Gout

LONDON – The prevalence of gout is increasing and to prevent an epidemic, rheumatologists and other physicians need to diagnose and treat cases promptly and better explain the treatment process to their patients, according to a Swedish expert on the disease.

“It’s a disease for which we understand the mechanisms, we know how to diagnose it, and we have had good treatments for the last 50 years,” said Dr. Lennart Jacobsson, professor of rheumatology at the University of Gothenburg in Sweden. “Despite that, we don’t treat it properly. It’s difficult to understand why that is the case, why there is such a lack of knowledge and such a lack of willingness to pursue treatment.”

Gout is the most common nondegenerative inflammatory joint disease, exemplified by a prevalence of 0.9%-2.5% in Europe and 3.9% in the United States. The incidence is increasing along with factors such as the aging population, as well as lifestyle changes such as rising body mass index and physical inactivity, Dr. Jacobsson said at the European Congress of Rheumatology.

“It’s the same story everywhere,” he said. “Gout is underdiagnosed, it’s diagnosed late, and once it’s diagnosed people don’t get treated with urate-lowering therapy, which aims at the heart of the disease. If they are treated, treatment often is discontinued, which we think is largely due to lack of education and information to patients.”

Urate crystals can build up over as much as a decade before a person experiences a first gout attack, Dr. Jacobsson said. “It can take 3-5 years of effective treatment to get rid of those masses within the body. Over that time, especially at the beginning, patients may still have gout attacks, which they often interpret as side effects of the medication or a misinterpretation that it doesn’t work because they’re not properly informed that medication needs to be a long-term treatment.”

Close to 10% of men aged 70-80 years have gout, he said, but it’s still unclear how many of those have mild, moderate, or severe disease. It’s also not well studied how gout itself can affect health-related quality of life and costs to society. “You can easily imagine that the costs are pretty large, however, and they will increase,” he said.

Gout is interrelated with several metabolic syndrome disorders such as obesity, hypertension, and diabetes, Dr. Jacobsson said: “If you have renal disease, you have higher uric acid levels and can more easily get gout, but from having high uric acid levels you may also get decreased renal function, so it’s sort of circular. The same is true of gout and hypertension.”

Once considered a disease of the wealthy, Dr. Jacobsson said, gout has recently been shown to be associated with lower income and socioeconomic class, as is the case for many other chronic diseases. There are still large opportunities for improvements regarding early detection and the initiation of urate-lowering therapy, he said, as well as counseling patients on lifestyle improvements.

“We know what to do, we have the tools, and we should start using them more effectively,” he said. “It’s really very simple, but that message has to get through. It’s an increasing problem, and it’s bad not just for the joints but also for quality of life and comorbidities.”

Dr. Jacobsson reported no relevant financial disclosures.

LONDON – The prevalence of gout is increasing and to prevent an epidemic, rheumatologists and other physicians need to diagnose and treat cases promptly and better explain the treatment process to their patients, according to a Swedish expert on the disease.

“It’s a disease for which we understand the mechanisms, we know how to diagnose it, and we have had good treatments for the last 50 years,” said Dr. Lennart Jacobsson, professor of rheumatology at the University of Gothenburg in Sweden. “Despite that, we don’t treat it properly. It’s difficult to understand why that is the case, why there is such a lack of knowledge and such a lack of willingness to pursue treatment.”

Gout is the most common nondegenerative inflammatory joint disease, exemplified by a prevalence of 0.9%-2.5% in Europe and 3.9% in the United States. The incidence is increasing along with factors such as the aging population, as well as lifestyle changes such as rising body mass index and physical inactivity, Dr. Jacobsson said at the European Congress of Rheumatology.

“It’s the same story everywhere,” he said. “Gout is underdiagnosed, it’s diagnosed late, and once it’s diagnosed people don’t get treated with urate-lowering therapy, which aims at the heart of the disease. If they are treated, treatment often is discontinued, which we think is largely due to lack of education and information to patients.”

Urate crystals can build up over as much as a decade before a person experiences a first gout attack, Dr. Jacobsson said. “It can take 3-5 years of effective treatment to get rid of those masses within the body. Over that time, especially at the beginning, patients may still have gout attacks, which they often interpret as side effects of the medication or a misinterpretation that it doesn’t work because they’re not properly informed that medication needs to be a long-term treatment.”

Close to 10% of men aged 70-80 years have gout, he said, but it’s still unclear how many of those have mild, moderate, or severe disease. It’s also not well studied how gout itself can affect health-related quality of life and costs to society. “You can easily imagine that the costs are pretty large, however, and they will increase,” he said.

Gout is interrelated with several metabolic syndrome disorders such as obesity, hypertension, and diabetes, Dr. Jacobsson said: “If you have renal disease, you have higher uric acid levels and can more easily get gout, but from having high uric acid levels you may also get decreased renal function, so it’s sort of circular. The same is true of gout and hypertension.”

Once considered a disease of the wealthy, Dr. Jacobsson said, gout has recently been shown to be associated with lower income and socioeconomic class, as is the case for many other chronic diseases. There are still large opportunities for improvements regarding early detection and the initiation of urate-lowering therapy, he said, as well as counseling patients on lifestyle improvements.

“We know what to do, we have the tools, and we should start using them more effectively,” he said. “It’s really very simple, but that message has to get through. It’s an increasing problem, and it’s bad not just for the joints but also for quality of life and comorbidities.”

Dr. Jacobsson reported no relevant financial disclosures.

LONDON – The prevalence of gout is increasing and to prevent an epidemic, rheumatologists and other physicians need to diagnose and treat cases promptly and better explain the treatment process to their patients, according to a Swedish expert on the disease.

“It’s a disease for which we understand the mechanisms, we know how to diagnose it, and we have had good treatments for the last 50 years,” said Dr. Lennart Jacobsson, professor of rheumatology at the University of Gothenburg in Sweden. “Despite that, we don’t treat it properly. It’s difficult to understand why that is the case, why there is such a lack of knowledge and such a lack of willingness to pursue treatment.”

Gout is the most common nondegenerative inflammatory joint disease, exemplified by a prevalence of 0.9%-2.5% in Europe and 3.9% in the United States. The incidence is increasing along with factors such as the aging population, as well as lifestyle changes such as rising body mass index and physical inactivity, Dr. Jacobsson said at the European Congress of Rheumatology.

“It’s the same story everywhere,” he said. “Gout is underdiagnosed, it’s diagnosed late, and once it’s diagnosed people don’t get treated with urate-lowering therapy, which aims at the heart of the disease. If they are treated, treatment often is discontinued, which we think is largely due to lack of education and information to patients.”

Urate crystals can build up over as much as a decade before a person experiences a first gout attack, Dr. Jacobsson said. “It can take 3-5 years of effective treatment to get rid of those masses within the body. Over that time, especially at the beginning, patients may still have gout attacks, which they often interpret as side effects of the medication or a misinterpretation that it doesn’t work because they’re not properly informed that medication needs to be a long-term treatment.”

Close to 10% of men aged 70-80 years have gout, he said, but it’s still unclear how many of those have mild, moderate, or severe disease. It’s also not well studied how gout itself can affect health-related quality of life and costs to society. “You can easily imagine that the costs are pretty large, however, and they will increase,” he said.

Gout is interrelated with several metabolic syndrome disorders such as obesity, hypertension, and diabetes, Dr. Jacobsson said: “If you have renal disease, you have higher uric acid levels and can more easily get gout, but from having high uric acid levels you may also get decreased renal function, so it’s sort of circular. The same is true of gout and hypertension.”

Once considered a disease of the wealthy, Dr. Jacobsson said, gout has recently been shown to be associated with lower income and socioeconomic class, as is the case for many other chronic diseases. There are still large opportunities for improvements regarding early detection and the initiation of urate-lowering therapy, he said, as well as counseling patients on lifestyle improvements.

“We know what to do, we have the tools, and we should start using them more effectively,” he said. “It’s really very simple, but that message has to get through. It’s an increasing problem, and it’s bad not just for the joints but also for quality of life and comorbidities.”

Dr. Jacobsson reported no relevant financial disclosures.

MAUI, HAWAII – The recently approved uric acid–lowering drug lesinurad received a lukewarm reception at best when introduced during a ‘highlights of the year in gout’ session presented at the 2016 Rheumatology Winter Clinical Symposium.

Panelist Martin J. Bergman presented a dispassionate overview of the data from four pivotal randomized trials which in late December 2015 resulted in Food and Drug Administration approval of lesinurad (Zurampic) at 200 mg/day in combination with a xanthine oxidase inhibitor, but not as monotherapy at 400 mg/day.

Bruce Jancin/Frontline Medical News

After highlighting the drug’s safety concerns, including the black box warning about lesinurad’s risk of acute renal failure and its numerous potential drug interactions, Dr. Bergman opened the floor to discussion. An audience member immediately shot up his hand and asked, “Isn’t this drug a crappy drug?”

Dr. Bergman, chief of rheumatology at Taylor Hospital in Ridley Park, Pa., answered diplomatically: “It’s not the strongest drug, it’s not the best. Is this going to be something which revolutionizes the care of gout? I don’t think so. But it does give us a way to get to the treatment goal of a serum uric acid below 6.0 mg/dL in gout patients unable to get there on allopurinol or febuxostat [Uloric] alone. “

Faculty member Dr. Eric M. Ruderman was blunt in his appraisal of lesinurad: “I really don’t understand the place for this drug.”

“In the trial of combination therapy with febuxostat [the 324-patient CRYSTAL study] it didn’t meet the primary endpoint at the 200 mg/day dose. It’s amazing to me that the FDA will approve a drug when one of the pivotal trials didn’t meet the primary endpoint at the dose they approved. That’s bizarre. And in the trials with allopurinol [CLEAR 1 and 2, with a total of 1,213 patients] they didn’t use maximum-dose allopurinol. So I don’t see where this drug adds anything to our treatment paradigm,” said Dr. Ruderman, professor of medicine at Northwestern University in Chicago.

In the pivotal clinical trials, the 400 mg/day dose was more effective than 200 mg/day, but it was also associated with a doubling of serum creatinine in 1 in every 12 treated patients, as compared with a 1%-2% incidence at 200 mg. That’s why the FDA didn’t approve the higher dose.

Lesinurad is a selective inhibitor of uric acid resorption which acts in the proximal tubule on URAT1, an inhibitor of uric acid transport.

Arhalofenate, a promising investigational gout drug, shares the same mechanism of action, but in addition it blocks release of interleukin-1beta. In a 239-patient, phase IIb trial presented at the 2015 annual meeting of the American College of Rheumatology, arhalofenate effectively reduced the rate of gout flares while lowering serum uric acid levels, and most notably it did so with no treatment-related serious adverse events and no cases of elevated serum creatinine. This is a drug to keep an eye on, according to Dr. Bergman.

Copanelist Dr. Orrin M. Troum of the University of Southern California, Los Angeles, presented highlights of other significant recent studies in the field of gout, some of them quite surprising:

• Colchicine reduces cardiovascular events in gout patients. A comparison between 501 Medicare gout patients on colchicine and an equal number of matched gout patients not on colchicine showed that during a median 16.5 months of follow-up, the colchicine users had an adjusted 49% reduction in the composite endpoint of acute MI, stroke, or TIA. They also had a 73% reduction in all-cause mortality, according to Dr. Daniel H. Solomon, professor of medicine at Harvard Medical School, Boston, and coinvestigators (Ann Rheum Dis. 2015 Nov 18. doi: 10.1136/annrheumdis-2015-207984).

“Once my gout patients stop clutching their chest when they see the price of colchicine, which actually increases their cardiovascular risk, they are very excited when I tell them about this study,” Dr. Bergman quipped. “This study controlled for other comorbidities and for serum uric acid levels. Those relative risk reductions are not to be sneezed at.”

