CV events.

There was an increase in the percentage of patients with diabetes from 18% to 43% (P = .00001), chronic heart disease from 35% to 53% (P = .00001), and heart failure from 10% to 28% (P = .0001). Alcohol use significantly decreased (92% vs. 63%; P less than .0001).

The frequency of subcutaneous tophi and chronic arthritis comparing the first and last visits was the same.

Just under a quarter (23.1%, n = 58) of patients experienced a CV event. There were 32 (13%) deaths reported of which 22 were from cardiovascular causes. There were 36 nonfatal CV events.

"In our cohort of patients with crystal proven gout, the following independent risk factors for all CV events have been highlighted: CRP, renal insufficiency, alcohol intake, coronary heart disease, and a family history of CV events," Dr. Barskova said in conclusion.

The key message for rheumatologists, she added, is that "tight control of inflammation, which is measured not only by the obvious arthritis, but also by the serum CRP level, may have a positive effect on cardiovascular events in patients with gout."

MADRID – Optimizing anti-inflammatory treatment may help to reduce the risk of heart-related problems in men with crystal-proven gout, judging from 7-year follow up data from a prospective study.

Five factors were found to increase substantially the risk for cardiovascular (CV) events in the 251-patient study: including: high levels of C-reactive protein (CRP); renal insufficiency; daily intake of more than 20 g of alcohol; current coronary heart disease (CHD); and a family history of premature CV events.

The odds ratio (OR) for any CV event was 5.71 for CRP levels greater than 5 mg/L on multivariate analysis. This increased to 10.31 and 14.26 when nonfatal and fatal CV events were considered separately.

Odds ratios for renal insufficiency, defined as a creatinine clearance of less than 60 mL/min per 1.73 m², were 4.76 for any CV event and 8.42 for fatal CV events. Respective values for a family history of CV events before the age of 55 years was 3.09 considering any CV event, but 7.53 if consideration was limited to fatal events only. Current CHD also increased the risk for any CV event (OR, 3.67) and for nonfatal events (OR, 10.41).

Alcohol intake of more than 20g/day carried an OR of 4.23 for any CV event.

"We have a cardiologist in our team to ensure the reliability of the cardiovascular outcomes," said Dr. Victoria Barskova of the Research Institute of Rheumatology in Moscow, who presented the findings at the annual European Congress of Rheumatology (Ann. Rheum. Dis. 2013;72[suppl. 3]:95). She explained that the study was designed to prospectively determine baseline factors that might influence the development of CV events in male patients with crystal-proven gout.

Between 2003 and 2006, a total of 407 men were screened and 301 deemed eligible for the study. Of these, 251 had follow-up data to 2010-2012. Data collected at baseline and at follow-up included patient demographics, including family history of gout and early CV disease, smoking history, and alcohol consumption. Comorbidities and gout characteristics were also assessed and all patients had an ECG and echocardiogram.

Comparing baseline clinical features with follow-up visit data, Dr. Barskova noted that the number of allopurinol users increased from 16% to 57% (P = .00001), although regular allopurinol use was not found to decrease the risk for CV events.

There was an increase in the percentage of patients with diabetes from 18% to 43% (P = .00001), chronic heart disease from 35% to 53% (P = .00001), and heart failure from 10% to 28% (P = .0001). Alcohol use significantly decreased (92% vs. 63%; P less than .0001).

The frequency of subcutaneous tophi and chronic arthritis comparing the first and last visits was the same.

Just under a quarter (23.1%, n = 58) of patients experienced a CV event. There were 32 (13%) deaths reported of which 22 were from cardiovascular causes. There were 36 nonfatal CV events.

"In our cohort of patients with crystal proven gout, the following independent risk factors for all CV events have been highlighted: CRP, renal insufficiency, alcohol intake, coronary heart disease, and a family history of CV events," Dr. Barskova said in conclusion.

The key message for rheumatologists, she added, is that "tight control of inflammation, which is measured not only by the obvious arthritis, but also by the serum CRP level, may have a positive effect on cardiovascular events in patients with gout."

MADRID – Optimizing anti-inflammatory treatment may help to reduce the risk of heart-related problems in men with crystal-proven gout, judging from 7-year follow up data from a prospective study.

Five factors were found to increase substantially the risk for cardiovascular (CV) events in the 251-patient study: including: high levels of C-reactive protein (CRP); renal insufficiency; daily intake of more than 20 g of alcohol; current coronary heart disease (CHD); and a family history of premature CV events.

The odds ratio (OR) for any CV event was 5.71 for CRP levels greater than 5 mg/L on multivariate analysis. This increased to 10.31 and 14.26 when nonfatal and fatal CV events were considered separately.

Odds ratios for renal insufficiency, defined as a creatinine clearance of less than 60 mL/min per 1.73 m², were 4.76 for any CV event and 8.42 for fatal CV events. Respective values for a family history of CV events before the age of 55 years was 3.09 considering any CV event, but 7.53 if consideration was limited to fatal events only. Current CHD also increased the risk for any CV event (OR, 3.67) and for nonfatal events (OR, 10.41).

Alcohol intake of more than 20g/day carried an OR of 4.23 for any CV event.

"We have a cardiologist in our team to ensure the reliability of the cardiovascular outcomes," said Dr. Victoria Barskova of the Research Institute of Rheumatology in Moscow, who presented the findings at the annual European Congress of Rheumatology (Ann. Rheum. Dis. 2013;72[suppl. 3]:95). She explained that the study was designed to prospectively determine baseline factors that might influence the development of CV events in male patients with crystal-proven gout.

Between 2003 and 2006, a total of 407 men were screened and 301 deemed eligible for the study. Of these, 251 had follow-up data to 2010-2012. Data collected at baseline and at follow-up included patient demographics, including family history of gout and early CV disease, smoking history, and alcohol consumption. Comorbidities and gout characteristics were also assessed and all patients had an ECG and echocardiogram.

Comparing baseline clinical features with follow-up visit data, Dr. Barskova noted that the number of allopurinol users increased from 16% to 57% (P = .00001), although regular allopurinol use was not found to decrease the risk for CV events.

There was an increase in the percentage of patients with diabetes from 18% to 43% (P = .00001), chronic heart disease from 35% to 53% (P = .00001), and heart failure from 10% to 28% (P = .0001). Alcohol use significantly decreased (92% vs. 63%; P less than .0001).

The frequency of subcutaneous tophi and chronic arthritis comparing the first and last visits was the same.

Just under a quarter (23.1%, n = 58) of patients experienced a CV event. There were 32 (13%) deaths reported of which 22 were from cardiovascular causes. There were 36 nonfatal CV events.

"In our cohort of patients with crystal proven gout, the following independent risk factors for all CV events have been highlighted: CRP, renal insufficiency, alcohol intake, coronary heart disease, and a family history of CV events," Dr. Barskova said in conclusion.

The key message for rheumatologists, she added, is that "tight control of inflammation, which is measured not only by the obvious arthritis, but also by the serum CRP level, may have a positive effect on cardiovascular events in patients with gout."

SAN FRANCISCO – The venerable antihyperuricemic agent allopurinol has shown early promise for two novel cardiovascular applications: prevention of atrial fibrillation in the setting of heart failure and reduction of left ventricular hypertrophy in patients with type 2 diabetes.

Allopurinol is a xanthine oxidase inhibitor and antigout drug. The rationale for the drug’s use in reducing the incidence of atrial fibrillation in patients with heart failure lies in the observation that serum uric acid has emerged as an independent marker of mortality and a predictor of new-onset atrial fibrillation in heart failure. Xanthine oxidase is not only a source of reactive oxygen species that adversely affect myocardial function, but it also catalyzes the conversion of xanthine to uric acid, Dr. Fernando E. Hernandez explained at the annual meeting of the American College of Cardiology.

He presented a retrospective cohort study involving 603 patients enrolled in the Miami Veterans Affairs heart failure clinic. The 103 on allopurinol, and the 500 who were not, matched up well in terms of baseline characteristics including age, prevalence of coronary artery disease, median left ventricular ejection, left atrial size, and use of guideline-recommended ACE inhibitors and beta-blockers.

During up to 5 years of follow-up, the incidence of new-onset atrial fibrillation was 184 cases/1,000 person-years in the allopurinol users compared with 252/1,000 person-years in controls. In a Cox proportional hazards analysis adjusted for small differences in potential confounders, the use of allopurinol was independently associated with a 47% reduction in the risk of atrial fibrillation (P = .04), reported Dr. Hernandez of the University of Miami.

This intriguing finding needs to be confirmed in randomized prospective trials, he noted.

In a separate presentation, Dr. Benjamin R. Szwejkowski noted that left ventricular hypertrophy (LVH) is common in patients with type 2 diabetes and contributes to their elevated risk of cardiovascular morbidity and mortality.

Based on their hypothesis that LVH is related in part to oxidative stress and reducing that stress via xanthine oxidase inhibition using allopurinol can cause LVH regression, the investigators conducted a randomized, double-blind placebo-controlled clinical trial. Sixty-six patients with type 2 diabetes and echocardiographic evidence of LVH were randomized to allopurinol at 600 mg/day or placebo for 9 months.

The primary study endpoint was change in left ventricular mass between baseline and 9 months, as measured by cardiac MRI. Allopurinol resulted in a significant mean 2.65-g reduction in LV mass, while in the control group LV mass increased by 1.21 g. Similarly, LV mass indexed to body surface area fell significantly by 1.32 g/m² in the allopurinol group while increasing by 0.65 g/m² in the placebo arm, reported Dr. Szwejkowski of the University of Dundee(Scotland).

"Allopurinol may be a useful therapy to reduce cardiovascular risk in type 2 diabetic patients with LVH," according to the cardiologist.

Flow-mediated dilatation didn’t change significantly over time in either study group.