• Treating gout improves survival. In a prospective case-matched cohort study, Taiwanese investigators compared 764 gout patients on urate-lowering therapy with an equal number of matched gout patients who did not take a urate-lowering drug. During 6.5 years of follow-up, the group on urate-lowering medication had a 71% lower risk of cardiovascular mortality and a 53% reduction in all-cause mortality, compared with gout patients not on urate-lowering therapy. Moreover, in a separate analysis comparing 1,189 gout patients not taking urate-lowering therapy and three times as many matched controls without gout, the gout patients had a 2.43-fold greater rate of cardiovascular mortality and a 1.45-fold increased risk of all-cause mortality (J Rheumatol. 2015 Sep;42[9]:1694-701).

• Gout is associated with reduced risk of Alzheimer’s disease. Using a U.K. electronic medical record database to track nearly 60,000 patients with gout and 239,000 matched controls, investigators determined that the incidence of Alzheimer’s disease during a median 5 years of follow-up was reduced by 24% in an analysis extensively adjusted for smoking, alcohol intake, medications, comorbid conditions, social deprivation, and other potential confounders. The researchers concluded based upon this and other evidence that uric acid appears to be neuroprotective (Ann Rheum Dis. 2016 Mar;75[3]:547-51).

• Sleep apnea is an independent risk factor for gout. Patients newly diagnosed with sleep apnea had a 50% greater risk of developing gout in the next year, compared with BMI-matched controls without sleep apnea in a population-based study conducted by investigators in Boston and the United Kingdom. The study included 9,865 patients with a new physician diagnosis of sleep apnea and nearly 44,000 matched controls. The incidence of newly diagnosed gout was 8.4 per 1,000 person-years in the group with sleep apnea and 4.8 per 1,000 person-years in the comparison group.

In a multivariate analysis adjusted for numerous potential confounders, new-onset sleep apnea remained an independent predictor of increased risk for gout. The results raise the testable hypothesis that effective treatment of sleep apnea might reduce the risk of hyperuricemia and gout flares (Arthritis Rheumatol. 2015 Dec;67[12]:3298-302).

• Gout linked to increased risk of septic arthritis. In a population-based study, investigators at Boston University and Massachusetts General Hospital turned to the U.K. Health Improvement Network general practice database, where they identified 72,073 new-onset gout patients and 358,342 matched controls without gout. The incidence rate of a septic arthritis diagnosis during follow-up was 0.24 cases per 1,000 person-years in the gout group and 0.09 per 1,000 person-years in controls. In a multivariate regression analysis, gout patients were at 2.6-fold greater risk of septic arthritis (Rheumatology [Oxford]. 2015 Nov;54[11]:2095-9).

• Gout is associated with increased risk of new-onset atrial fibrillation. A cohort study conducted using a U.S. commercial health insurance database identified 70,015 patients with gout and 210,045 with osteoarthritis. During a mean 2 years of follow-up, newly diagnosed atrial fibrillation occurred at a rate of 7.19 cases per 1,000 person-years in the gout group and 5.87 per 1,000 in the osteoarthritis patients. In a multivariate regression analysis, patients with gout had a 13% increased risk of new-onset atrial fibrillation, compared with the osteoarthritis group (Ann Rheum Dis. 2015 Aug 31. doi: 10.1136/annrheumdis-2015-208161).

• Genetic screening test enables patients to avoid allopurinol-induced severe cutaneous adverse reactions. In a prospective cohort study, Taiwanese investigators performed screening for the HLA-B*58:01 allele in 2,926 patients of Han Chinese descent who had an indication for treatment with allopurinol. Those who tested positive – 571 patients, or 19.6% – received some alternative drug, while those who were HLA-B*58:01-negative were placed on allopurinol. All subjects were interviewed once weekly for the next 2 months, and hospital admissions for adverse drug reactions were monitored nationwide. Not a single study participant developed an allopurinol-induced severe cutaneous adverse reaction. Based upon historical incidence, seven cases would have been expected in the study population (BMJ. 2015 Sep 23;351:h4848. doi: 10.1136/bmj.h4848).

Dr. Bergman and Dr. Troum reported having no financial conflicts regarding their presentation.

[email protected]

MAUI, HAWAII – The recently approved uric acid–lowering drug lesinurad received a lukewarm reception at best when introduced during a ‘highlights of the year in gout’ session presented at the 2016 Rheumatology Winter Clinical Symposium.

Panelist Martin J. Bergman presented a dispassionate overview of the data from four pivotal randomized trials which in late December 2015 resulted in Food and Drug Administration approval of lesinurad (Zurampic) at 200 mg/day in combination with a xanthine oxidase inhibitor, but not as monotherapy at 400 mg/day.

Bruce Jancin/Frontline Medical News

After highlighting the drug’s safety concerns, including the black box warning about lesinurad’s risk of acute renal failure and its numerous potential drug interactions, Dr. Bergman opened the floor to discussion. An audience member immediately shot up his hand and asked, “Isn’t this drug a crappy drug?”

Dr. Bergman, chief of rheumatology at Taylor Hospital in Ridley Park, Pa., answered diplomatically: “It’s not the strongest drug, it’s not the best. Is this going to be something which revolutionizes the care of gout? I don’t think so. But it does give us a way to get to the treatment goal of a serum uric acid below 6.0 mg/dL in gout patients unable to get there on allopurinol or febuxostat [Uloric] alone. “

Faculty member Dr. Eric M. Ruderman was blunt in his appraisal of lesinurad: “I really don’t understand the place for this drug.”

“In the trial of combination therapy with febuxostat [the 324-patient CRYSTAL study] it didn’t meet the primary endpoint at the 200 mg/day dose. It’s amazing to me that the FDA will approve a drug when one of the pivotal trials didn’t meet the primary endpoint at the dose they approved. That’s bizarre. And in the trials with allopurinol [CLEAR 1 and 2, with a total of 1,213 patients] they didn’t use maximum-dose allopurinol. So I don’t see where this drug adds anything to our treatment paradigm,” said Dr. Ruderman, professor of medicine at Northwestern University in Chicago.

In the pivotal clinical trials, the 400 mg/day dose was more effective than 200 mg/day, but it was also associated with a doubling of serum creatinine in 1 in every 12 treated patients, as compared with a 1%-2% incidence at 200 mg. That’s why the FDA didn’t approve the higher dose.

Lesinurad is a selective inhibitor of uric acid resorption which acts in the proximal tubule on URAT1, an inhibitor of uric acid transport.

Arhalofenate, a promising investigational gout drug, shares the same mechanism of action, but in addition it blocks release of interleukin-1beta. In a 239-patient, phase IIb trial presented at the 2015 annual meeting of the American College of Rheumatology, arhalofenate effectively reduced the rate of gout flares while lowering serum uric acid levels, and most notably it did so with no treatment-related serious adverse events and no cases of elevated serum creatinine. This is a drug to keep an eye on, according to Dr. Bergman.

Copanelist Dr. Orrin M. Troum of the University of Southern California, Los Angeles, presented highlights of other significant recent studies in the field of gout, some of them quite surprising:

• Colchicine reduces cardiovascular events in gout patients. A comparison between 501 Medicare gout patients on colchicine and an equal number of matched gout patients not on colchicine showed that during a median 16.5 months of follow-up, the colchicine users had an adjusted 49% reduction in the composite endpoint of acute MI, stroke, or TIA. They also had a 73% reduction in all-cause mortality, according to Dr. Daniel H. Solomon, professor of medicine at Harvard Medical School, Boston, and coinvestigators (Ann Rheum Dis. 2015 Nov 18. doi: 10.1136/annrheumdis-2015-207984).

“Once my gout patients stop clutching their chest when they see the price of colchicine, which actually increases their cardiovascular risk, they are very excited when I tell them about this study,” Dr. Bergman quipped. “This study controlled for other comorbidities and for serum uric acid levels. Those relative risk reductions are not to be sneezed at.”

• Treating gout improves survival. In a prospective case-matched cohort study, Taiwanese investigators compared 764 gout patients on urate-lowering therapy with an equal number of matched gout patients who did not take a urate-lowering drug. During 6.5 years of follow-up, the group on urate-lowering medication had a 71% lower risk of cardiovascular mortality and a 53% reduction in all-cause mortality, compared with gout patients not on urate-lowering therapy. Moreover, in a separate analysis comparing 1,189 gout patients not taking urate-lowering therapy and three times as many matched controls without gout, the gout patients had a 2.43-fold greater rate of cardiovascular mortality and a 1.45-fold increased risk of all-cause mortality (J Rheumatol. 2015 Sep;42[9]:1694-701).

• Gout is associated with reduced risk of Alzheimer’s disease. Using a U.K. electronic medical record database to track nearly 60,000 patients with gout and 239,000 matched controls, investigators determined that the incidence of Alzheimer’s disease during a median 5 years of follow-up was reduced by 24% in an analysis extensively adjusted for smoking, alcohol intake, medications, comorbid conditions, social deprivation, and other potential confounders. The researchers concluded based upon this and other evidence that uric acid appears to be neuroprotective (Ann Rheum Dis. 2016 Mar;75[3]:547-51).

• Sleep apnea is an independent risk factor for gout. Patients newly diagnosed with sleep apnea had a 50% greater risk of developing gout in the next year, compared with BMI-matched controls without sleep apnea in a population-based study conducted by investigators in Boston and the United Kingdom. The study included 9,865 patients with a new physician diagnosis of sleep apnea and nearly 44,000 matched controls. The incidence of newly diagnosed gout was 8.4 per 1,000 person-years in the group with sleep apnea and 4.8 per 1,000 person-years in the comparison group.

In a multivariate analysis adjusted for numerous potential confounders, new-onset sleep apnea remained an independent predictor of increased risk for gout. The results raise the testable hypothesis that effective treatment of sleep apnea might reduce the risk of hyperuricemia and gout flares (Arthritis Rheumatol. 2015 Dec;67[12]:3298-302).

• Gout linked to increased risk of septic arthritis. In a population-based study, investigators at Boston University and Massachusetts General Hospital turned to the U.K. Health Improvement Network general practice database, where they identified 72,073 new-onset gout patients and 358,342 matched controls without gout. The incidence rate of a septic arthritis diagnosis during follow-up was 0.24 cases per 1,000 person-years in the gout group and 0.09 per 1,000 person-years in controls. In a multivariate regression analysis, gout patients were at 2.6-fold greater risk of septic arthritis (Rheumatology [Oxford]. 2015 Nov;54[11]:2095-9).

• Gout is associated with increased risk of new-onset atrial fibrillation. A cohort study conducted using a U.S. commercial health insurance database identified 70,015 patients with gout and 210,045 with osteoarthritis. During a mean 2 years of follow-up, newly diagnosed atrial fibrillation occurred at a rate of 7.19 cases per 1,000 person-years in the gout group and 5.87 per 1,000 in the osteoarthritis patients. In a multivariate regression analysis, patients with gout had a 13% increased risk of new-onset atrial fibrillation, compared with the osteoarthritis group (Ann Rheum Dis. 2015 Aug 31. doi: 10.1136/annrheumdis-2015-208161).

• Genetic screening test enables patients to avoid allopurinol-induced severe cutaneous adverse reactions. In a prospective cohort study, Taiwanese investigators performed screening for the HLA-B*58:01 allele in 2,926 patients of Han Chinese descent who had an indication for treatment with allopurinol. Those who tested positive – 571 patients, or 19.6% – received some alternative drug, while those who were HLA-B*58:01-negative were placed on allopurinol. All subjects were interviewed once weekly for the next 2 months, and hospital admissions for adverse drug reactions were monitored nationwide. Not a single study participant developed an allopurinol-induced severe cutaneous adverse reaction. Based upon historical incidence, seven cases would have been expected in the study population (BMJ. 2015 Sep 23;351:h4848. doi: 10.1136/bmj.h4848).

Dr. Bergman and Dr. Troum reported having no financial conflicts regarding their presentation.

[email protected]

MAUI, HAWAII – The recently approved uric acid–lowering drug lesinurad received a lukewarm reception at best when introduced during a ‘highlights of the year in gout’ session presented at the 2016 Rheumatology Winter Clinical Symposium.