Dr. Szwejkowski and Dr. Hernandez reported having no relevant financial conflicts.

[email protected]

SAN FRANCISCO – The venerable antihyperuricemic agent allopurinol has shown early promise for two novel cardiovascular applications: prevention of atrial fibrillation in the setting of heart failure and reduction of left ventricular hypertrophy in patients with type 2 diabetes.

Allopurinol is a xanthine oxidase inhibitor and antigout drug. The rationale for the drug’s use in reducing the incidence of atrial fibrillation in patients with heart failure lies in the observation that serum uric acid has emerged as an independent marker of mortality and a predictor of new-onset atrial fibrillation in heart failure. Xanthine oxidase is not only a source of reactive oxygen species that adversely affect myocardial function, but it also catalyzes the conversion of xanthine to uric acid, Dr. Fernando E. Hernandez explained at the annual meeting of the American College of Cardiology.

He presented a retrospective cohort study involving 603 patients enrolled in the Miami Veterans Affairs heart failure clinic. The 103 on allopurinol, and the 500 who were not, matched up well in terms of baseline characteristics including age, prevalence of coronary artery disease, median left ventricular ejection, left atrial size, and use of guideline-recommended ACE inhibitors and beta-blockers.

During up to 5 years of follow-up, the incidence of new-onset atrial fibrillation was 184 cases/1,000 person-years in the allopurinol users compared with 252/1,000 person-years in controls. In a Cox proportional hazards analysis adjusted for small differences in potential confounders, the use of allopurinol was independently associated with a 47% reduction in the risk of atrial fibrillation (P = .04), reported Dr. Hernandez of the University of Miami.

This intriguing finding needs to be confirmed in randomized prospective trials, he noted.

In a separate presentation, Dr. Benjamin R. Szwejkowski noted that left ventricular hypertrophy (LVH) is common in patients with type 2 diabetes and contributes to their elevated risk of cardiovascular morbidity and mortality.

Based on their hypothesis that LVH is related in part to oxidative stress and reducing that stress via xanthine oxidase inhibition using allopurinol can cause LVH regression, the investigators conducted a randomized, double-blind placebo-controlled clinical trial. Sixty-six patients with type 2 diabetes and echocardiographic evidence of LVH were randomized to allopurinol at 600 mg/day or placebo for 9 months.

The primary study endpoint was change in left ventricular mass between baseline and 9 months, as measured by cardiac MRI. Allopurinol resulted in a significant mean 2.65-g reduction in LV mass, while in the control group LV mass increased by 1.21 g. Similarly, LV mass indexed to body surface area fell significantly by 1.32 g/m² in the allopurinol group while increasing by 0.65 g/m² in the placebo arm, reported Dr. Szwejkowski of the University of Dundee(Scotland).

"Allopurinol may be a useful therapy to reduce cardiovascular risk in type 2 diabetic patients with LVH," according to the cardiologist.

Flow-mediated dilatation didn’t change significantly over time in either study group.

Dr. Szwejkowski and Dr. Hernandez reported having no relevant financial conflicts.

[email protected]

SAN FRANCISCO – The venerable antihyperuricemic agent allopurinol has shown early promise for two novel cardiovascular applications: prevention of atrial fibrillation in the setting of heart failure and reduction of left ventricular hypertrophy in patients with type 2 diabetes.

Allopurinol is a xanthine oxidase inhibitor and antigout drug. The rationale for the drug’s use in reducing the incidence of atrial fibrillation in patients with heart failure lies in the observation that serum uric acid has emerged as an independent marker of mortality and a predictor of new-onset atrial fibrillation in heart failure. Xanthine oxidase is not only a source of reactive oxygen species that adversely affect myocardial function, but it also catalyzes the conversion of xanthine to uric acid, Dr. Fernando E. Hernandez explained at the annual meeting of the American College of Cardiology.

He presented a retrospective cohort study involving 603 patients enrolled in the Miami Veterans Affairs heart failure clinic. The 103 on allopurinol, and the 500 who were not, matched up well in terms of baseline characteristics including age, prevalence of coronary artery disease, median left ventricular ejection, left atrial size, and use of guideline-recommended ACE inhibitors and beta-blockers.

During up to 5 years of follow-up, the incidence of new-onset atrial fibrillation was 184 cases/1,000 person-years in the allopurinol users compared with 252/1,000 person-years in controls. In a Cox proportional hazards analysis adjusted for small differences in potential confounders, the use of allopurinol was independently associated with a 47% reduction in the risk of atrial fibrillation (P = .04), reported Dr. Hernandez of the University of Miami.

This intriguing finding needs to be confirmed in randomized prospective trials, he noted.

In a separate presentation, Dr. Benjamin R. Szwejkowski noted that left ventricular hypertrophy (LVH) is common in patients with type 2 diabetes and contributes to their elevated risk of cardiovascular morbidity and mortality.

Based on their hypothesis that LVH is related in part to oxidative stress and reducing that stress via xanthine oxidase inhibition using allopurinol can cause LVH regression, the investigators conducted a randomized, double-blind placebo-controlled clinical trial. Sixty-six patients with type 2 diabetes and echocardiographic evidence of LVH were randomized to allopurinol at 600 mg/day or placebo for 9 months.

The primary study endpoint was change in left ventricular mass between baseline and 9 months, as measured by cardiac MRI. Allopurinol resulted in a significant mean 2.65-g reduction in LV mass, while in the control group LV mass increased by 1.21 g. Similarly, LV mass indexed to body surface area fell significantly by 1.32 g/m² in the allopurinol group while increasing by 0.65 g/m² in the placebo arm, reported Dr. Szwejkowski of the University of Dundee(Scotland).

"Allopurinol may be a useful therapy to reduce cardiovascular risk in type 2 diabetic patients with LVH," according to the cardiologist.

Flow-mediated dilatation didn’t change significantly over time in either study group.

Dr. Szwejkowski and Dr. Hernandez reported having no relevant financial conflicts.

[email protected]

WASHINGTON – Gout does occur in patients with rheumatoid arthritis, though at a lower rate than in the general population, Dr. Adlene Jebakumar said at the annual meeting of the American College of Rheumatology.

This finding comes from a review of a population-based cohort of 813 people diagnosed with rheumatoid arthritis (RA) between 1980 and 2007. Diagnoses were made either clinically including typical monosodium urate crystal positivity in synovial fluid or 1977 criteria developed by an ACR precursor organization, the American Rheumatology Association criteria. All subjects were longitudinally followed through their complete community medical records until April 2012 or they died or moved away.

Of the study cohort, 537 (66%) were rheumatoid factor positive; 33% had rheumatoid nodules, and 53% had erosive joint disease. During 9,771 total person-years of follow-up (mean 12 years per RA patient), 22 patients developed gout as defined by clinical criteria. The great toe was the most common site of gout (12 of 22 patients). The 25-year cumulative incidence of gout diagnosed by clinical criteria was 5.3%. Typical intracellular monosodium urate crystals were present in 9 of 22 patients with acute gout; all had developed gout after the RA incidence date. The 25-year cumulative incidence of gout diagnosed by clinical criteria including presence of urate crystals is 1.3%. The prevalence of gout in RA on Jan 1, 2008, was 1.9% (11 of 582 patients) as opposed to expected prevalence of 5.2% (or 30 patients) based on National Health and Nutrition Examination Survey data using age and sex-specific prevalence rates.

Risk factors for gout in RA were: older age (hazard ratio, 1.5/10-year increase; P = .04), male sex (HR, 3.18; P = .03) and obesity (HR, 3.5; P = .03). The presence of erosive RA joint disease reduced the risk of gout (HR, 0.24; P = .03). Gout has become more common in patients diagnosed with RA in recent years (1995-2007) than in previous years (1980-1994; HR, 5.6; P = .007).

Dr. Eric L. Matteson noted in an interview that when an RA patient develops a hot and tender big toe, rheumatologists are likely to presume it is an RA flare. In part, this is because there is a myth in rheumatology that patients with RA cannot get gout, Dr. Eric L. Matteson noted in an interview. The literature contains reports of only 30 such cases. In fact, as the study findings show, that hot and tender toe may be gout. The best course of action is to aspirate the toe joint and look at the synovial fluid for crystals.

The treatment of gout in an RA patient can involve administration of prednisone, anakinra, allopurinol, or febuxostat. Drug-drug interactions between the agents used to treat gout and those for RA may be a problem in some cases.

Some of the treatments used in RA may explain why there are so few gout flares in RA patients. High doses of aspirin, which are an RA treatment, significantly lower uric acid levels. In what he described as being speculation, Dr. Matteson, chair of the department of rheumatology at the Mayo Clinic, Rochester, Minn., suggested that the "push away" from use of NSAIDs long term and in high doses to help manage RA may be resulting in more gout flares in these patients.

Dr. Jebakumar and Dr. Matteson reported having no relevant financial conflicts of interest.

WASHINGTON – Gout does occur in patients with rheumatoid arthritis, though at a lower rate than in the general population, Dr. Adlene Jebakumar said at the annual meeting of the American College of Rheumatology.

This finding comes from a review of a population-based cohort of 813 people diagnosed with rheumatoid arthritis (RA) between 1980 and 2007. Diagnoses were made either clinically including typical monosodium urate crystal positivity in synovial fluid or 1977 criteria developed by an ACR precursor organization, the American Rheumatology Association criteria. All subjects were longitudinally followed through their complete community medical records until April 2012 or they died or moved away.