Panelist Martin J. Bergman presented a dispassionate overview of the data from four pivotal randomized trials which in late December 2015 resulted in Food and Drug Administration approval of lesinurad (Zurampic) at 200 mg/day in combination with a xanthine oxidase inhibitor, but not as monotherapy at 400 mg/day.

Bruce Jancin/Frontline Medical News

After highlighting the drug’s safety concerns, including the black box warning about lesinurad’s risk of acute renal failure and its numerous potential drug interactions, Dr. Bergman opened the floor to discussion. An audience member immediately shot up his hand and asked, “Isn’t this drug a crappy drug?”

Dr. Bergman, chief of rheumatology at Taylor Hospital in Ridley Park, Pa., answered diplomatically: “It’s not the strongest drug, it’s not the best. Is this going to be something which revolutionizes the care of gout? I don’t think so. But it does give us a way to get to the treatment goal of a serum uric acid below 6.0 mg/dL in gout patients unable to get there on allopurinol or febuxostat [Uloric] alone. “

Faculty member Dr. Eric M. Ruderman was blunt in his appraisal of lesinurad: “I really don’t understand the place for this drug.”

“In the trial of combination therapy with febuxostat [the 324-patient CRYSTAL study] it didn’t meet the primary endpoint at the 200 mg/day dose. It’s amazing to me that the FDA will approve a drug when one of the pivotal trials didn’t meet the primary endpoint at the dose they approved. That’s bizarre. And in the trials with allopurinol [CLEAR 1 and 2, with a total of 1,213 patients] they didn’t use maximum-dose allopurinol. So I don’t see where this drug adds anything to our treatment paradigm,” said Dr. Ruderman, professor of medicine at Northwestern University in Chicago.

In the pivotal clinical trials, the 400 mg/day dose was more effective than 200 mg/day, but it was also associated with a doubling of serum creatinine in 1 in every 12 treated patients, as compared with a 1%-2% incidence at 200 mg. That’s why the FDA didn’t approve the higher dose.

Lesinurad is a selective inhibitor of uric acid resorption which acts in the proximal tubule on URAT1, an inhibitor of uric acid transport.

Arhalofenate, a promising investigational gout drug, shares the same mechanism of action, but in addition it blocks release of interleukin-1beta. In a 239-patient, phase IIb trial presented at the 2015 annual meeting of the American College of Rheumatology, arhalofenate effectively reduced the rate of gout flares while lowering serum uric acid levels, and most notably it did so with no treatment-related serious adverse events and no cases of elevated serum creatinine. This is a drug to keep an eye on, according to Dr. Bergman.

Copanelist Dr. Orrin M. Troum of the University of Southern California, Los Angeles, presented highlights of other significant recent studies in the field of gout, some of them quite surprising:

• Colchicine reduces cardiovascular events in gout patients. A comparison between 501 Medicare gout patients on colchicine and an equal number of matched gout patients not on colchicine showed that during a median 16.5 months of follow-up, the colchicine users had an adjusted 49% reduction in the composite endpoint of acute MI, stroke, or TIA. They also had a 73% reduction in all-cause mortality, according to Dr. Daniel H. Solomon, professor of medicine at Harvard Medical School, Boston, and coinvestigators (Ann Rheum Dis. 2015 Nov 18. doi: 10.1136/annrheumdis-2015-207984).

“Once my gout patients stop clutching their chest when they see the price of colchicine, which actually increases their cardiovascular risk, they are very excited when I tell them about this study,” Dr. Bergman quipped. “This study controlled for other comorbidities and for serum uric acid levels. Those relative risk reductions are not to be sneezed at.”

• Treating gout improves survival. In a prospective case-matched cohort study, Taiwanese investigators compared 764 gout patients on urate-lowering therapy with an equal number of matched gout patients who did not take a urate-lowering drug. During 6.5 years of follow-up, the group on urate-lowering medication had a 71% lower risk of cardiovascular mortality and a 53% reduction in all-cause mortality, compared with gout patients not on urate-lowering therapy. Moreover, in a separate analysis comparing 1,189 gout patients not taking urate-lowering therapy and three times as many matched controls without gout, the gout patients had a 2.43-fold greater rate of cardiovascular mortality and a 1.45-fold increased risk of all-cause mortality (J Rheumatol. 2015 Sep;42[9]:1694-701).

• Gout is associated with reduced risk of Alzheimer’s disease. Using a U.K. electronic medical record database to track nearly 60,000 patients with gout and 239,000 matched controls, investigators determined that the incidence of Alzheimer’s disease during a median 5 years of follow-up was reduced by 24% in an analysis extensively adjusted for smoking, alcohol intake, medications, comorbid conditions, social deprivation, and other potential confounders. The researchers concluded based upon this and other evidence that uric acid appears to be neuroprotective (Ann Rheum Dis. 2016 Mar;75[3]:547-51).

• Sleep apnea is an independent risk factor for gout. Patients newly diagnosed with sleep apnea had a 50% greater risk of developing gout in the next year, compared with BMI-matched controls without sleep apnea in a population-based study conducted by investigators in Boston and the United Kingdom. The study included 9,865 patients with a new physician diagnosis of sleep apnea and nearly 44,000 matched controls. The incidence of newly diagnosed gout was 8.4 per 1,000 person-years in the group with sleep apnea and 4.8 per 1,000 person-years in the comparison group.

In a multivariate analysis adjusted for numerous potential confounders, new-onset sleep apnea remained an independent predictor of increased risk for gout. The results raise the testable hypothesis that effective treatment of sleep apnea might reduce the risk of hyperuricemia and gout flares (Arthritis Rheumatol. 2015 Dec;67[12]:3298-302).

• Gout linked to increased risk of septic arthritis. In a population-based study, investigators at Boston University and Massachusetts General Hospital turned to the U.K. Health Improvement Network general practice database, where they identified 72,073 new-onset gout patients and 358,342 matched controls without gout. The incidence rate of a septic arthritis diagnosis during follow-up was 0.24 cases per 1,000 person-years in the gout group and 0.09 per 1,000 person-years in controls. In a multivariate regression analysis, gout patients were at 2.6-fold greater risk of septic arthritis (Rheumatology [Oxford]. 2015 Nov;54[11]:2095-9).

• Gout is associated with increased risk of new-onset atrial fibrillation. A cohort study conducted using a U.S. commercial health insurance database identified 70,015 patients with gout and 210,045 with osteoarthritis. During a mean 2 years of follow-up, newly diagnosed atrial fibrillation occurred at a rate of 7.19 cases per 1,000 person-years in the gout group and 5.87 per 1,000 in the osteoarthritis patients. In a multivariate regression analysis, patients with gout had a 13% increased risk of new-onset atrial fibrillation, compared with the osteoarthritis group (Ann Rheum Dis. 2015 Aug 31. doi: 10.1136/annrheumdis-2015-208161).

• Genetic screening test enables patients to avoid allopurinol-induced severe cutaneous adverse reactions. In a prospective cohort study, Taiwanese investigators performed screening for the HLA-B*58:01 allele in 2,926 patients of Han Chinese descent who had an indication for treatment with allopurinol. Those who tested positive – 571 patients, or 19.6% – received some alternative drug, while those who were HLA-B*58:01-negative were placed on allopurinol. All subjects were interviewed once weekly for the next 2 months, and hospital admissions for adverse drug reactions were monitored nationwide. Not a single study participant developed an allopurinol-induced severe cutaneous adverse reaction. Based upon historical incidence, seven cases would have been expected in the study population (BMJ. 2015 Sep 23;351:h4848. doi: 10.1136/bmj.h4848).

Dr. Bergman and Dr. Troum reported having no financial conflicts regarding their presentation.

[email protected]

The novel uricosuric drug arhalofenate significantly reduced the incidence of gout flares, compared with allopurinol alone and placebo, and also modestly lowered serum urate levels in a phase IIb trial.

However, arhalofenate alone did not lower serum uric acid levels as much as did allopurinol plus colchicine, potentially making it “better suited for a combination regimen with a xanthine-oxidase inhibitor,” first author Dr. Jeffrey Poiley of Arthritis Associates in Orlando, and his coauthors at CymaBay Therapeutics in Newark, Calif.

The double-blind, randomized, placebo- and active-drug controlled trial of 239 gout patients showed that arhalofenate at a dose of 800 mg daily significantly reduced gout flares over 12 weeks by 46% versus allopurinol at a dose of 300 mg daily (0.66 flares vs. 1.24; P = .0056) and by 41% versus placebo (0.66 vs. 1.13; P = .049).

The 12-week incidence of flares with the 800-mg dose was no better than the combination of allopurinol 300 mg with 0.6 mg colchicine a day (0.40), but the study was not powered to detect this comparison. “The clinical utility of arhalofenate 800 mg will have to be judged in the context of the respective risk/benefit ratio of each flare treatment,” the study authors said (Arthritis Rheumatol. 2016 Mar 18. doi: 101002/art.39684).

The flare rate for arhalofenate at a lower daily dose of 600 mg was not significantly different from allopurinol 300 mg without flare prophylaxis (1.04 vs. 1.24, respectively).

Secondary outcomes of the study revealed that arhalofenate had modest effects on serum urate levels, compared with allopurinol on its own and in combination with colchicine. The average percentage change in serum uric acid levels from baseline to week 12 were –12.5% with 600 mg of arhalofenate; –16.5% with 800 mg; –28.8% with allopurinol 300 mg, and –24.9% for allopurinol plus colchicine, and –0.9% with placebo.

Arhalofenate lowers serum urate by blocking its reabsorption by the proximal tubules of the kidney via inhibition of the urate transporter 1. In animal studies of urate crystal–induced inflammation, arhalofenate suppressed the release of proinflammatory cytokines and prevented the movement of neutrophils to the site of inflammation. Prior studies of arhalofenate in gout patients treated with colchicine suggested that the drug could prevent flares, but this was impossible to prove definitively because of the simultaneous use of colchicine, the authors wrote.

The study authors will now confirm their findings in a phase III trial with a treatment regimen that combines arhalofenate with febuxostat.

Patients involved in the study had more than three flares in the previous year, had discontinued urate-lowering therapy and colchicine, and had a serum urate level of 7.5-12 mg/dL.

They were randomized in a 2:2:2:2:1 fashion to one of five treatment groups: daily arhalofenate 600 mg or 800 mg, allopurinol 300 mg, allopurinol 300 mg together with 0.6 mg of colchicine, or placebo.

The researchers said there were no meaningful differences in adverse events between treatment groups. There were no significant changes in estimated creatinine clearance in any treatment group, including no declines in any group receiving arhalofenate.

The study was sponsored by CymaBay Therapeutics. Dr. Poiley was an investigator in the study, and five other authors are employees of CymaBay.

The novel uricosuric drug arhalofenate significantly reduced the incidence of gout flares, compared with allopurinol alone and placebo, and also modestly lowered serum urate levels in a phase IIb trial.

However, arhalofenate alone did not lower serum uric acid levels as much as did allopurinol plus colchicine, potentially making it “better suited for a combination regimen with a xanthine-oxidase inhibitor,” first author Dr. Jeffrey Poiley of Arthritis Associates in Orlando, and his coauthors at CymaBay Therapeutics in Newark, Calif.

The double-blind, randomized, placebo- and active-drug controlled trial of 239 gout patients showed that arhalofenate at a dose of 800 mg daily significantly reduced gout flares over 12 weeks by 46% versus allopurinol at a dose of 300 mg daily (0.66 flares vs. 1.24; P = .0056) and by 41% versus placebo (0.66 vs. 1.13; P = .049).

The 12-week incidence of flares with the 800-mg dose was no better than the combination of allopurinol 300 mg with 0.6 mg colchicine a day (0.40), but the study was not powered to detect this comparison. “The clinical utility of arhalofenate 800 mg will have to be judged in the context of the respective risk/benefit ratio of each flare treatment,” the study authors said (Arthritis Rheumatol. 2016 Mar 18. doi: 101002/art.39684).