Of the study cohort, 537 (66%) were rheumatoid factor positive; 33% had rheumatoid nodules, and 53% had erosive joint disease. During 9,771 total person-years of follow-up (mean 12 years per RA patient), 22 patients developed gout as defined by clinical criteria. The great toe was the most common site of gout (12 of 22 patients). The 25-year cumulative incidence of gout diagnosed by clinical criteria was 5.3%. Typical intracellular monosodium urate crystals were present in 9 of 22 patients with acute gout; all had developed gout after the RA incidence date. The 25-year cumulative incidence of gout diagnosed by clinical criteria including presence of urate crystals is 1.3%. The prevalence of gout in RA on Jan 1, 2008, was 1.9% (11 of 582 patients) as opposed to expected prevalence of 5.2% (or 30 patients) based on National Health and Nutrition Examination Survey data using age and sex-specific prevalence rates.

Risk factors for gout in RA were: older age (hazard ratio, 1.5/10-year increase; P = .04), male sex (HR, 3.18; P = .03) and obesity (HR, 3.5; P = .03). The presence of erosive RA joint disease reduced the risk of gout (HR, 0.24; P = .03). Gout has become more common in patients diagnosed with RA in recent years (1995-2007) than in previous years (1980-1994; HR, 5.6; P = .007).

Dr. Eric L. Matteson noted in an interview that when an RA patient develops a hot and tender big toe, rheumatologists are likely to presume it is an RA flare. In part, this is because there is a myth in rheumatology that patients with RA cannot get gout, Dr. Eric L. Matteson noted in an interview. The literature contains reports of only 30 such cases. In fact, as the study findings show, that hot and tender toe may be gout. The best course of action is to aspirate the toe joint and look at the synovial fluid for crystals.

The treatment of gout in an RA patient can involve administration of prednisone, anakinra, allopurinol, or febuxostat. Drug-drug interactions between the agents used to treat gout and those for RA may be a problem in some cases.

Some of the treatments used in RA may explain why there are so few gout flares in RA patients. High doses of aspirin, which are an RA treatment, significantly lower uric acid levels. In what he described as being speculation, Dr. Matteson, chair of the department of rheumatology at the Mayo Clinic, Rochester, Minn., suggested that the "push away" from use of NSAIDs long term and in high doses to help manage RA may be resulting in more gout flares in these patients.

Dr. Jebakumar and Dr. Matteson reported having no relevant financial conflicts of interest.

WASHINGTON – Gout does occur in patients with rheumatoid arthritis, though at a lower rate than in the general population, Dr. Adlene Jebakumar said at the annual meeting of the American College of Rheumatology.

This finding comes from a review of a population-based cohort of 813 people diagnosed with rheumatoid arthritis (RA) between 1980 and 2007. Diagnoses were made either clinically including typical monosodium urate crystal positivity in synovial fluid or 1977 criteria developed by an ACR precursor organization, the American Rheumatology Association criteria. All subjects were longitudinally followed through their complete community medical records until April 2012 or they died or moved away.

Of the study cohort, 537 (66%) were rheumatoid factor positive; 33% had rheumatoid nodules, and 53% had erosive joint disease. During 9,771 total person-years of follow-up (mean 12 years per RA patient), 22 patients developed gout as defined by clinical criteria. The great toe was the most common site of gout (12 of 22 patients). The 25-year cumulative incidence of gout diagnosed by clinical criteria was 5.3%. Typical intracellular monosodium urate crystals were present in 9 of 22 patients with acute gout; all had developed gout after the RA incidence date. The 25-year cumulative incidence of gout diagnosed by clinical criteria including presence of urate crystals is 1.3%. The prevalence of gout in RA on Jan 1, 2008, was 1.9% (11 of 582 patients) as opposed to expected prevalence of 5.2% (or 30 patients) based on National Health and Nutrition Examination Survey data using age and sex-specific prevalence rates.

Risk factors for gout in RA were: older age (hazard ratio, 1.5/10-year increase; P = .04), male sex (HR, 3.18; P = .03) and obesity (HR, 3.5; P = .03). The presence of erosive RA joint disease reduced the risk of gout (HR, 0.24; P = .03). Gout has become more common in patients diagnosed with RA in recent years (1995-2007) than in previous years (1980-1994; HR, 5.6; P = .007).

Dr. Eric L. Matteson noted in an interview that when an RA patient develops a hot and tender big toe, rheumatologists are likely to presume it is an RA flare. In part, this is because there is a myth in rheumatology that patients with RA cannot get gout, Dr. Eric L. Matteson noted in an interview. The literature contains reports of only 30 such cases. In fact, as the study findings show, that hot and tender toe may be gout. The best course of action is to aspirate the toe joint and look at the synovial fluid for crystals.

The treatment of gout in an RA patient can involve administration of prednisone, anakinra, allopurinol, or febuxostat. Drug-drug interactions between the agents used to treat gout and those for RA may be a problem in some cases.

Some of the treatments used in RA may explain why there are so few gout flares in RA patients. High doses of aspirin, which are an RA treatment, significantly lower uric acid levels. In what he described as being speculation, Dr. Matteson, chair of the department of rheumatology at the Mayo Clinic, Rochester, Minn., suggested that the "push away" from use of NSAIDs long term and in high doses to help manage RA may be resulting in more gout flares in these patients.

Dr. Jebakumar and Dr. Matteson reported having no relevant financial conflicts of interest.

NEWPORT BEACH, CALIF. – Most gout patients need more than the standard and widely used dose of 300 mg/day of allopurinol to lower their serum urate level enough to prevent flares, according to gout expert Dr. Brian Mandell.

Probably more than half of people need more than 300 mg "if you are going to get to the target level of [6 mg/dL serum urate or lower]. Most people probably need closer to 400 mg," he said (Ann. Rheum. Dis. 1998;57:545-9).

A good target serum urate level is 6 mg/dL. "If you’re at 6, the urate is unlikely to precipitate, [and] you really do dramatically decrease the frequency of attacks," he said at Perspectives in Rheumatic Diseases 2012, held by Global Academy for Medical Education. GAME and this news organization are owned by Frontline Medical Communications.

In a bid to get physicians to use a treat-to-target approach in gout management, Dr. Mandell noted that "you can only treat urate successfully if you measure it after you start therapy," something not all clinicians do. "The correct dose is the dose that drops your urate," said Dr. Mandell, professor and chair of medicine at the Cleveland Clinic.

To avoid triggering a gout flare from too-abrupt urate lowering and to help avoid hypersensitivity reactions, "I always start low at 50 mg/dL" and titrate upward, he said.

"There’s no rush in trying to drop the level. It’s a lifelong disease." When counseling patients about hypersensitivity reactions, Dr. Mandell said that he advises them to stop the drug as soon as they notice a rash and then call him.

Pegylated uricase is "incredibly effective for lowering serum urate," as well, he said. When pegylated uricase is "given as an IV infusion, serum urate plummets to about 0.5 mg/dL and stays down for 2 weeks or longer," Dr. Mandell noted.

Patients should be warned, however, of the risk of flares with the quick urate drop. Also, if they don’t have such a robust response, it probably means they have antibodies to pegylated uricase, which also increases their risk of an infusion reaction. In that case, "stop the drug," he said.

For management of an acute gout attack, Dr. Mandell said he often chooses anakinra (Kineret) so long as patients are in the hospital and can be monitored for infections and other potential problems.

Indomethacin is another option. In fact, "any NSAID will work if you use high enough doses. You need to treat until the attack resolves and then for a couple days longer to really make sure the attack is gone," he advised.

Colchicine can work "if you catch the attack early, but it’s not a panacea. It’s a great drug for prophylaxis but not to treat acute attacks," he said.

Narcotics don’t work well on inflammatory pain and so are not a good choice for an acute attack, Dr. Mandell noted.

A normal serum urate level does not necessarily rule out a gout attack. "Stick a needle in the joint at some point in time to make sure gout is the diagnosis," he said.

Dr. Mandell is a consultant for Novartis, Pfizer, Takeda, and other companies.

SDEF and this news organization are owned by Frontline Medical Communications.

NEWPORT BEACH, CALIF. – Most gout patients need more than the standard and widely used dose of 300 mg/day of allopurinol to lower their serum urate level enough to prevent flares, according to gout expert Dr. Brian Mandell.

Probably more than half of people need more than 300 mg "if you are going to get to the target level of [6 mg/dL serum urate or lower]. Most people probably need closer to 400 mg," he said (Ann. Rheum. Dis. 1998;57:545-9).

A good target serum urate level is 6 mg/dL. "If you’re at 6, the urate is unlikely to precipitate, [and] you really do dramatically decrease the frequency of attacks," he said at Perspectives in Rheumatic Diseases 2012, held by Global Academy for Medical Education. GAME and this news organization are owned by Frontline Medical Communications.

In a bid to get physicians to use a treat-to-target approach in gout management, Dr. Mandell noted that "you can only treat urate successfully if you measure it after you start therapy," something not all clinicians do. "The correct dose is the dose that drops your urate," said Dr. Mandell, professor and chair of medicine at the Cleveland Clinic.

To avoid triggering a gout flare from too-abrupt urate lowering and to help avoid hypersensitivity reactions, "I always start low at 50 mg/dL" and titrate upward, he said.

"There’s no rush in trying to drop the level. It’s a lifelong disease." When counseling patients about hypersensitivity reactions, Dr. Mandell said that he advises them to stop the drug as soon as they notice a rash and then call him.

Pegylated uricase is "incredibly effective for lowering serum urate," as well, he said. When pegylated uricase is "given as an IV infusion, serum urate plummets to about 0.5 mg/dL and stays down for 2 weeks or longer," Dr. Mandell noted.

Patients should be warned, however, of the risk of flares with the quick urate drop. Also, if they don’t have such a robust response, it probably means they have antibodies to pegylated uricase, which also increases their risk of an infusion reaction. In that case, "stop the drug," he said.

For management of an acute gout attack, Dr. Mandell said he often chooses anakinra (Kineret) so long as patients are in the hospital and can be monitored for infections and other potential problems.