The flare rate for arhalofenate at a lower daily dose of 600 mg was not significantly different from allopurinol 300 mg without flare prophylaxis (1.04 vs. 1.24, respectively).

Secondary outcomes of the study revealed that arhalofenate had modest effects on serum urate levels, compared with allopurinol on its own and in combination with colchicine. The average percentage change in serum uric acid levels from baseline to week 12 were –12.5% with 600 mg of arhalofenate; –16.5% with 800 mg; –28.8% with allopurinol 300 mg, and –24.9% for allopurinol plus colchicine, and –0.9% with placebo.

Arhalofenate lowers serum urate by blocking its reabsorption by the proximal tubules of the kidney via inhibition of the urate transporter 1. In animal studies of urate crystal–induced inflammation, arhalofenate suppressed the release of proinflammatory cytokines and prevented the movement of neutrophils to the site of inflammation. Prior studies of arhalofenate in gout patients treated with colchicine suggested that the drug could prevent flares, but this was impossible to prove definitively because of the simultaneous use of colchicine, the authors wrote.

The study authors will now confirm their findings in a phase III trial with a treatment regimen that combines arhalofenate with febuxostat.

Patients involved in the study had more than three flares in the previous year, had discontinued urate-lowering therapy and colchicine, and had a serum urate level of 7.5-12 mg/dL.

They were randomized in a 2:2:2:2:1 fashion to one of five treatment groups: daily arhalofenate 600 mg or 800 mg, allopurinol 300 mg, allopurinol 300 mg together with 0.6 mg of colchicine, or placebo.

The researchers said there were no meaningful differences in adverse events between treatment groups. There were no significant changes in estimated creatinine clearance in any treatment group, including no declines in any group receiving arhalofenate.

The study was sponsored by CymaBay Therapeutics. Dr. Poiley was an investigator in the study, and five other authors are employees of CymaBay.

The novel uricosuric drug arhalofenate significantly reduced the incidence of gout flares, compared with allopurinol alone and placebo, and also modestly lowered serum urate levels in a phase IIb trial.

However, arhalofenate alone did not lower serum uric acid levels as much as did allopurinol plus colchicine, potentially making it “better suited for a combination regimen with a xanthine-oxidase inhibitor,” first author Dr. Jeffrey Poiley of Arthritis Associates in Orlando, and his coauthors at CymaBay Therapeutics in Newark, Calif.

The double-blind, randomized, placebo- and active-drug controlled trial of 239 gout patients showed that arhalofenate at a dose of 800 mg daily significantly reduced gout flares over 12 weeks by 46% versus allopurinol at a dose of 300 mg daily (0.66 flares vs. 1.24; P = .0056) and by 41% versus placebo (0.66 vs. 1.13; P = .049).

The 12-week incidence of flares with the 800-mg dose was no better than the combination of allopurinol 300 mg with 0.6 mg colchicine a day (0.40), but the study was not powered to detect this comparison. “The clinical utility of arhalofenate 800 mg will have to be judged in the context of the respective risk/benefit ratio of each flare treatment,” the study authors said (Arthritis Rheumatol. 2016 Mar 18. doi: 101002/art.39684).

The flare rate for arhalofenate at a lower daily dose of 600 mg was not significantly different from allopurinol 300 mg without flare prophylaxis (1.04 vs. 1.24, respectively).

Secondary outcomes of the study revealed that arhalofenate had modest effects on serum urate levels, compared with allopurinol on its own and in combination with colchicine. The average percentage change in serum uric acid levels from baseline to week 12 were –12.5% with 600 mg of arhalofenate; –16.5% with 800 mg; –28.8% with allopurinol 300 mg, and –24.9% for allopurinol plus colchicine, and –0.9% with placebo.

Arhalofenate lowers serum urate by blocking its reabsorption by the proximal tubules of the kidney via inhibition of the urate transporter 1. In animal studies of urate crystal–induced inflammation, arhalofenate suppressed the release of proinflammatory cytokines and prevented the movement of neutrophils to the site of inflammation. Prior studies of arhalofenate in gout patients treated with colchicine suggested that the drug could prevent flares, but this was impossible to prove definitively because of the simultaneous use of colchicine, the authors wrote.

The study authors will now confirm their findings in a phase III trial with a treatment regimen that combines arhalofenate with febuxostat.

Patients involved in the study had more than three flares in the previous year, had discontinued urate-lowering therapy and colchicine, and had a serum urate level of 7.5-12 mg/dL.

They were randomized in a 2:2:2:2:1 fashion to one of five treatment groups: daily arhalofenate 600 mg or 800 mg, allopurinol 300 mg, allopurinol 300 mg together with 0.6 mg of colchicine, or placebo.

The researchers said there were no meaningful differences in adverse events between treatment groups. There were no significant changes in estimated creatinine clearance in any treatment group, including no declines in any group receiving arhalofenate.

The study was sponsored by CymaBay Therapeutics. Dr. Poiley was an investigator in the study, and five other authors are employees of CymaBay.

Therapeutic goals set the tone for the American College of Rheumatology National Research Agenda 2016-2020 by calling for the discovery and development of new therapies for rheumatic disease; finding predictors of response and nonresponse to, and adverse events from therapy; and improving the understanding of how therapies should be used.

Those are the top 3 out of 15 goals facilitated by the ACR’s Committee on Research, which finalized the agenda after seeking input from members of the ACR and Association of Rheumatology Health Professionals (ARHP) living in the United States, and going through several rounds of refining and prioritizing the importance of goals through the input of clinicians, researchers, patients, and stakeholders. The Committee on Research uses the agenda to “set the compass for the organization in terms of research initiatives and facilitate the ACR’s advocacy for the research goals identified.”

©Tashatuvango/Thinkstock

Dr. Alexis R. Ogdie-Beatty, who jointly led the development of the agenda for the Committee on Research along with Dr. S. Louis Bridges, said that while the goals for 2016-2020 had a great deal of overlap with those of 2011-2015, “some of the topics that came up were different. Some of the topics were more specific than in the previous agenda. We have some idea how important these issues were to rheumatologists, given that rheumatologists (and patients) rated the importance of the items. Defining new therapeutic targets and developing new therapies for rheumatic diseases was by far the most highly rated goal by rheumatologists. Next most highly rated was to advocate for increased support for rheumatology research and rheumatology investigators – this was included as a supplementary goal that supports the rest of the agenda. Other newer items were those around determining how the changing health care landscape affects rheumatology patients and clinicians. In addition, nonpharmacologic therapy, adult outcomes of pediatric disease, and optimizing patient engagement were topics that were felt to be important. I think these highlight the input of clinicians in identifying research objectives.”

The 2016-2020 agenda is the third set of goals developed by the committee since 2005, and the first to “crowdsource” the important questions to ACR and ARHP members rather than be assembled solely by the committee.

The agenda arose from a multistage process that began with a web-based survey to the ACR/ARHP membership that asked respondents to “list the five most important research questions that need to be addressed over the next 5 years in order to improve the care for patients with rheumatic disease.” A selected group of 100 individuals representing patients, clinicians (academic and community), research (all types with diverse areas/diseases of interest), allied health professionals, pediatric and adult rheumatology, men and women, all career stages, and all regions of the country, used a Delphi exercise to rate 30 statements generated from the survey on a scale from 1 (not important) to 10 (very important). They had the option to provide comments. At a Leadership Summit, stakeholders from various nonprofit foundations associated with rheumatic diseases, the National Institutes of Health, and the president of the Rheumatology Research Foundation gave comments on a draft agenda to the Committee on Research, after which the committee discussed the results and input and then solicited further 1-10 ratings and comments on preliminary agenda goals from the same group of 100 individuals as in the second phase, plus an additional 17 clinicians.

Up next in the rank-ordering after therapeutic goals were three goals about understanding:

• The etiology, pathogenesis, and genetic basis of rheumatic diseases.

• Early disease states to improve early diagnosis, develop biomarkers for early detection, and determine how earlier treatment changes outcomes.

• The immune system and autoimmunity by defining autoimmunity triggers and determining how epigenetics affect disease susceptibility and inflammation.

The 5-year plan proposed developing improved outcome measures that incorporate patient self-reports, imaging, and measures of clinical response and disease activity. The agenda also seeks to gain better understanding of how patients with rheumatic disease, rheumatologists, and rheumatology health professionals are being affected by the changing U.S. health care landscape.

The plan calls for determining the role of nonpharmacologic therapy in the management of rheumatic disease (promoting and improving adherence to physical activity, finding optimal exercise prescriptions, and determining the role of diet on disease activity), as well as evaluating the role of regenerative medicine.

The agenda spells out the need for better engagement of patients in their care as well as for understanding how comorbidities are influenced by rheumatic disease and how pain and fatigue arise in rheumatic disease.

In two separate goals, committee members listed the importance of determining adult outcomes of pediatric rheumatic diseases and the effect of aging on the development, progression, and management of rheumatic diseases.

The Committee on Research identified three supplemental goals that support the others:

• Advocating for increased support for rheumatology research and rheumatology investigators.

• Harmonizing data from existing cohorts and registries to optimize research capabilities.

• Improving patient research partner involvement in research protocols.

[email protected]

Therapeutic goals set the tone for the American College of Rheumatology National Research Agenda 2016-2020 by calling for the discovery and development of new therapies for rheumatic disease; finding predictors of response and nonresponse to, and adverse events from therapy; and improving the understanding of how therapies should be used.

Those are the top 3 out of 15 goals facilitated by the ACR’s Committee on Research, which finalized the agenda after seeking input from members of the ACR and Association of Rheumatology Health Professionals (ARHP) living in the United States, and going through several rounds of refining and prioritizing the importance of goals through the input of clinicians, researchers, patients, and stakeholders. The Committee on Research uses the agenda to “set the compass for the organization in terms of research initiatives and facilitate the ACR’s advocacy for the research goals identified.”

©Tashatuvango/Thinkstock

Dr. Alexis R. Ogdie-Beatty, who jointly led the development of the agenda for the Committee on Research along with Dr. S. Louis Bridges, said that while the goals for 2016-2020 had a great deal of overlap with those of 2011-2015, “some of the topics that came up were different. Some of the topics were more specific than in the previous agenda. We have some idea how important these issues were to rheumatologists, given that rheumatologists (and patients) rated the importance of the items. Defining new therapeutic targets and developing new therapies for rheumatic diseases was by far the most highly rated goal by rheumatologists. Next most highly rated was to advocate for increased support for rheumatology research and rheumatology investigators – this was included as a supplementary goal that supports the rest of the agenda. Other newer items were those around determining how the changing health care landscape affects rheumatology patients and clinicians. In addition, nonpharmacologic therapy, adult outcomes of pediatric disease, and optimizing patient engagement were topics that were felt to be important. I think these highlight the input of clinicians in identifying research objectives.”

The 2016-2020 agenda is the third set of goals developed by the committee since 2005, and the first to “crowdsource” the important questions to ACR and ARHP members rather than be assembled solely by the committee.

The agenda arose from a multistage process that began with a web-based survey to the ACR/ARHP membership that asked respondents to “list the five most important research questions that need to be addressed over the next 5 years in order to improve the care for patients with rheumatic disease.” A selected group of 100 individuals representing patients, clinicians (academic and community), research (all types with diverse areas/diseases of interest), allied health professionals, pediatric and adult rheumatology, men and women, all career stages, and all regions of the country, used a Delphi exercise to rate 30 statements generated from the survey on a scale from 1 (not important) to 10 (very important). They had the option to provide comments. At a Leadership Summit, stakeholders from various nonprofit foundations associated with rheumatic diseases, the National Institutes of Health, and the president of the Rheumatology Research Foundation gave comments on a draft agenda to the Committee on Research, after which the committee discussed the results and input and then solicited further 1-10 ratings and comments on preliminary agenda goals from the same group of 100 individuals as in the second phase, plus an additional 17 clinicians.

Up next in the rank-ordering after therapeutic goals were three goals about understanding:

• The etiology, pathogenesis, and genetic basis of rheumatic diseases.