Indomethacin is another option. In fact, "any NSAID will work if you use high enough doses. You need to treat until the attack resolves and then for a couple days longer to really make sure the attack is gone," he advised.

Colchicine can work "if you catch the attack early, but it’s not a panacea. It’s a great drug for prophylaxis but not to treat acute attacks," he said.

Narcotics don’t work well on inflammatory pain and so are not a good choice for an acute attack, Dr. Mandell noted.

A normal serum urate level does not necessarily rule out a gout attack. "Stick a needle in the joint at some point in time to make sure gout is the diagnosis," he said.

Dr. Mandell is a consultant for Novartis, Pfizer, Takeda, and other companies.

SDEF and this news organization are owned by Frontline Medical Communications.

NEWPORT BEACH, CALIF. – Most gout patients need more than the standard and widely used dose of 300 mg/day of allopurinol to lower their serum urate level enough to prevent flares, according to gout expert Dr. Brian Mandell.

Probably more than half of people need more than 300 mg "if you are going to get to the target level of [6 mg/dL serum urate or lower]. Most people probably need closer to 400 mg," he said (Ann. Rheum. Dis. 1998;57:545-9).

A good target serum urate level is 6 mg/dL. "If you’re at 6, the urate is unlikely to precipitate, [and] you really do dramatically decrease the frequency of attacks," he said at Perspectives in Rheumatic Diseases 2012, held by Global Academy for Medical Education. GAME and this news organization are owned by Frontline Medical Communications.

In a bid to get physicians to use a treat-to-target approach in gout management, Dr. Mandell noted that "you can only treat urate successfully if you measure it after you start therapy," something not all clinicians do. "The correct dose is the dose that drops your urate," said Dr. Mandell, professor and chair of medicine at the Cleveland Clinic.

To avoid triggering a gout flare from too-abrupt urate lowering and to help avoid hypersensitivity reactions, "I always start low at 50 mg/dL" and titrate upward, he said.

"There’s no rush in trying to drop the level. It’s a lifelong disease." When counseling patients about hypersensitivity reactions, Dr. Mandell said that he advises them to stop the drug as soon as they notice a rash and then call him.

Pegylated uricase is "incredibly effective for lowering serum urate," as well, he said. When pegylated uricase is "given as an IV infusion, serum urate plummets to about 0.5 mg/dL and stays down for 2 weeks or longer," Dr. Mandell noted.

Patients should be warned, however, of the risk of flares with the quick urate drop. Also, if they don’t have such a robust response, it probably means they have antibodies to pegylated uricase, which also increases their risk of an infusion reaction. In that case, "stop the drug," he said.

For management of an acute gout attack, Dr. Mandell said he often chooses anakinra (Kineret) so long as patients are in the hospital and can be monitored for infections and other potential problems.

Indomethacin is another option. In fact, "any NSAID will work if you use high enough doses. You need to treat until the attack resolves and then for a couple days longer to really make sure the attack is gone," he advised.

Colchicine can work "if you catch the attack early, but it’s not a panacea. It’s a great drug for prophylaxis but not to treat acute attacks," he said.

Narcotics don’t work well on inflammatory pain and so are not a good choice for an acute attack, Dr. Mandell noted.

A normal serum urate level does not necessarily rule out a gout attack. "Stick a needle in the joint at some point in time to make sure gout is the diagnosis," he said.

Dr. Mandell is a consultant for Novartis, Pfizer, Takeda, and other companies.

SDEF and this news organization are owned by Frontline Medical Communications.

General internists often continue to treat gout the way they were taught to as medical students, and the result of that approach has been that patients continue to have gout attacks and joint damage. Physicians can do much better than that by using available medications to lower the patient’s serum urate level below 6 mg/dL, according to Dr. Brian Mandell, Professor and Chairman of Medicine at the Cleveland Clinic. This interview was conducted at the 5th Annual Perspectives in Rheumatic Diseases Seminar. 

General internists often continue to treat gout the way they were taught to as medical students, and the result of that approach has been that patients continue to have gout attacks and joint damage. Physicians can do much better than that by using available medications to lower the patient’s serum urate level below 6 mg/dL, according to Dr. Brian Mandell, Professor and Chairman of Medicine at the Cleveland Clinic. This interview was conducted at the 5th Annual Perspectives in Rheumatic Diseases Seminar. 

General internists often continue to treat gout the way they were taught to as medical students, and the result of that approach has been that patients continue to have gout attacks and joint damage. Physicians can do much better than that by using available medications to lower the patient’s serum urate level below 6 mg/dL, according to Dr. Brian Mandell, Professor and Chairman of Medicine at the Cleveland Clinic. This interview was conducted at the 5th Annual Perspectives in Rheumatic Diseases Seminar. 

The first guidelines on the management of gout from the American College of Rheumatology recommend new ways of using old drugs and changes in prophylaxis strategies, among other things.

The two-part guidelines, published online Sept. 28, should help speed up effective treatment of gout and get physicians to treat patients to a target urate level of less than 6 mg/dL in order to improve symptoms, Dr. John D. FitzGerald said in an interview.

"There has been a fair amount of recent movement on gout medications" including new alternatives to allopurinol and colchicine and new data on how to use those traditional drugs in safer ways, said Dr. FitzGerald, acting chief of the rheumatology division at the University of California, Los Angeles. "It’s a fair number of changes for medications that people had been using for decades."

The documents update previous guidelines from medical organizations in Europe, the Netherlands, and Japan. The new guidelines will be published in October 2012 by the journal Arthritis Care & Research.

Part 1 of the American College of Rheumatology (ACR) guidelines covers nonpharmacologic and pharmacologic approaches to managing hyperuricemia (Arthritis Care Res. 2012;64:1431-46 [doi:10.1002/acr.21772]).

Part 2 addresses prophylaxis and treatment for acute gouty arthritis (Arthritis Care Res. 2012;64:1447-61 [doi.wiley.com/10.1002/acr.21773]).

Dr. FitzGerald and two other co-leaders of the project, Dr. Dinesh Khanna of the University of Michigan, Ann Arbor and Dr. Robert Terkeltaub of the University of California, San Diego, reviewed the medical literature on gout from the 1950s to the present and drew up nine clinical case scenarios commonly seen in practice. A task force panel comprising seven rheumatologists, two primary care physicians, a nephrologist, and a patient representative used the scenarios to create consensus recommendations.

Among the recommendations, for example, on the use of allopurinol is to start at a low dose of 100 mg/day (instead of the common practice of starting with 300 mg/day), or even lower for patients with chronic kidney disease, and then gradually titrate upward every 2-5 weeks. That recommendation supports previous statements from the Food and Drug Administration and the European League Against Rheumatism.

Also, allopurinol therapy should be actively managed and patients followed to make sure the uric acid target is achieved. "You can’t just give a prescription and say your job is done," though some recent studies suggest that many physicians do just that, Dr. FitzGerald said. "The corollary would be if someone gave blood pressure medication and then didn’t follow the patient’s blood pressure. That wouldn’t be seen as good medicine."

Maintenance doses of allopurinol to prevent acute gout attacks can exceed 300 mg even in patients with chronic kidney disease provided there is adequate patient education and monitoring.

A new recommendation drops the starting dose of oral colchicine for acute gout attacks to a loading dose of 1.2 mg, followed by 0.6 mg an hour later, and then starting prophylaxis 12 hours later at dosing of 0.6 mg once or twice daily.

"We used to give up to eight tablets a day," Dr. FitzGerald said. "That is dropped down to three to four tablets at the start of an attacks, because of findings that more colchicine didn’t really help outcomes" and that smaller doses are safer. The authors called this recommendation from ACR "a paradigm shift" that’s in accordance with Food and Drug Administration-approved label language.

Other highlights of the new ACR recommendations include sections on screening for HLA-B*5801 in patients at high risk of severe adverse reaction to allopurinol, combination therapy when target urate levels are not achieved, medication options including new drugs, and more.

Although the reports are titled "Guidelines," the text makes clear that they are expert recommendations and that clinicians are expected to take active roles in choosing the best management strategies for their particular patients. The authors were "very concerned" that the guidelines not be used by third-party payers to restrict access to medications or to promote one drug over another if there isn’t clear evidence to support it, Dr. FitzGerald said.

The methodology of the project precluded evaluations of costs and cost effectiveness, instead focusing on efficacy. So, for example, the guidelines say that allopurinol and febuxostat can be used equivalently in some circumstances, but clinicians need to consider all other aspects of these options including cost, patient preference, and more.

The ACR plans to update the guidelines as new data become available. The task force panel did create specific indications for use of imaging studies because results should be available in the next few years from studies on the use of high-resolution ultrasound and dual-energy CT for patients with gout.

In the United States, gout affects an estimated 4% of adults – more than 8 million people.

"I’m most excited and hopeful about trying to get this out to internal medicine and family practice doctors," Dr. FitzGerald said. "They see more gout than rheumatologists."

Dr. FitzGerald reported having no financial disclosures. Some members of the task force reported financial associations with multiple pharmaceutical companies but, by design, a majority of task force members had no perceived potential conflicts of interest. 

The first guidelines on the management of gout from the American College of Rheumatology recommend new ways of using old drugs and changes in prophylaxis strategies, among other things.

The two-part guidelines, published online Sept. 28, should help speed up effective treatment of gout and get physicians to treat patients to a target urate level of less than 6 mg/dL in order to improve symptoms, Dr. John D. FitzGerald said in an interview.

"There has been a fair amount of recent movement on gout medications" including new alternatives to allopurinol and colchicine and new data on how to use those traditional drugs in safer ways, said Dr. FitzGerald, acting chief of the rheumatology division at the University of California, Los Angeles. "It’s a fair number of changes for medications that people had been using for decades."