• Early disease states to improve early diagnosis, develop biomarkers for early detection, and determine how earlier treatment changes outcomes.

• The immune system and autoimmunity by defining autoimmunity triggers and determining how epigenetics affect disease susceptibility and inflammation.

The 5-year plan proposed developing improved outcome measures that incorporate patient self-reports, imaging, and measures of clinical response and disease activity. The agenda also seeks to gain better understanding of how patients with rheumatic disease, rheumatologists, and rheumatology health professionals are being affected by the changing U.S. health care landscape.

The plan calls for determining the role of nonpharmacologic therapy in the management of rheumatic disease (promoting and improving adherence to physical activity, finding optimal exercise prescriptions, and determining the role of diet on disease activity), as well as evaluating the role of regenerative medicine.

The agenda spells out the need for better engagement of patients in their care as well as for understanding how comorbidities are influenced by rheumatic disease and how pain and fatigue arise in rheumatic disease.

In two separate goals, committee members listed the importance of determining adult outcomes of pediatric rheumatic diseases and the effect of aging on the development, progression, and management of rheumatic diseases.

The Committee on Research identified three supplemental goals that support the others:

• Advocating for increased support for rheumatology research and rheumatology investigators.

• Harmonizing data from existing cohorts and registries to optimize research capabilities.

• Improving patient research partner involvement in research protocols.

[email protected]

Therapeutic goals set the tone for the American College of Rheumatology National Research Agenda 2016-2020 by calling for the discovery and development of new therapies for rheumatic disease; finding predictors of response and nonresponse to, and adverse events from therapy; and improving the understanding of how therapies should be used.

Those are the top 3 out of 15 goals facilitated by the ACR’s Committee on Research, which finalized the agenda after seeking input from members of the ACR and Association of Rheumatology Health Professionals (ARHP) living in the United States, and going through several rounds of refining and prioritizing the importance of goals through the input of clinicians, researchers, patients, and stakeholders. The Committee on Research uses the agenda to “set the compass for the organization in terms of research initiatives and facilitate the ACR’s advocacy for the research goals identified.”

©Tashatuvango/Thinkstock

Dr. Alexis R. Ogdie-Beatty, who jointly led the development of the agenda for the Committee on Research along with Dr. S. Louis Bridges, said that while the goals for 2016-2020 had a great deal of overlap with those of 2011-2015, “some of the topics that came up were different. Some of the topics were more specific than in the previous agenda. We have some idea how important these issues were to rheumatologists, given that rheumatologists (and patients) rated the importance of the items. Defining new therapeutic targets and developing new therapies for rheumatic diseases was by far the most highly rated goal by rheumatologists. Next most highly rated was to advocate for increased support for rheumatology research and rheumatology investigators – this was included as a supplementary goal that supports the rest of the agenda. Other newer items were those around determining how the changing health care landscape affects rheumatology patients and clinicians. In addition, nonpharmacologic therapy, adult outcomes of pediatric disease, and optimizing patient engagement were topics that were felt to be important. I think these highlight the input of clinicians in identifying research objectives.”

The 2016-2020 agenda is the third set of goals developed by the committee since 2005, and the first to “crowdsource” the important questions to ACR and ARHP members rather than be assembled solely by the committee.

The agenda arose from a multistage process that began with a web-based survey to the ACR/ARHP membership that asked respondents to “list the five most important research questions that need to be addressed over the next 5 years in order to improve the care for patients with rheumatic disease.” A selected group of 100 individuals representing patients, clinicians (academic and community), research (all types with diverse areas/diseases of interest), allied health professionals, pediatric and adult rheumatology, men and women, all career stages, and all regions of the country, used a Delphi exercise to rate 30 statements generated from the survey on a scale from 1 (not important) to 10 (very important). They had the option to provide comments. At a Leadership Summit, stakeholders from various nonprofit foundations associated with rheumatic diseases, the National Institutes of Health, and the president of the Rheumatology Research Foundation gave comments on a draft agenda to the Committee on Research, after which the committee discussed the results and input and then solicited further 1-10 ratings and comments on preliminary agenda goals from the same group of 100 individuals as in the second phase, plus an additional 17 clinicians.

Up next in the rank-ordering after therapeutic goals were three goals about understanding:

• The etiology, pathogenesis, and genetic basis of rheumatic diseases.

• Early disease states to improve early diagnosis, develop biomarkers for early detection, and determine how earlier treatment changes outcomes.

• The immune system and autoimmunity by defining autoimmunity triggers and determining how epigenetics affect disease susceptibility and inflammation.

The 5-year plan proposed developing improved outcome measures that incorporate patient self-reports, imaging, and measures of clinical response and disease activity. The agenda also seeks to gain better understanding of how patients with rheumatic disease, rheumatologists, and rheumatology health professionals are being affected by the changing U.S. health care landscape.

The plan calls for determining the role of nonpharmacologic therapy in the management of rheumatic disease (promoting and improving adherence to physical activity, finding optimal exercise prescriptions, and determining the role of diet on disease activity), as well as evaluating the role of regenerative medicine.

The agenda spells out the need for better engagement of patients in their care as well as for understanding how comorbidities are influenced by rheumatic disease and how pain and fatigue arise in rheumatic disease.

In two separate goals, committee members listed the importance of determining adult outcomes of pediatric rheumatic diseases and the effect of aging on the development, progression, and management of rheumatic diseases.

The Committee on Research identified three supplemental goals that support the others:

• Advocating for increased support for rheumatology research and rheumatology investigators.

• Harmonizing data from existing cohorts and registries to optimize research capabilities.

• Improving patient research partner involvement in research protocols.

[email protected]

Oral prednisolone is as effective as indomethacin for relieving pain in acute gout and should be considered a first-line treatment option, according to a report published online Feb. 22 in Annals of Internal Medicine.

Colchicine and nonsteroidal anti-inflammatory drugs have been considered the first-line treatment for acute gout for many years. “However, their use is limited in elderly adults and in patients with comorbid conditions (such as renal insufficiency or gastrointestinal disease) because of their potential adverse effects and drug interactions,” said Dr. Timothy Hudson Rainer of the emergency medicine academic unit, Cardiff (Wales) University, and his associates.

©ThamKC/Thinkstock

They performed a double-blind, randomized trial comparing oral indomethacin against oral prednisolone in 416 patients who presented during a 2-year period to the emergency departments of four Hong Kong hospitals, where acute gout typically is treated in the ED. Those who were randomized to indomethacin initially received 50 mg (two 25-mg tablets) of the drug three times a day and six tablets of oral placebo prednisolone once a day for 2 days, followed by 25 mg of indomethacin three times a day and six tablets of placebo prednisolone once a day for 3 days. Prednisolone-treated patients initially received 30 mg (three 10-mg tablets) of the drug once a day and two tablets of placebo indomethacin three times a day for 2 days, followed by 30 mg (three 10-mg tablets) of prednisolone once a day and one tablet of placebo indomethacin three times a day for 3 days. All the patients received 1 g oral paracetamol to be taken every 6 hours as needed. The mean patient age was 65 years, and most (74%) of the study participants had a history of recurrent gout. The patients were followed for 2 weeks.

Scores on several measures of joint pain, redness, and tenderness were equivalent between the two treatment groups throughout the study period. During a 2-hour period at the emergency department, 100-mm visual analog scale (VAS) pain scores at rest declined by 6.54 mm/hour with indomethacin and by 5.05 mm/hour with prednisolone, and with activity, the declines were 11.69 mm/hour and 11.38 mm/hour, respectively. VAS scores declined during days 1-14 of treatment by similar mean amounts both at rest (1.80 mm/day for indomethacin and 1.68 mm/day for prednisolone) and with activity (2.96 mm/day vs. 3.19 mm/day, respectively). All VAS pain score improvements except for the one at rest in the ED exceeded 13 mm, meeting the definition for clinically meaningful improvement. The number of patients who showed clinically meaningful declines in pain scores also was equivalent between the two groups in both the intention-to-treat and the per-protocol analyses, the investigators said (Ann Intern Med. 2016 Feb 23. doi: 10.7326/M14-2070).

Both groups also showed similar responses in secondary endpoints of improvement in redness and tenderness of the affected joints, need for additional paracetamol, and patient satisfaction with analgesia.

There were no serious adverse events, but seven patients in the indomethacin group and one in the prednisolone group discontinued treatment because of adverse signs or symptoms. This included abdominal pain, dizziness, and lethargy among patients taking indomethacin and mild hyperkalemia in the patient taking prednisolone. The rate of minor adverse events was significantly higher with indomethacin (19%) than with prednisolone (6%).

“Our study provides robust evidence that oral corticosteroids are as effective at treating pain and as acceptable to patients as NSAIDs,” Dr. Rainer and his associates noted.

This trial was supported by the Hong Kong government’s Health and Health Services Research Grant Committee. Dr. Rainer and his associates reported having no relevant financial disclosures.

Oral prednisolone is as effective as indomethacin for relieving pain in acute gout and should be considered a first-line treatment option, according to a report published online Feb. 22 in Annals of Internal Medicine.

Colchicine and nonsteroidal anti-inflammatory drugs have been considered the first-line treatment for acute gout for many years. “However, their use is limited in elderly adults and in patients with comorbid conditions (such as renal insufficiency or gastrointestinal disease) because of their potential adverse effects and drug interactions,” said Dr. Timothy Hudson Rainer of the emergency medicine academic unit, Cardiff (Wales) University, and his associates.

©ThamKC/Thinkstock

They performed a double-blind, randomized trial comparing oral indomethacin against oral prednisolone in 416 patients who presented during a 2-year period to the emergency departments of four Hong Kong hospitals, where acute gout typically is treated in the ED. Those who were randomized to indomethacin initially received 50 mg (two 25-mg tablets) of the drug three times a day and six tablets of oral placebo prednisolone once a day for 2 days, followed by 25 mg of indomethacin three times a day and six tablets of placebo prednisolone once a day for 3 days. Prednisolone-treated patients initially received 30 mg (three 10-mg tablets) of the drug once a day and two tablets of placebo indomethacin three times a day for 2 days, followed by 30 mg (three 10-mg tablets) of prednisolone once a day and one tablet of placebo indomethacin three times a day for 3 days. All the patients received 1 g oral paracetamol to be taken every 6 hours as needed. The mean patient age was 65 years, and most (74%) of the study participants had a history of recurrent gout. The patients were followed for 2 weeks.

Scores on several measures of joint pain, redness, and tenderness were equivalent between the two treatment groups throughout the study period. During a 2-hour period at the emergency department, 100-mm visual analog scale (VAS) pain scores at rest declined by 6.54 mm/hour with indomethacin and by 5.05 mm/hour with prednisolone, and with activity, the declines were 11.69 mm/hour and 11.38 mm/hour, respectively. VAS scores declined during days 1-14 of treatment by similar mean amounts both at rest (1.80 mm/day for indomethacin and 1.68 mm/day for prednisolone) and with activity (2.96 mm/day vs. 3.19 mm/day, respectively). All VAS pain score improvements except for the one at rest in the ED exceeded 13 mm, meeting the definition for clinically meaningful improvement. The number of patients who showed clinically meaningful declines in pain scores also was equivalent between the two groups in both the intention-to-treat and the per-protocol analyses, the investigators said (Ann Intern Med. 2016 Feb 23. doi: 10.7326/M14-2070).

Both groups also showed similar responses in secondary endpoints of improvement in redness and tenderness of the affected joints, need for additional paracetamol, and patient satisfaction with analgesia.

There were no serious adverse events, but seven patients in the indomethacin group and one in the prednisolone group discontinued treatment because of adverse signs or symptoms. This included abdominal pain, dizziness, and lethargy among patients taking indomethacin and mild hyperkalemia in the patient taking prednisolone. The rate of minor adverse events was significantly higher with indomethacin (19%) than with prednisolone (6%).

“Our study provides robust evidence that oral corticosteroids are as effective at treating pain and as acceptable to patients as NSAIDs,” Dr. Rainer and his associates noted.