The documents update previous guidelines from medical organizations in Europe, the Netherlands, and Japan. The new guidelines will be published in October 2012 by the journal Arthritis Care & Research.

Part 1 of the American College of Rheumatology (ACR) guidelines covers nonpharmacologic and pharmacologic approaches to managing hyperuricemia (Arthritis Care Res. 2012;64:1431-46 [doi:10.1002/acr.21772]).

Part 2 addresses prophylaxis and treatment for acute gouty arthritis (Arthritis Care Res. 2012;64:1447-61 [doi.wiley.com/10.1002/acr.21773]).

Dr. FitzGerald and two other co-leaders of the project, Dr. Dinesh Khanna of the University of Michigan, Ann Arbor and Dr. Robert Terkeltaub of the University of California, San Diego, reviewed the medical literature on gout from the 1950s to the present and drew up nine clinical case scenarios commonly seen in practice. A task force panel comprising seven rheumatologists, two primary care physicians, a nephrologist, and a patient representative used the scenarios to create consensus recommendations.

Among the recommendations, for example, on the use of allopurinol is to start at a low dose of 100 mg/day (instead of the common practice of starting with 300 mg/day), or even lower for patients with chronic kidney disease, and then gradually titrate upward every 2-5 weeks. That recommendation supports previous statements from the Food and Drug Administration and the European League Against Rheumatism.

Also, allopurinol therapy should be actively managed and patients followed to make sure the uric acid target is achieved. "You can’t just give a prescription and say your job is done," though some recent studies suggest that many physicians do just that, Dr. FitzGerald said. "The corollary would be if someone gave blood pressure medication and then didn’t follow the patient’s blood pressure. That wouldn’t be seen as good medicine."

Maintenance doses of allopurinol to prevent acute gout attacks can exceed 300 mg even in patients with chronic kidney disease provided there is adequate patient education and monitoring.

A new recommendation drops the starting dose of oral colchicine for acute gout attacks to a loading dose of 1.2 mg, followed by 0.6 mg an hour later, and then starting prophylaxis 12 hours later at dosing of 0.6 mg once or twice daily.

"We used to give up to eight tablets a day," Dr. FitzGerald said. "That is dropped down to three to four tablets at the start of an attacks, because of findings that more colchicine didn’t really help outcomes" and that smaller doses are safer. The authors called this recommendation from ACR "a paradigm shift" that’s in accordance with Food and Drug Administration-approved label language.

Other highlights of the new ACR recommendations include sections on screening for HLA-B*5801 in patients at high risk of severe adverse reaction to allopurinol, combination therapy when target urate levels are not achieved, medication options including new drugs, and more.

Although the reports are titled "Guidelines," the text makes clear that they are expert recommendations and that clinicians are expected to take active roles in choosing the best management strategies for their particular patients. The authors were "very concerned" that the guidelines not be used by third-party payers to restrict access to medications or to promote one drug over another if there isn’t clear evidence to support it, Dr. FitzGerald said.

The methodology of the project precluded evaluations of costs and cost effectiveness, instead focusing on efficacy. So, for example, the guidelines say that allopurinol and febuxostat can be used equivalently in some circumstances, but clinicians need to consider all other aspects of these options including cost, patient preference, and more.

The ACR plans to update the guidelines as new data become available. The task force panel did create specific indications for use of imaging studies because results should be available in the next few years from studies on the use of high-resolution ultrasound and dual-energy CT for patients with gout.

In the United States, gout affects an estimated 4% of adults – more than 8 million people.

"I’m most excited and hopeful about trying to get this out to internal medicine and family practice doctors," Dr. FitzGerald said. "They see more gout than rheumatologists."

Dr. FitzGerald reported having no financial disclosures. Some members of the task force reported financial associations with multiple pharmaceutical companies but, by design, a majority of task force members had no perceived potential conflicts of interest. 

The first guidelines on the management of gout from the American College of Rheumatology recommend new ways of using old drugs and changes in prophylaxis strategies, among other things.

The two-part guidelines, published online Sept. 28, should help speed up effective treatment of gout and get physicians to treat patients to a target urate level of less than 6 mg/dL in order to improve symptoms, Dr. John D. FitzGerald said in an interview.

"There has been a fair amount of recent movement on gout medications" including new alternatives to allopurinol and colchicine and new data on how to use those traditional drugs in safer ways, said Dr. FitzGerald, acting chief of the rheumatology division at the University of California, Los Angeles. "It’s a fair number of changes for medications that people had been using for decades."

The documents update previous guidelines from medical organizations in Europe, the Netherlands, and Japan. The new guidelines will be published in October 2012 by the journal Arthritis Care & Research.

Part 1 of the American College of Rheumatology (ACR) guidelines covers nonpharmacologic and pharmacologic approaches to managing hyperuricemia (Arthritis Care Res. 2012;64:1431-46 [doi:10.1002/acr.21772]).

Part 2 addresses prophylaxis and treatment for acute gouty arthritis (Arthritis Care Res. 2012;64:1447-61 [doi.wiley.com/10.1002/acr.21773]).

Dr. FitzGerald and two other co-leaders of the project, Dr. Dinesh Khanna of the University of Michigan, Ann Arbor and Dr. Robert Terkeltaub of the University of California, San Diego, reviewed the medical literature on gout from the 1950s to the present and drew up nine clinical case scenarios commonly seen in practice. A task force panel comprising seven rheumatologists, two primary care physicians, a nephrologist, and a patient representative used the scenarios to create consensus recommendations.

Among the recommendations, for example, on the use of allopurinol is to start at a low dose of 100 mg/day (instead of the common practice of starting with 300 mg/day), or even lower for patients with chronic kidney disease, and then gradually titrate upward every 2-5 weeks. That recommendation supports previous statements from the Food and Drug Administration and the European League Against Rheumatism.

Also, allopurinol therapy should be actively managed and patients followed to make sure the uric acid target is achieved. "You can’t just give a prescription and say your job is done," though some recent studies suggest that many physicians do just that, Dr. FitzGerald said. "The corollary would be if someone gave blood pressure medication and then didn’t follow the patient’s blood pressure. That wouldn’t be seen as good medicine."

Maintenance doses of allopurinol to prevent acute gout attacks can exceed 300 mg even in patients with chronic kidney disease provided there is adequate patient education and monitoring.

A new recommendation drops the starting dose of oral colchicine for acute gout attacks to a loading dose of 1.2 mg, followed by 0.6 mg an hour later, and then starting prophylaxis 12 hours later at dosing of 0.6 mg once or twice daily.

"We used to give up to eight tablets a day," Dr. FitzGerald said. "That is dropped down to three to four tablets at the start of an attacks, because of findings that more colchicine didn’t really help outcomes" and that smaller doses are safer. The authors called this recommendation from ACR "a paradigm shift" that’s in accordance with Food and Drug Administration-approved label language.

Other highlights of the new ACR recommendations include sections on screening for HLA-B*5801 in patients at high risk of severe adverse reaction to allopurinol, combination therapy when target urate levels are not achieved, medication options including new drugs, and more.

Although the reports are titled "Guidelines," the text makes clear that they are expert recommendations and that clinicians are expected to take active roles in choosing the best management strategies for their particular patients. The authors were "very concerned" that the guidelines not be used by third-party payers to restrict access to medications or to promote one drug over another if there isn’t clear evidence to support it, Dr. FitzGerald said.

The methodology of the project precluded evaluations of costs and cost effectiveness, instead focusing on efficacy. So, for example, the guidelines say that allopurinol and febuxostat can be used equivalently in some circumstances, but clinicians need to consider all other aspects of these options including cost, patient preference, and more.

The ACR plans to update the guidelines as new data become available. The task force panel did create specific indications for use of imaging studies because results should be available in the next few years from studies on the use of high-resolution ultrasound and dual-energy CT for patients with gout.

In the United States, gout affects an estimated 4% of adults – more than 8 million people.

"I’m most excited and hopeful about trying to get this out to internal medicine and family practice doctors," Dr. FitzGerald said. "They see more gout than rheumatologists."

Dr. FitzGerald reported having no financial disclosures. Some members of the task force reported financial associations with multiple pharmaceutical companies but, by design, a majority of task force members had no perceived potential conflicts of interest. 

SILVER SPRING, MD. – Lack of data on patients with refractory gout has scuttled for now any recommendation to approve the interleukin-1 inhibitor rilonacept.*

The Food and Drug Administration’s Arthritis Advisory Committee voted 11 to 0 that the safety and efficacy data on rilonacept did not support its approval for the prevention of gout flares during the initiation of uric acid-lowering therapy in adults with gout.

Although most panelists agreed there was evidence that the treatment was effective in reducing gout flares, they said the effect was modest, and that they would be reluctant to use it as a first-line treatment. They said that it would be useful for patients who are intolerant or refractory to NSAIDs and/or colchicine, but added that these types of patients comprised only a small group of patients in the 16 week pivotal trials, and that this length of time was not enough to evaluate safety because it was likely that the treatment would be used for longer periods of time.

Rilonacept, marketed as Arcalyst, was approved by the FDA in 2008 for the chronic treatment of familial cold autoinflammatory syndrome and Muckle-Wells syndrome (or cryopyrin-associated periodic syndromes), rare genetic disorders. Preclinical and clinical data indicate that interleukin-1 (IL-1) plays a role in triggering gout flares during the initiation of uric acid–lowering therapy, according to Regeneron Pharmaceuticals, which makes the drug. The dose for which Regeneron was seeking approval was a loading dose of 160 mg followed by a weekly dose of 80 mg for 16 weeks.

The manufacturer presented data to the FDA panel from two studies of almost 500 largely middle-aged men with moderate to severe gout. Their gout’s severity was characterized by a serum uric acid level of at least 7.5 mg/dL and at least two gout flares during the previous year. Patients were randomized to a dose of 80 mg subcutaneously, a dose of 160 mg administered once a week (after a 320-mg loading dose) given subcutaneously, or placebo. At the same time, all the participants initiated uric acid–lowering treatment with allopurinol. The prophylactic use of NSAIDs, glucocorticoids, or colchicine was not allowed. One study was conducted in the United States and Canada; the other was conducted in Germany, India, Indonesia, South Africa, and Taiwan.

Over a period of 16 weeks, treatment with the 80-mg dose was associated with a statistically significant reduction in the mean number of gout flares – the primary end point – compared with placebo. Those on the 80-mg dose had a mean of 0.29-0.35 gout flares per patient, compared with a mean of about one gout flare per patient on placebo, with no significant differences between the two rilonacept doses. In the two studies, 19% and almost 26% of those on the 80-mg dose had at least one gout flare, compared with almost half of those on placebo. Several panelists raised the issue of whether it was worth exposing patients to a biologic therapy when they had a 50% chance of not having a flare.

In a pooled database of the two pivotal studies and two other gout studies comparing the effectiveness of the 160-mg dose of rilonacept in about 1,000 patients to placebo in almost 400 patients, no significant increase in serious infections was observed in patients treated for 16 weeks. However, six malignancies were diagnosed during treatment with rilonacept, compared with none among those on placebo. FDA reviewers noted that while this number was low and the types of malignancies were not unusual for the typical gout patient, the lack of any malignancies among those on placebo and the biologic plausibility for an increased malignancy risk with a biologic immunosuppressant was a concern and suggested it would be useful to have data on a period longer than 16 weeks.

Although most panelists agreed there was evidence that the treatment was effective in reducing gout flares, they said the effect was modest, and that they would be reluctant to use it as a first-line treatment. They said that it would be useful for patients who are intolerant or refractory to NSAIDs and/or colchicine, but added that these types of patients comprised only a small group of patients in the pivotal trial, and that 16 weeks was not long enough to evaluate safety because it was likely that the treatment would be used for longer periods of time.

Several panel members questioned why the company did not compare rilonacept to an active control, such as colchicine, which is one of the main drugs used to prevent gout flares during the initiation of uric acid–lowering therapy.

The FDA usually follows the recommendations of its advisory panels. The panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver but not at this meeting.

*Correction, 5/9/2012: A previous version of this story misstated the panelists' concern about the drug's potential to cause cancer.

SILVER SPRING, MD. – Lack of data on patients with refractory gout has scuttled for now any recommendation to approve the interleukin-1 inhibitor rilonacept.*

The Food and Drug Administration’s Arthritis Advisory Committee voted 11 to 0 that the safety and efficacy data on rilonacept did not support its approval for the prevention of gout flares during the initiation of uric acid-lowering therapy in adults with gout.

Although most panelists agreed there was evidence that the treatment was effective in reducing gout flares, they said the effect was modest, and that they would be reluctant to use it as a first-line treatment. They said that it would be useful for patients who are intolerant or refractory to NSAIDs and/or colchicine, but added that these types of patients comprised only a small group of patients in the 16 week pivotal trials, and that this length of time was not enough to evaluate safety because it was likely that the treatment would be used for longer periods of time.

Rilonacept, marketed as Arcalyst, was approved by the FDA in 2008 for the chronic treatment of familial cold autoinflammatory syndrome and Muckle-Wells syndrome (or cryopyrin-associated periodic syndromes), rare genetic disorders. Preclinical and clinical data indicate that interleukin-1 (IL-1) plays a role in triggering gout flares during the initiation of uric acid–lowering therapy, according to Regeneron Pharmaceuticals, which makes the drug. The dose for which Regeneron was seeking approval was a loading dose of 160 mg followed by a weekly dose of 80 mg for 16 weeks.

The manufacturer presented data to the FDA panel from two studies of almost 500 largely middle-aged men with moderate to severe gout. Their gout’s severity was characterized by a serum uric acid level of at least 7.5 mg/dL and at least two gout flares during the previous year. Patients were randomized to a dose of 80 mg subcutaneously, a dose of 160 mg administered once a week (after a 320-mg loading dose) given subcutaneously, or placebo. At the same time, all the participants initiated uric acid–lowering treatment with allopurinol. The prophylactic use of NSAIDs, glucocorticoids, or colchicine was not allowed. One study was conducted in the United States and Canada; the other was conducted in Germany, India, Indonesia, South Africa, and Taiwan.

Over a period of 16 weeks, treatment with the 80-mg dose was associated with a statistically significant reduction in the mean number of gout flares – the primary end point – compared with placebo. Those on the 80-mg dose had a mean of 0.29-0.35 gout flares per patient, compared with a mean of about one gout flare per patient on placebo, with no significant differences between the two rilonacept doses. In the two studies, 19% and almost 26% of those on the 80-mg dose had at least one gout flare, compared with almost half of those on placebo. Several panelists raised the issue of whether it was worth exposing patients to a biologic therapy when they had a 50% chance of not having a flare.

In a pooled database of the two pivotal studies and two other gout studies comparing the effectiveness of the 160-mg dose of rilonacept in about 1,000 patients to placebo in almost 400 patients, no significant increase in serious infections was observed in patients treated for 16 weeks. However, six malignancies were diagnosed during treatment with rilonacept, compared with none among those on placebo. FDA reviewers noted that while this number was low and the types of malignancies were not unusual for the typical gout patient, the lack of any malignancies among those on placebo and the biologic plausibility for an increased malignancy risk with a biologic immunosuppressant was a concern and suggested it would be useful to have data on a period longer than 16 weeks.

Although most panelists agreed there was evidence that the treatment was effective in reducing gout flares, they said the effect was modest, and that they would be reluctant to use it as a first-line treatment. They said that it would be useful for patients who are intolerant or refractory to NSAIDs and/or colchicine, but added that these types of patients comprised only a small group of patients in the pivotal trial, and that 16 weeks was not long enough to evaluate safety because it was likely that the treatment would be used for longer periods of time.

Several panel members questioned why the company did not compare rilonacept to an active control, such as colchicine, which is one of the main drugs used to prevent gout flares during the initiation of uric acid–lowering therapy.

The FDA usually follows the recommendations of its advisory panels. The panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver but not at this meeting.

*Correction, 5/9/2012: A previous version of this story misstated the panelists' concern about the drug's potential to cause cancer.

SILVER SPRING, MD. – Lack of data on patients with refractory gout has scuttled for now any recommendation to approve the interleukin-1 inhibitor rilonacept.*

The Food and Drug Administration’s Arthritis Advisory Committee voted 11 to 0 that the safety and efficacy data on rilonacept did not support its approval for the prevention of gout flares during the initiation of uric acid-lowering therapy in adults with gout.

Although most panelists agreed there was evidence that the treatment was effective in reducing gout flares, they said the effect was modest, and that they would be reluctant to use it as a first-line treatment. They said that it would be useful for patients who are intolerant or refractory to NSAIDs and/or colchicine, but added that these types of patients comprised only a small group of patients in the 16 week pivotal trials, and that this length of time was not enough to evaluate safety because it was likely that the treatment would be used for longer periods of time.

Rilonacept, marketed as Arcalyst, was approved by the FDA in 2008 for the chronic treatment of familial cold autoinflammatory syndrome and Muckle-Wells syndrome (or cryopyrin-associated periodic syndromes), rare genetic disorders. Preclinical and clinical data indicate that interleukin-1 (IL-1) plays a role in triggering gout flares during the initiation of uric acid–lowering therapy, according to Regeneron Pharmaceuticals, which makes the drug. The dose for which Regeneron was seeking approval was a loading dose of 160 mg followed by a weekly dose of 80 mg for 16 weeks.

The manufacturer presented data to the FDA panel from two studies of almost 500 largely middle-aged men with moderate to severe gout. Their gout’s severity was characterized by a serum uric acid level of at least 7.5 mg/dL and at least two gout flares during the previous year. Patients were randomized to a dose of 80 mg subcutaneously, a dose of 160 mg administered once a week (after a 320-mg loading dose) given subcutaneously, or placebo. At the same time, all the participants initiated uric acid–lowering treatment with allopurinol. The prophylactic use of NSAIDs, glucocorticoids, or colchicine was not allowed. One study was conducted in the United States and Canada; the other was conducted in Germany, India, Indonesia, South Africa, and Taiwan.

Over a period of 16 weeks, treatment with the 80-mg dose was associated with a statistically significant reduction in the mean number of gout flares – the primary end point – compared with placebo. Those on the 80-mg dose had a mean of 0.29-0.35 gout flares per patient, compared with a mean of about one gout flare per patient on placebo, with no significant differences between the two rilonacept doses. In the two studies, 19% and almost 26% of those on the 80-mg dose had at least one gout flare, compared with almost half of those on placebo. Several panelists raised the issue of whether it was worth exposing patients to a biologic therapy when they had a 50% chance of not having a flare.

In a pooled database of the two pivotal studies and two other gout studies comparing the effectiveness of the 160-mg dose of rilonacept in about 1,000 patients to placebo in almost 400 patients, no significant increase in serious infections was observed in patients treated for 16 weeks. However, six malignancies were diagnosed during treatment with rilonacept, compared with none among those on placebo. FDA reviewers noted that while this number was low and the types of malignancies were not unusual for the typical gout patient, the lack of any malignancies among those on placebo and the biologic plausibility for an increased malignancy risk with a biologic immunosuppressant was a concern and suggested it would be useful to have data on a period longer than 16 weeks.