This trial was supported by the Hong Kong government’s Health and Health Services Research Grant Committee. Dr. Rainer and his associates reported having no relevant financial disclosures.

Oral prednisolone is as effective as indomethacin for relieving pain in acute gout and should be considered a first-line treatment option, according to a report published online Feb. 22 in Annals of Internal Medicine.

Colchicine and nonsteroidal anti-inflammatory drugs have been considered the first-line treatment for acute gout for many years. “However, their use is limited in elderly adults and in patients with comorbid conditions (such as renal insufficiency or gastrointestinal disease) because of their potential adverse effects and drug interactions,” said Dr. Timothy Hudson Rainer of the emergency medicine academic unit, Cardiff (Wales) University, and his associates.

©ThamKC/Thinkstock

They performed a double-blind, randomized trial comparing oral indomethacin against oral prednisolone in 416 patients who presented during a 2-year period to the emergency departments of four Hong Kong hospitals, where acute gout typically is treated in the ED. Those who were randomized to indomethacin initially received 50 mg (two 25-mg tablets) of the drug three times a day and six tablets of oral placebo prednisolone once a day for 2 days, followed by 25 mg of indomethacin three times a day and six tablets of placebo prednisolone once a day for 3 days. Prednisolone-treated patients initially received 30 mg (three 10-mg tablets) of the drug once a day and two tablets of placebo indomethacin three times a day for 2 days, followed by 30 mg (three 10-mg tablets) of prednisolone once a day and one tablet of placebo indomethacin three times a day for 3 days. All the patients received 1 g oral paracetamol to be taken every 6 hours as needed. The mean patient age was 65 years, and most (74%) of the study participants had a history of recurrent gout. The patients were followed for 2 weeks.

Scores on several measures of joint pain, redness, and tenderness were equivalent between the two treatment groups throughout the study period. During a 2-hour period at the emergency department, 100-mm visual analog scale (VAS) pain scores at rest declined by 6.54 mm/hour with indomethacin and by 5.05 mm/hour with prednisolone, and with activity, the declines were 11.69 mm/hour and 11.38 mm/hour, respectively. VAS scores declined during days 1-14 of treatment by similar mean amounts both at rest (1.80 mm/day for indomethacin and 1.68 mm/day for prednisolone) and with activity (2.96 mm/day vs. 3.19 mm/day, respectively). All VAS pain score improvements except for the one at rest in the ED exceeded 13 mm, meeting the definition for clinically meaningful improvement. The number of patients who showed clinically meaningful declines in pain scores also was equivalent between the two groups in both the intention-to-treat and the per-protocol analyses, the investigators said (Ann Intern Med. 2016 Feb 23. doi: 10.7326/M14-2070).

Both groups also showed similar responses in secondary endpoints of improvement in redness and tenderness of the affected joints, need for additional paracetamol, and patient satisfaction with analgesia.

There were no serious adverse events, but seven patients in the indomethacin group and one in the prednisolone group discontinued treatment because of adverse signs or symptoms. This included abdominal pain, dizziness, and lethargy among patients taking indomethacin and mild hyperkalemia in the patient taking prednisolone. The rate of minor adverse events was significantly higher with indomethacin (19%) than with prednisolone (6%).

“Our study provides robust evidence that oral corticosteroids are as effective at treating pain and as acceptable to patients as NSAIDs,” Dr. Rainer and his associates noted.

This trial was supported by the Hong Kong government’s Health and Health Services Research Grant Committee. Dr. Rainer and his associates reported having no relevant financial disclosures.

Lesinurad (Zurampic) has been approved to treat hyperuricemia associated with gout, when used in combination with a xanthine oxidase inhibitor, the Food and Drug Administration announced on Dec. 22.

Lesinurad promotes uric acid excretion by inhibiting the function of transporter proteins involved in uric acid reabsorption in the kidney.

“Zurampic provides a new treatment option for the millions of people who may develop gout over their lifetimes,” said Dr. Badrul Chowdhury, director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.

The drug’s safety and efficacy were evaluated in 1,537 participants in three randomized, placebo-controlled studies of its use in combination with a xanthine oxidase inhibitor. Participants treated for up to 12 months with lesinurad experienced reduced serum uric acid levels, compared with participants given placebo.

The most common adverse reactions in the clinical trials were headache, influenza, increased blood creatinine, and gastroesophageal reflux disease. Lesinurad has a boxed warning that provides important safety information, including the risk for acute renal failure, which is more common when lesinurad is used without a xanthine oxidase inhibitor and with higher-than-approved doses.

The FDA also said in its statement that the agency is requiring a postmarketing study to further evaluate the renal and cardiovascular safety of lesinurad.

Zurampic is manufactured by AstraZeneca Pharmaceuticals.

[email protected]

On Twitter @maryjodales

Lesinurad (Zurampic) has been approved to treat hyperuricemia associated with gout, when used in combination with a xanthine oxidase inhibitor, the Food and Drug Administration announced on Dec. 22.

Lesinurad promotes uric acid excretion by inhibiting the function of transporter proteins involved in uric acid reabsorption in the kidney.

“Zurampic provides a new treatment option for the millions of people who may develop gout over their lifetimes,” said Dr. Badrul Chowdhury, director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.

The drug’s safety and efficacy were evaluated in 1,537 participants in three randomized, placebo-controlled studies of its use in combination with a xanthine oxidase inhibitor. Participants treated for up to 12 months with lesinurad experienced reduced serum uric acid levels, compared with participants given placebo.

The most common adverse reactions in the clinical trials were headache, influenza, increased blood creatinine, and gastroesophageal reflux disease. Lesinurad has a boxed warning that provides important safety information, including the risk for acute renal failure, which is more common when lesinurad is used without a xanthine oxidase inhibitor and with higher-than-approved doses.

The FDA also said in its statement that the agency is requiring a postmarketing study to further evaluate the renal and cardiovascular safety of lesinurad.

Zurampic is manufactured by AstraZeneca Pharmaceuticals.

[email protected]

On Twitter @maryjodales

Lesinurad (Zurampic) has been approved to treat hyperuricemia associated with gout, when used in combination with a xanthine oxidase inhibitor, the Food and Drug Administration announced on Dec. 22.

Lesinurad promotes uric acid excretion by inhibiting the function of transporter proteins involved in uric acid reabsorption in the kidney.

“Zurampic provides a new treatment option for the millions of people who may develop gout over their lifetimes,” said Dr. Badrul Chowdhury, director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.

The drug’s safety and efficacy were evaluated in 1,537 participants in three randomized, placebo-controlled studies of its use in combination with a xanthine oxidase inhibitor. Participants treated for up to 12 months with lesinurad experienced reduced serum uric acid levels, compared with participants given placebo.

The most common adverse reactions in the clinical trials were headache, influenza, increased blood creatinine, and gastroesophageal reflux disease. Lesinurad has a boxed warning that provides important safety information, including the risk for acute renal failure, which is more common when lesinurad is used without a xanthine oxidase inhibitor and with higher-than-approved doses.

The FDA also said in its statement that the agency is requiring a postmarketing study to further evaluate the renal and cardiovascular safety of lesinurad.

Zurampic is manufactured by AstraZeneca Pharmaceuticals.

[email protected]

On Twitter @maryjodales

SAN FRANCISCO – Hold off on surgery in patients with presumed septic arthritis if they’re not otherwise too sick and their cultures don’t grow out a pathogenic organism within 48 hours.

The reason is because those patients are likely to have synovial fluid that was contaminated during collection, not a true joint infection.

The advice comes from investigators at Beth Israel Deaconess Medical Center, Boston, who compared 425 monoarticular septic arthritis cases with 25 cases that turned out to be false positives due to synovial fluid contamination; most of the false positives got antibiotics, and three (12%) had joint operations that they did not need.

“Rushing off to the operating room isn’t” always warranted. “You can suspect contamination if patients have milder disease manifestations and cultures grow late,” said investigator Dr. Robert H. Shmerling, clinical chief of Beth Israel’s division of rheumatology.

The findings help determine when – and when not – to be aggressive with patients who present with what looks to be septic arthritis. “No one’s ever really looked at this before,” he said at the annual meeting of the American College of Rheumatology.

“These are very different sorts of patients. Look at the full range of clinical characteristics and lab values, not just the synovial fluid tap. If contamination is suspected, you can wait until the cultures come back or possibly do serial taps before going to the operating room,” said coinvestigator Clara Zhu, a medical student at Boston University.

Patients with true joint infections had higher mean peripheral polymorphonuclear neutrophil percentages (78% vs. 68% in false positives) and synovial fluid polymorphonuclear cell percentages (88% vs. 74% in false positives). True cases also had substantially higher mean synovial fluid white blood cell counts (88,000 vs. 29,000).

Unlike true cases, contaminated synovial fluid took about 4 days to grow out a positive culture, and the most common organisms by far were coagulase-negative staphylococci, typically normal skin bacteria.

Patients with contaminated fluid also tended to be older (71 vs. 59 years), with fewer prior admissions. They were far less likely to have had recent joint procedures and histories of septic arthritis but were more likely to have synovial fluid crystals, as in gout. False positives also left the hospital sooner (7 vs. 11 days) and were less likely to be readmitted within 2 months. They were also less likely to present with fever (19% vs. 37%) but not significantly so.

This “study suggests that contaminated synovial fluid is found in up to 6% of patients with suspected septic arthritis and positive synovial fluid or synovial biopsy cultures. We recommend a conservative approach for patients with ... mild disease manifestations and no growth of pathogenic organisms within the first 48 hours,” the investigators concluded.

The authors have no disclosures, and there was no outside funding for the work.

[email protected]

SAN FRANCISCO – Hold off on surgery in patients with presumed septic arthritis if they’re not otherwise too sick and their cultures don’t grow out a pathogenic organism within 48 hours.

The reason is because those patients are likely to have synovial fluid that was contaminated during collection, not a true joint infection.

The advice comes from investigators at Beth Israel Deaconess Medical Center, Boston, who compared 425 monoarticular septic arthritis cases with 25 cases that turned out to be false positives due to synovial fluid contamination; most of the false positives got antibiotics, and three (12%) had joint operations that they did not need.

“Rushing off to the operating room isn’t” always warranted. “You can suspect contamination if patients have milder disease manifestations and cultures grow late,” said investigator Dr. Robert H. Shmerling, clinical chief of Beth Israel’s division of rheumatology.

The findings help determine when – and when not – to be aggressive with patients who present with what looks to be septic arthritis. “No one’s ever really looked at this before,” he said at the annual meeting of the American College of Rheumatology.

“These are very different sorts of patients. Look at the full range of clinical characteristics and lab values, not just the synovial fluid tap. If contamination is suspected, you can wait until the cultures come back or possibly do serial taps before going to the operating room,” said coinvestigator Clara Zhu, a medical student at Boston University.

Patients with true joint infections had higher mean peripheral polymorphonuclear neutrophil percentages (78% vs. 68% in false positives) and synovial fluid polymorphonuclear cell percentages (88% vs. 74% in false positives). True cases also had substantially higher mean synovial fluid white blood cell counts (88,000 vs. 29,000).

Unlike true cases, contaminated synovial fluid took about 4 days to grow out a positive culture, and the most common organisms by far were coagulase-negative staphylococci, typically normal skin bacteria.

Patients with contaminated fluid also tended to be older (71 vs. 59 years), with fewer prior admissions. They were far less likely to have had recent joint procedures and histories of septic arthritis but were more likely to have synovial fluid crystals, as in gout. False positives also left the hospital sooner (7 vs. 11 days) and were less likely to be readmitted within 2 months. They were also less likely to present with fever (19% vs. 37%) but not significantly so.

This “study suggests that contaminated synovial fluid is found in up to 6% of patients with suspected septic arthritis and positive synovial fluid or synovial biopsy cultures. We recommend a conservative approach for patients with ... mild disease manifestations and no growth of pathogenic organisms within the first 48 hours,” the investigators concluded.

The authors have no disclosures, and there was no outside funding for the work.