Although most panelists agreed there was evidence that the treatment was effective in reducing gout flares, they said the effect was modest, and that they would be reluctant to use it as a first-line treatment. They said that it would be useful for patients who are intolerant or refractory to NSAIDs and/or colchicine, but added that these types of patients comprised only a small group of patients in the pivotal trial, and that 16 weeks was not long enough to evaluate safety because it was likely that the treatment would be used for longer periods of time.

Several panel members questioned why the company did not compare rilonacept to an active control, such as colchicine, which is one of the main drugs used to prevent gout flares during the initiation of uric acid–lowering therapy.

The FDA usually follows the recommendations of its advisory panels. The panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver but not at this meeting.

*Correction, 5/9/2012: A previous version of this story misstated the panelists' concern about the drug's potential to cause cancer.

NEW YORK – The prevalence of gout has increased by 40% over almost 2 decades, judging from recent data discussed by Dr. Michael Pillinger at a rheumatology meeting sponsored by New York University. At the same time, other research has shown that there is greater recognition of its ill effects, including increased risk of osteoarthritis, heart failure, and death.

"Gout continues to be on the rise," according to Dr. Pillinger, citing the results of a recently published analysis of gout prevalence based on two large nationally representative samples (Arthritis Rheum. 2011;63:3136-41). By comparing data from 5,707 participants of the National Health and Nutrition Examination Survey (NHANES, 2007-2008) to 18,825 participants in NHANES-III (1988-1994), the researchers found that the prevalence of gout increased by 1.2%, from 2.7% to 3.9%. The rise was greater for men than women, with an increase of 2.1% for men and 0.4% for women. The most striking gain was found in those over the age of 80 years old (men and women), which saw an increase of 6.7% (from 5.9% to 12.6%).

"Something very significant is going on," says Dr. Pillinger, suggesting that factors such as longer life span, kidney disease, increased diuretic use, diet, and obesity may all be contributing to the findings.

While few patients die as a result of a gout attack, just having the disease shortens survival by 10% to 15%, says Dr. Pillinger, director of the rheumatology fellowship program at New York University and director of rheumatology at the Manhattan campus of the VA New York Harbor Healthcare System.

An examination of the National Death Registry of Taiwan of 6,631 people who were diagnosed with gout in 2000 and followed for 8 years (representing 53,048 person-years of follow-up) showed that crude mortality for men and women combined was 21.3 per 1,000 patient-years, which was significantly higher than that of the national population (Joint Bone Spine 2011;78:577-80). The all-cause standardized mortality ratio was 1.29 for men and 1.70 for women, with higher mortality ratios due to death from kidney diseases, endocrine and metabolic, and cardiovascular diseases in both sexes.

Gout is often accompanied by several serious comorbidities. Results from the New York Veterans Affairs Gout Cohort, a database analysis of 575 people with gout in the VA system, found that the average gout patient has four or five comorbidities. In their sample, nearly 90% were found to have hypertension, 60% hyperlipidemia, and 40-50% chronic kidney disease, diabetes, and coronary artery disease (Am. J. Med. 2011;124:155-63). The presence of comorbidities result in a high frequency of contraindications to approved gout medication, so these patients can be difficult to treat, says Dr. Pillinger, a coauthor of the study.

Now heart failure can be added to the list of gout-related comorbidities. In a post-hoc, longitudinal and cross-sectional analysis of 4,989 patients enrolled in the Framingham Offspring Study (BMJ Open 2012 Feb. 15 [doi: 10.1136/bmjopen-2011-000282]), the researchers found that those with gout (n = 228) had two to three times higher incidence of clinical heart failure compared with those without. Examining the cardiac characteristics of patients with and without gout (2,326 had echocardiograms), those with gout were four times more likely to have systolic dysfunction (P less than .001) and three times more likely to have low ejection fraction (P less than .001).

The study began in 1971 and patients were examined approximately every 4 years, with the last data collection in 2008. Longitudinal analysis showed that the risk of clinical heart failure did not become apparent until after the patients had gout for 10 or 12 years. These findings suggest that while clinical heart failure is not a problem when patients with gout are first seen when they are younger, the risk of clinical heart failure as patients age should be something to be cognizant of for possible early intervention, says Dr. Pillinger.

Participants with gout had greater mortality than those without (adjusted hazard ratio, 1.58; 95% confidence interval, 1.40 to 1.78). In those with heart failure, those with gout were more likely to die than those without the disease (adjusted HR, 1.50; 95% CI, 1.3 to 1.73). "This study adds to the growing body of evidence suggesting that gout has major consequences on the cardiovascular system," according to Dr. Krishnan.

Gout appears to also increase the prevalence and severity of osteoarthritis (OA). Using both ACR clinical and radiographic criteria, the prevalence of OA in both knees was significantly higher in those with gout compared to normal controls or those with asymptomatic hyperuricemia (68% vs. 28%, P less than or equal to .05), according to data presented at the 2011 annual meeting of the American College of Rheumatology. The severity of osteoarthritis was also higher in those with gout compared to normal controls using both Kellgren-Lawrence and Western Ontario and McMaster Universities Arthritis Index scores, but differences between groups did not reach statistical significance.

"If you have gout in an older person, you better look for OA," says Dr. Pillinger, a coauthor. He attributed the lack of statistical significance to the small size of the study (25 in each group of gout, normal controls, and those with asymptomatic hyperuricemia, age greater than 60 years).

Dr. Pillinger reported financial relationships with Takeda and URL Pharma.

NEW YORK – The prevalence of gout has increased by 40% over almost 2 decades, judging from recent data discussed by Dr. Michael Pillinger at a rheumatology meeting sponsored by New York University. At the same time, other research has shown that there is greater recognition of its ill effects, including increased risk of osteoarthritis, heart failure, and death.

"Gout continues to be on the rise," according to Dr. Pillinger, citing the results of a recently published analysis of gout prevalence based on two large nationally representative samples (Arthritis Rheum. 2011;63:3136-41). By comparing data from 5,707 participants of the National Health and Nutrition Examination Survey (NHANES, 2007-2008) to 18,825 participants in NHANES-III (1988-1994), the researchers found that the prevalence of gout increased by 1.2%, from 2.7% to 3.9%. The rise was greater for men than women, with an increase of 2.1% for men and 0.4% for women. The most striking gain was found in those over the age of 80 years old (men and women), which saw an increase of 6.7% (from 5.9% to 12.6%).

"Something very significant is going on," says Dr. Pillinger, suggesting that factors such as longer life span, kidney disease, increased diuretic use, diet, and obesity may all be contributing to the findings.

While few patients die as a result of a gout attack, just having the disease shortens survival by 10% to 15%, says Dr. Pillinger, director of the rheumatology fellowship program at New York University and director of rheumatology at the Manhattan campus of the VA New York Harbor Healthcare System.

An examination of the National Death Registry of Taiwan of 6,631 people who were diagnosed with gout in 2000 and followed for 8 years (representing 53,048 person-years of follow-up) showed that crude mortality for men and women combined was 21.3 per 1,000 patient-years, which was significantly higher than that of the national population (Joint Bone Spine 2011;78:577-80). The all-cause standardized mortality ratio was 1.29 for men and 1.70 for women, with higher mortality ratios due to death from kidney diseases, endocrine and metabolic, and cardiovascular diseases in both sexes.

Gout is often accompanied by several serious comorbidities. Results from the New York Veterans Affairs Gout Cohort, a database analysis of 575 people with gout in the VA system, found that the average gout patient has four or five comorbidities. In their sample, nearly 90% were found to have hypertension, 60% hyperlipidemia, and 40-50% chronic kidney disease, diabetes, and coronary artery disease (Am. J. Med. 2011;124:155-63). The presence of comorbidities result in a high frequency of contraindications to approved gout medication, so these patients can be difficult to treat, says Dr. Pillinger, a coauthor of the study.

Now heart failure can be added to the list of gout-related comorbidities. In a post-hoc, longitudinal and cross-sectional analysis of 4,989 patients enrolled in the Framingham Offspring Study (BMJ Open 2012 Feb. 15 [doi: 10.1136/bmjopen-2011-000282]), the researchers found that those with gout (n = 228) had two to three times higher incidence of clinical heart failure compared with those without. Examining the cardiac characteristics of patients with and without gout (2,326 had echocardiograms), those with gout were four times more likely to have systolic dysfunction (P less than .001) and three times more likely to have low ejection fraction (P less than .001).

The study began in 1971 and patients were examined approximately every 4 years, with the last data collection in 2008. Longitudinal analysis showed that the risk of clinical heart failure did not become apparent until after the patients had gout for 10 or 12 years. These findings suggest that while clinical heart failure is not a problem when patients with gout are first seen when they are younger, the risk of clinical heart failure as patients age should be something to be cognizant of for possible early intervention, says Dr. Pillinger.

Participants with gout had greater mortality than those without (adjusted hazard ratio, 1.58; 95% confidence interval, 1.40 to 1.78). In those with heart failure, those with gout were more likely to die than those without the disease (adjusted HR, 1.50; 95% CI, 1.3 to 1.73). "This study adds to the growing body of evidence suggesting that gout has major consequences on the cardiovascular system," according to Dr. Krishnan.

Gout appears to also increase the prevalence and severity of osteoarthritis (OA). Using both ACR clinical and radiographic criteria, the prevalence of OA in both knees was significantly higher in those with gout compared to normal controls or those with asymptomatic hyperuricemia (68% vs. 28%, P less than or equal to .05), according to data presented at the 2011 annual meeting of the American College of Rheumatology. The severity of osteoarthritis was also higher in those with gout compared to normal controls using both Kellgren-Lawrence and Western Ontario and McMaster Universities Arthritis Index scores, but differences between groups did not reach statistical significance.

"If you have gout in an older person, you better look for OA," says Dr. Pillinger, a coauthor. He attributed the lack of statistical significance to the small size of the study (25 in each group of gout, normal controls, and those with asymptomatic hyperuricemia, age greater than 60 years).