[email protected]

SAN FRANCISCO – Hold off on surgery in patients with presumed septic arthritis if they’re not otherwise too sick and their cultures don’t grow out a pathogenic organism within 48 hours.

The reason is because those patients are likely to have synovial fluid that was contaminated during collection, not a true joint infection.

The advice comes from investigators at Beth Israel Deaconess Medical Center, Boston, who compared 425 monoarticular septic arthritis cases with 25 cases that turned out to be false positives due to synovial fluid contamination; most of the false positives got antibiotics, and three (12%) had joint operations that they did not need.

“Rushing off to the operating room isn’t” always warranted. “You can suspect contamination if patients have milder disease manifestations and cultures grow late,” said investigator Dr. Robert H. Shmerling, clinical chief of Beth Israel’s division of rheumatology.

The findings help determine when – and when not – to be aggressive with patients who present with what looks to be septic arthritis. “No one’s ever really looked at this before,” he said at the annual meeting of the American College of Rheumatology.

“These are very different sorts of patients. Look at the full range of clinical characteristics and lab values, not just the synovial fluid tap. If contamination is suspected, you can wait until the cultures come back or possibly do serial taps before going to the operating room,” said coinvestigator Clara Zhu, a medical student at Boston University.

Patients with true joint infections had higher mean peripheral polymorphonuclear neutrophil percentages (78% vs. 68% in false positives) and synovial fluid polymorphonuclear cell percentages (88% vs. 74% in false positives). True cases also had substantially higher mean synovial fluid white blood cell counts (88,000 vs. 29,000).

Unlike true cases, contaminated synovial fluid took about 4 days to grow out a positive culture, and the most common organisms by far were coagulase-negative staphylococci, typically normal skin bacteria.

Patients with contaminated fluid also tended to be older (71 vs. 59 years), with fewer prior admissions. They were far less likely to have had recent joint procedures and histories of septic arthritis but were more likely to have synovial fluid crystals, as in gout. False positives also left the hospital sooner (7 vs. 11 days) and were less likely to be readmitted within 2 months. They were also less likely to present with fever (19% vs. 37%) but not significantly so.

This “study suggests that contaminated synovial fluid is found in up to 6% of patients with suspected septic arthritis and positive synovial fluid or synovial biopsy cultures. We recommend a conservative approach for patients with ... mild disease manifestations and no growth of pathogenic organisms within the first 48 hours,” the investigators concluded.

The authors have no disclosures, and there was no outside funding for the work.

[email protected]

SAN FRANCISCO – Hospitalization rates for gout doubled between 1993 and 2011, while those for rheumatoid arthritis fell by 67%, Dr. Sian Yik Lim reported at the annual meeting of the American College of Rheumatology.

The trends reveal marked progress in the treatment of rheumatoid arthritis, but “also highlight a critical need to improve gout care” and to implement measures to combat its rising prevalence, said Dr. Lim, a research fellow in medicine at Massachusetts General Hospital, Boston.

The study is “a very nice piece of work,” added Dr. James Galloway, who helped moderate the session at the meeting and is a lecturer in rheumatology at King’s College Hospital in London. “It makes us wonder whether we should spend more time teaching our primary care physician colleagues more about gout than rheumatoid arthritis.”

©Kimberly Pack/Thinkstock.com

Gout and rheumatoid arthritis are the two most common inflammatory joint diseases, but few longitudinal studies have examined trends in related hospital admissions or costs, Dr. Lim said. Therefore, he and his associates extracted primary hospital discharge ICD-9 diagnosis codes from the National Inpatient Sample and also studied primary procedure codes for total knee replacement, total hip replacement, and other major joint surgeries for 1993 through 2011. In addition, they merged these with cost data from the Healthcare Cost and Utilization Project for 2001 to 2011.

Hospitalizations for gout and rheumatoid arthritis “crisscrossed” during the study period, Dr. Lim said. While there were more than three times as many hospitalizations for rheumatoid arthritis (26,712) as for gout (8,485) in 1993, by 2011, there were nearly twice as many admissions for gout (20,949) as for rheumatoid arthritis (11,015). Likewise, hospitalization rates for gout rose from 4.5 to 9 per 100,000 adults, while rheumatoid arthritis admissions fell by about two-thirds, from 14 to 5 per 100,000 adults. For the entire study period, hospital admissions for gout totaled 254,982, compared with 323,649 for rheumatoid arthritis, Dr. Lim added.

The investigators also documented a steady drop in admissions for total knee replacement, total hip replacement, and other major joint surgeries among rheumatoid arthritis patients, mirroring the results of recent multicenter studies in California (Ann Rheum Dis. 2009 Jul 5. doi: 10.1136/ard.2009.112474), the United Kingdom (Rheumatology [Oxford]. 2015 Apr;54[4]:666-71), and Germany (Ann Rheum Dis. 2015;74:738-45), Dr. Lim said. “This finding contrasts with the overall dramatic increase in these surgeries in the general United States population in recent years,” he added.

Inflation-adjusted hospital costs for gout and rheumatoid arthritis also converged during the study period, and by 2011, costs for gout actually exceeded those for rheumatoid arthritis, Dr. Lim said.

Overall, the findings reflect stark differences in care for gout and rheumatoid arthritis in the United States, he added. “New and potent drugs, effective combination regimens, and management strategies are increasingly being adopted for rheumatoid arthritis, but care for gout remains suboptimal, even though its prevalence and incidence are increasing,” he said. “Although the vast majority of gout patients are indicated for urate-lowering therapy, only a small proportion retrieve treatment, and the level of uric acid is not even measured in the vast majority of patients.”

Surveys also indicate that patients with gout often do not receive clear explanations about their disease, which may explain why as few as 10% follow treatment recommendations, according to Dr. Lim. He pointed to a hospital-based, retrospective cohort study reported at last year’s ACR annual meeting in which 89% of hospitalizations for gout were considered preventable. “These data support the need to improve gout prevention and care,” he said.

Dr. Lim had no disclosures. Dr. Hyon Choi, the senior author, reported having served on advisory boards for Takeda and AstraZeneca.

SAN FRANCISCO – Hospitalization rates for gout doubled between 1993 and 2011, while those for rheumatoid arthritis fell by 67%, Dr. Sian Yik Lim reported at the annual meeting of the American College of Rheumatology.

The trends reveal marked progress in the treatment of rheumatoid arthritis, but “also highlight a critical need to improve gout care” and to implement measures to combat its rising prevalence, said Dr. Lim, a research fellow in medicine at Massachusetts General Hospital, Boston.

The study is “a very nice piece of work,” added Dr. James Galloway, who helped moderate the session at the meeting and is a lecturer in rheumatology at King’s College Hospital in London. “It makes us wonder whether we should spend more time teaching our primary care physician colleagues more about gout than rheumatoid arthritis.”

©Kimberly Pack/Thinkstock.com

Gout and rheumatoid arthritis are the two most common inflammatory joint diseases, but few longitudinal studies have examined trends in related hospital admissions or costs, Dr. Lim said. Therefore, he and his associates extracted primary hospital discharge ICD-9 diagnosis codes from the National Inpatient Sample and also studied primary procedure codes for total knee replacement, total hip replacement, and other major joint surgeries for 1993 through 2011. In addition, they merged these with cost data from the Healthcare Cost and Utilization Project for 2001 to 2011.

Hospitalizations for gout and rheumatoid arthritis “crisscrossed” during the study period, Dr. Lim said. While there were more than three times as many hospitalizations for rheumatoid arthritis (26,712) as for gout (8,485) in 1993, by 2011, there were nearly twice as many admissions for gout (20,949) as for rheumatoid arthritis (11,015). Likewise, hospitalization rates for gout rose from 4.5 to 9 per 100,000 adults, while rheumatoid arthritis admissions fell by about two-thirds, from 14 to 5 per 100,000 adults. For the entire study period, hospital admissions for gout totaled 254,982, compared with 323,649 for rheumatoid arthritis, Dr. Lim added.

The investigators also documented a steady drop in admissions for total knee replacement, total hip replacement, and other major joint surgeries among rheumatoid arthritis patients, mirroring the results of recent multicenter studies in California (Ann Rheum Dis. 2009 Jul 5. doi: 10.1136/ard.2009.112474), the United Kingdom (Rheumatology [Oxford]. 2015 Apr;54[4]:666-71), and Germany (Ann Rheum Dis. 2015;74:738-45), Dr. Lim said. “This finding contrasts with the overall dramatic increase in these surgeries in the general United States population in recent years,” he added.

Inflation-adjusted hospital costs for gout and rheumatoid arthritis also converged during the study period, and by 2011, costs for gout actually exceeded those for rheumatoid arthritis, Dr. Lim said.

Overall, the findings reflect stark differences in care for gout and rheumatoid arthritis in the United States, he added. “New and potent drugs, effective combination regimens, and management strategies are increasingly being adopted for rheumatoid arthritis, but care for gout remains suboptimal, even though its prevalence and incidence are increasing,” he said. “Although the vast majority of gout patients are indicated for urate-lowering therapy, only a small proportion retrieve treatment, and the level of uric acid is not even measured in the vast majority of patients.”

Surveys also indicate that patients with gout often do not receive clear explanations about their disease, which may explain why as few as 10% follow treatment recommendations, according to Dr. Lim. He pointed to a hospital-based, retrospective cohort study reported at last year’s ACR annual meeting in which 89% of hospitalizations for gout were considered preventable. “These data support the need to improve gout prevention and care,” he said.

Dr. Lim had no disclosures. Dr. Hyon Choi, the senior author, reported having served on advisory boards for Takeda and AstraZeneca.

SAN FRANCISCO – Hospitalization rates for gout doubled between 1993 and 2011, while those for rheumatoid arthritis fell by 67%, Dr. Sian Yik Lim reported at the annual meeting of the American College of Rheumatology.

The trends reveal marked progress in the treatment of rheumatoid arthritis, but “also highlight a critical need to improve gout care” and to implement measures to combat its rising prevalence, said Dr. Lim, a research fellow in medicine at Massachusetts General Hospital, Boston.

The study is “a very nice piece of work,” added Dr. James Galloway, who helped moderate the session at the meeting and is a lecturer in rheumatology at King’s College Hospital in London. “It makes us wonder whether we should spend more time teaching our primary care physician colleagues more about gout than rheumatoid arthritis.”

©Kimberly Pack/Thinkstock.com

Gout and rheumatoid arthritis are the two most common inflammatory joint diseases, but few longitudinal studies have examined trends in related hospital admissions or costs, Dr. Lim said. Therefore, he and his associates extracted primary hospital discharge ICD-9 diagnosis codes from the National Inpatient Sample and also studied primary procedure codes for total knee replacement, total hip replacement, and other major joint surgeries for 1993 through 2011. In addition, they merged these with cost data from the Healthcare Cost and Utilization Project for 2001 to 2011.

Hospitalizations for gout and rheumatoid arthritis “crisscrossed” during the study period, Dr. Lim said. While there were more than three times as many hospitalizations for rheumatoid arthritis (26,712) as for gout (8,485) in 1993, by 2011, there were nearly twice as many admissions for gout (20,949) as for rheumatoid arthritis (11,015). Likewise, hospitalization rates for gout rose from 4.5 to 9 per 100,000 adults, while rheumatoid arthritis admissions fell by about two-thirds, from 14 to 5 per 100,000 adults. For the entire study period, hospital admissions for gout totaled 254,982, compared with 323,649 for rheumatoid arthritis, Dr. Lim added.

The investigators also documented a steady drop in admissions for total knee replacement, total hip replacement, and other major joint surgeries among rheumatoid arthritis patients, mirroring the results of recent multicenter studies in California (Ann Rheum Dis. 2009 Jul 5. doi: 10.1136/ard.2009.112474), the United Kingdom (Rheumatology [Oxford]. 2015 Apr;54[4]:666-71), and Germany (Ann Rheum Dis. 2015;74:738-45), Dr. Lim said. “This finding contrasts with the overall dramatic increase in these surgeries in the general United States population in recent years,” he added.