Dr. Pillinger reported financial relationships with Takeda and URL Pharma.

NEW YORK – The prevalence of gout has increased by 40% over almost 2 decades, judging from recent data discussed by Dr. Michael Pillinger at a rheumatology meeting sponsored by New York University. At the same time, other research has shown that there is greater recognition of its ill effects, including increased risk of osteoarthritis, heart failure, and death.

"Gout continues to be on the rise," according to Dr. Pillinger, citing the results of a recently published analysis of gout prevalence based on two large nationally representative samples (Arthritis Rheum. 2011;63:3136-41). By comparing data from 5,707 participants of the National Health and Nutrition Examination Survey (NHANES, 2007-2008) to 18,825 participants in NHANES-III (1988-1994), the researchers found that the prevalence of gout increased by 1.2%, from 2.7% to 3.9%. The rise was greater for men than women, with an increase of 2.1% for men and 0.4% for women. The most striking gain was found in those over the age of 80 years old (men and women), which saw an increase of 6.7% (from 5.9% to 12.6%).

"Something very significant is going on," says Dr. Pillinger, suggesting that factors such as longer life span, kidney disease, increased diuretic use, diet, and obesity may all be contributing to the findings.

While few patients die as a result of a gout attack, just having the disease shortens survival by 10% to 15%, says Dr. Pillinger, director of the rheumatology fellowship program at New York University and director of rheumatology at the Manhattan campus of the VA New York Harbor Healthcare System.

An examination of the National Death Registry of Taiwan of 6,631 people who were diagnosed with gout in 2000 and followed for 8 years (representing 53,048 person-years of follow-up) showed that crude mortality for men and women combined was 21.3 per 1,000 patient-years, which was significantly higher than that of the national population (Joint Bone Spine 2011;78:577-80). The all-cause standardized mortality ratio was 1.29 for men and 1.70 for women, with higher mortality ratios due to death from kidney diseases, endocrine and metabolic, and cardiovascular diseases in both sexes.

Gout is often accompanied by several serious comorbidities. Results from the New York Veterans Affairs Gout Cohort, a database analysis of 575 people with gout in the VA system, found that the average gout patient has four or five comorbidities. In their sample, nearly 90% were found to have hypertension, 60% hyperlipidemia, and 40-50% chronic kidney disease, diabetes, and coronary artery disease (Am. J. Med. 2011;124:155-63). The presence of comorbidities result in a high frequency of contraindications to approved gout medication, so these patients can be difficult to treat, says Dr. Pillinger, a coauthor of the study.

Now heart failure can be added to the list of gout-related comorbidities. In a post-hoc, longitudinal and cross-sectional analysis of 4,989 patients enrolled in the Framingham Offspring Study (BMJ Open 2012 Feb. 15 [doi: 10.1136/bmjopen-2011-000282]), the researchers found that those with gout (n = 228) had two to three times higher incidence of clinical heart failure compared with those without. Examining the cardiac characteristics of patients with and without gout (2,326 had echocardiograms), those with gout were four times more likely to have systolic dysfunction (P less than .001) and three times more likely to have low ejection fraction (P less than .001).

The study began in 1971 and patients were examined approximately every 4 years, with the last data collection in 2008. Longitudinal analysis showed that the risk of clinical heart failure did not become apparent until after the patients had gout for 10 or 12 years. These findings suggest that while clinical heart failure is not a problem when patients with gout are first seen when they are younger, the risk of clinical heart failure as patients age should be something to be cognizant of for possible early intervention, says Dr. Pillinger.

Participants with gout had greater mortality than those without (adjusted hazard ratio, 1.58; 95% confidence interval, 1.40 to 1.78). In those with heart failure, those with gout were more likely to die than those without the disease (adjusted HR, 1.50; 95% CI, 1.3 to 1.73). "This study adds to the growing body of evidence suggesting that gout has major consequences on the cardiovascular system," according to Dr. Krishnan.

Gout appears to also increase the prevalence and severity of osteoarthritis (OA). Using both ACR clinical and radiographic criteria, the prevalence of OA in both knees was significantly higher in those with gout compared to normal controls or those with asymptomatic hyperuricemia (68% vs. 28%, P less than or equal to .05), according to data presented at the 2011 annual meeting of the American College of Rheumatology. The severity of osteoarthritis was also higher in those with gout compared to normal controls using both Kellgren-Lawrence and Western Ontario and McMaster Universities Arthritis Index scores, but differences between groups did not reach statistical significance.

"If you have gout in an older person, you better look for OA," says Dr. Pillinger, a coauthor. He attributed the lack of statistical significance to the small size of the study (25 in each group of gout, normal controls, and those with asymptomatic hyperuricemia, age greater than 60 years).

Dr. Pillinger reported financial relationships with Takeda and URL Pharma.

NEW YORK – Patients with gout who took colchicine had less than one-half the risk of having a myocardial infarction that was seen in patients who were untreated for their gout. But this protective effect was not seen for patients taking allopurinol, Dr. Michael Pillinger, a coauthor of the study, said at a rheumatology meeting sponsored by New York University.

In this retrospective analysis of data from 1,300 patients from the New York Veterans Affairs Gout Cohort, about 0.5% of those taking colchicine had an MI, compared with 3% of those not taking any antigout medication (P less than .05). The MI rate for those taking allopurinol was slightly more than 2%, which was not significantly different from the rate in the untreated group. A significant reduction was seen for those taking both colchicine and allopurinol. Death rates were comparable among the groups.

"When we stepped out of the database and read the charts, we found [that] several of the patients who were categorized as having MIs on colchicine actually had been put on colchicine after their MI, so when we corrected for this, the difference was even greater," said Dr. Pillinger, director of the rheumatology fellowship program at New York University and director of rheumatology at the Manhattan campus of the VA New York Harbor Healthcare System.

"These are very provocative findings," he added. His group is currently undertaking more rigorous retrospective analyses and hopes to begin a prospective study.

Dr. Pillinger postulated that the lack of significant effect of allopurinol was due to its inconsistency in lowering urate levels. "In our hands, allopurinol does not always reduce urate levels," he noted.

These data confirm findings from an earlier study by Dr. Pillinger and his associates that looked at 45,000 Taiwanese men with hyperuricemia or gout. Those findings showed that treating hyperuricemia and gout could help control comorbid cardiovascular disease.

Dr. Pillinger reported financial relationships with Takeda (the study site) and URL Pharma (an investigator-initiated grant).

NEW YORK – Patients with gout who took colchicine had less than one-half the risk of having a myocardial infarction that was seen in patients who were untreated for their gout. But this protective effect was not seen for patients taking allopurinol, Dr. Michael Pillinger, a coauthor of the study, said at a rheumatology meeting sponsored by New York University.

In this retrospective analysis of data from 1,300 patients from the New York Veterans Affairs Gout Cohort, about 0.5% of those taking colchicine had an MI, compared with 3% of those not taking any antigout medication (P less than .05). The MI rate for those taking allopurinol was slightly more than 2%, which was not significantly different from the rate in the untreated group. A significant reduction was seen for those taking both colchicine and allopurinol. Death rates were comparable among the groups.

"When we stepped out of the database and read the charts, we found [that] several of the patients who were categorized as having MIs on colchicine actually had been put on colchicine after their MI, so when we corrected for this, the difference was even greater," said Dr. Pillinger, director of the rheumatology fellowship program at New York University and director of rheumatology at the Manhattan campus of the VA New York Harbor Healthcare System.

"These are very provocative findings," he added. His group is currently undertaking more rigorous retrospective analyses and hopes to begin a prospective study.

Dr. Pillinger postulated that the lack of significant effect of allopurinol was due to its inconsistency in lowering urate levels. "In our hands, allopurinol does not always reduce urate levels," he noted.

These data confirm findings from an earlier study by Dr. Pillinger and his associates that looked at 45,000 Taiwanese men with hyperuricemia or gout. Those findings showed that treating hyperuricemia and gout could help control comorbid cardiovascular disease.

Dr. Pillinger reported financial relationships with Takeda (the study site) and URL Pharma (an investigator-initiated grant).

NEW YORK – Patients with gout who took colchicine had less than one-half the risk of having a myocardial infarction that was seen in patients who were untreated for their gout. But this protective effect was not seen for patients taking allopurinol, Dr. Michael Pillinger, a coauthor of the study, said at a rheumatology meeting sponsored by New York University.

In this retrospective analysis of data from 1,300 patients from the New York Veterans Affairs Gout Cohort, about 0.5% of those taking colchicine had an MI, compared with 3% of those not taking any antigout medication (P less than .05). The MI rate for those taking allopurinol was slightly more than 2%, which was not significantly different from the rate in the untreated group. A significant reduction was seen for those taking both colchicine and allopurinol. Death rates were comparable among the groups.

"When we stepped out of the database and read the charts, we found [that] several of the patients who were categorized as having MIs on colchicine actually had been put on colchicine after their MI, so when we corrected for this, the difference was even greater," said Dr. Pillinger, director of the rheumatology fellowship program at New York University and director of rheumatology at the Manhattan campus of the VA New York Harbor Healthcare System.

"These are very provocative findings," he added. His group is currently undertaking more rigorous retrospective analyses and hopes to begin a prospective study.

Dr. Pillinger postulated that the lack of significant effect of allopurinol was due to its inconsistency in lowering urate levels. "In our hands, allopurinol does not always reduce urate levels," he noted.

These data confirm findings from an earlier study by Dr. Pillinger and his associates that looked at 45,000 Taiwanese men with hyperuricemia or gout. Those findings showed that treating hyperuricemia and gout could help control comorbid cardiovascular disease.

Dr. Pillinger reported financial relationships with Takeda (the study site) and URL Pharma (an investigator-initiated grant).