Inflation-adjusted hospital costs for gout and rheumatoid arthritis also converged during the study period, and by 2011, costs for gout actually exceeded those for rheumatoid arthritis, Dr. Lim said.

Overall, the findings reflect stark differences in care for gout and rheumatoid arthritis in the United States, he added. “New and potent drugs, effective combination regimens, and management strategies are increasingly being adopted for rheumatoid arthritis, but care for gout remains suboptimal, even though its prevalence and incidence are increasing,” he said. “Although the vast majority of gout patients are indicated for urate-lowering therapy, only a small proportion retrieve treatment, and the level of uric acid is not even measured in the vast majority of patients.”

Surveys also indicate that patients with gout often do not receive clear explanations about their disease, which may explain why as few as 10% follow treatment recommendations, according to Dr. Lim. He pointed to a hospital-based, retrospective cohort study reported at last year’s ACR annual meeting in which 89% of hospitalizations for gout were considered preventable. “These data support the need to improve gout prevention and care,” he said.

Dr. Lim had no disclosures. Dr. Hyon Choi, the senior author, reported having served on advisory boards for Takeda and AstraZeneca.

SAN FRANCISCO – Patients with gout who fail to sufficiently lower their serum urate level despite adherence to a regimen of allopurinol 300 mg/day may have a genetic polymorphism affecting their response to the medication, according to new findings presented at the annual meeting of the American College of Rheumatology.

“ABCG2 genotyping may identify patients who will not reach target serum urate levels on standard allopurinol doses,” said study presenter and principal investigator Dr. Lisa K. Stamp of the University of Otago, Christchurch, New Zealand.

Sustained lowering of serum urate (SU) to less than 6 mg/dL – achieved most commonly by inhibition of xanthine oxidase using allopurinol – is crucial for the long-term management of gout. Yet, in clinical practice, less than half of patients treated with allopurinol achieve this SU target. This is usually because of poor adherence or an inappropriately low dose of the drug. But, in some patients, the response can be poor even despite allopurinol 300 mg daily. The reason for failure of allopurinol treatment in these poor responders has been unknown.

©ThamKC/Thinkstock

“It is important to consider genes that might help predict response or toxicity. To date, pharmacogenetic studies of allopurinol have focused on adverse effects. However, we were more interested in predicting response. The ability to predict poor response is important because it can influence drug choice and shorten the time to achieve target SU,” Dr. Stamp said.

The present study helps to validate the results of a previous genomewide association study in which the single nucleotide polymorphism (SNP) rs2231142 in ABCG2 was associated with poor response to allopurinol (Clin Pharmacol Ther. 2015 May;97[5]:518-25). Adherence to allopurinol was not examined in that study, so Dr. Stamp and her colleagues set out to make sure that it was not a confounder. The current study examined the SNP’s association with allopurinol response more closely in 264 gout patients who were well characterized phenotypically. All were being treated with allopurinol and all adhered to their treatment regimen. Overall, 120 were deemed good responders, with SU of 6 mg/dL or less on daily allopurinol of 300 mg or less, and 68 were poor responders, with SU of 6 mg/dL or higher despite a daily dose of allopurinol exceeding 300 mg. Another 76 patients were nonadherent/nonclassifiable. The poor responders tended to be younger and were more likely to be male, nonwhite, and heavier than their counterparts who responded well.

Genotyping for the rs2231142 SNP revealed a greater preponderance of the minor genotype in poor responders, compared with good responders (39% vs. 18%). This genotype was significantly associated with poor response after adjusting for age, sex, body-mass index, and ethnicity (odds ratio, 2.91; 95% confidence interval, 1.71-5.17; P = .00015). The mechanism – still to be proven – may involve reduced urate excretion from the gut.

There may not be a case for screening for the genotype just yet, according to Dr. Christopher M. Burns, a rheumatologist at Dartmouth Hitchcock Medical Center, Lebanon, N.H., who was not involved in the study. He said “it’s hard to see why you would screen for this variant, as it doesn’t account for all resistance, and you would still end up pushing the allopurinol dose up to achieve a SU of less than 6.0 mg/dL anyway. Since it’s not an adverse event warning signal, but simply one marker of possibly requiring a higher allopurinol dose, and allopurinol is an inexpensive drug, why would you check it? At least, that’s my sense. The findings may be more important simply for a better understanding of urate metabolism and the mechanism of action of allopurinol and oxypurinol.”

Dr. Stamp reported a financial disclosure with AstraZeneca.

SAN FRANCISCO – Patients with gout who fail to sufficiently lower their serum urate level despite adherence to a regimen of allopurinol 300 mg/day may have a genetic polymorphism affecting their response to the medication, according to new findings presented at the annual meeting of the American College of Rheumatology.

“ABCG2 genotyping may identify patients who will not reach target serum urate levels on standard allopurinol doses,” said study presenter and principal investigator Dr. Lisa K. Stamp of the University of Otago, Christchurch, New Zealand.

Sustained lowering of serum urate (SU) to less than 6 mg/dL – achieved most commonly by inhibition of xanthine oxidase using allopurinol – is crucial for the long-term management of gout. Yet, in clinical practice, less than half of patients treated with allopurinol achieve this SU target. This is usually because of poor adherence or an inappropriately low dose of the drug. But, in some patients, the response can be poor even despite allopurinol 300 mg daily. The reason for failure of allopurinol treatment in these poor responders has been unknown.

©ThamKC/Thinkstock

“It is important to consider genes that might help predict response or toxicity. To date, pharmacogenetic studies of allopurinol have focused on adverse effects. However, we were more interested in predicting response. The ability to predict poor response is important because it can influence drug choice and shorten the time to achieve target SU,” Dr. Stamp said.

The present study helps to validate the results of a previous genomewide association study in which the single nucleotide polymorphism (SNP) rs2231142 in ABCG2 was associated with poor response to allopurinol (Clin Pharmacol Ther. 2015 May;97[5]:518-25). Adherence to allopurinol was not examined in that study, so Dr. Stamp and her colleagues set out to make sure that it was not a confounder. The current study examined the SNP’s association with allopurinol response more closely in 264 gout patients who were well characterized phenotypically. All were being treated with allopurinol and all adhered to their treatment regimen. Overall, 120 were deemed good responders, with SU of 6 mg/dL or less on daily allopurinol of 300 mg or less, and 68 were poor responders, with SU of 6 mg/dL or higher despite a daily dose of allopurinol exceeding 300 mg. Another 76 patients were nonadherent/nonclassifiable. The poor responders tended to be younger and were more likely to be male, nonwhite, and heavier than their counterparts who responded well.

Genotyping for the rs2231142 SNP revealed a greater preponderance of the minor genotype in poor responders, compared with good responders (39% vs. 18%). This genotype was significantly associated with poor response after adjusting for age, sex, body-mass index, and ethnicity (odds ratio, 2.91; 95% confidence interval, 1.71-5.17; P = .00015). The mechanism – still to be proven – may involve reduced urate excretion from the gut.

There may not be a case for screening for the genotype just yet, according to Dr. Christopher M. Burns, a rheumatologist at Dartmouth Hitchcock Medical Center, Lebanon, N.H., who was not involved in the study. He said “it’s hard to see why you would screen for this variant, as it doesn’t account for all resistance, and you would still end up pushing the allopurinol dose up to achieve a SU of less than 6.0 mg/dL anyway. Since it’s not an adverse event warning signal, but simply one marker of possibly requiring a higher allopurinol dose, and allopurinol is an inexpensive drug, why would you check it? At least, that’s my sense. The findings may be more important simply for a better understanding of urate metabolism and the mechanism of action of allopurinol and oxypurinol.”

Dr. Stamp reported a financial disclosure with AstraZeneca.

SAN FRANCISCO – Patients with gout who fail to sufficiently lower their serum urate level despite adherence to a regimen of allopurinol 300 mg/day may have a genetic polymorphism affecting their response to the medication, according to new findings presented at the annual meeting of the American College of Rheumatology.

“ABCG2 genotyping may identify patients who will not reach target serum urate levels on standard allopurinol doses,” said study presenter and principal investigator Dr. Lisa K. Stamp of the University of Otago, Christchurch, New Zealand.

Sustained lowering of serum urate (SU) to less than 6 mg/dL – achieved most commonly by inhibition of xanthine oxidase using allopurinol – is crucial for the long-term management of gout. Yet, in clinical practice, less than half of patients treated with allopurinol achieve this SU target. This is usually because of poor adherence or an inappropriately low dose of the drug. But, in some patients, the response can be poor even despite allopurinol 300 mg daily. The reason for failure of allopurinol treatment in these poor responders has been unknown.

©ThamKC/Thinkstock

“It is important to consider genes that might help predict response or toxicity. To date, pharmacogenetic studies of allopurinol have focused on adverse effects. However, we were more interested in predicting response. The ability to predict poor response is important because it can influence drug choice and shorten the time to achieve target SU,” Dr. Stamp said.

The present study helps to validate the results of a previous genomewide association study in which the single nucleotide polymorphism (SNP) rs2231142 in ABCG2 was associated with poor response to allopurinol (Clin Pharmacol Ther. 2015 May;97[5]:518-25). Adherence to allopurinol was not examined in that study, so Dr. Stamp and her colleagues set out to make sure that it was not a confounder. The current study examined the SNP’s association with allopurinol response more closely in 264 gout patients who were well characterized phenotypically. All were being treated with allopurinol and all adhered to their treatment regimen. Overall, 120 were deemed good responders, with SU of 6 mg/dL or less on daily allopurinol of 300 mg or less, and 68 were poor responders, with SU of 6 mg/dL or higher despite a daily dose of allopurinol exceeding 300 mg. Another 76 patients were nonadherent/nonclassifiable. The poor responders tended to be younger and were more likely to be male, nonwhite, and heavier than their counterparts who responded well.

Genotyping for the rs2231142 SNP revealed a greater preponderance of the minor genotype in poor responders, compared with good responders (39% vs. 18%). This genotype was significantly associated with poor response after adjusting for age, sex, body-mass index, and ethnicity (odds ratio, 2.91; 95% confidence interval, 1.71-5.17; P = .00015). The mechanism – still to be proven – may involve reduced urate excretion from the gut.

There may not be a case for screening for the genotype just yet, according to Dr. Christopher M. Burns, a rheumatologist at Dartmouth Hitchcock Medical Center, Lebanon, N.H., who was not involved in the study. He said “it’s hard to see why you would screen for this variant, as it doesn’t account for all resistance, and you would still end up pushing the allopurinol dose up to achieve a SU of less than 6.0 mg/dL anyway. Since it’s not an adverse event warning signal, but simply one marker of possibly requiring a higher allopurinol dose, and allopurinol is an inexpensive drug, why would you check it? At least, that’s my sense. The findings may be more important simply for a better understanding of urate metabolism and the mechanism of action of allopurinol and oxypurinol.”

Dr. Stamp reported a financial disclosure with AstraZeneca.

This article was updated on 10/27/15.

Members of the Food and Drug Administration’s Arthritis Advisory Committee have voted in favor of recommending approval of the investigational uricosuric drug lesinurad at 200 mg daily for the proposed indication of treatment of hyperuricemia associated with gout in combination with a xanthine oxidase inhibitor, such as allopurinol or febuxostat.

The committee’s 10-4 vote on recommending approval came with much discussion over the benefit-to-risk analysis of lesinurad. Members voted 14-0 that the data in the four pivotal phase III trials submitted to the FDA contained enough evidence of a clinically meaningful beneficial effect of lesinurad in combination with a xanthine oxidase inhibitor (XOI) in the treatment of hyperuricemia associated with gout. However, committee members were much less certain of lesinurad’s safety profile, which indicated a narrow therapeutic index, and voted 7-6 in favor of adequate safety data to support approval, with 1 abstention.

Lesinurad 200 mg daily lowered serum uric acid (sUA) levels 1.1-1.3 mg/dL on top of what is already achieved with an XOI in its pivotal phase III trials, but it did not consistently improve patient outcomes, such as reducing gout flares, resolving tophi, and improving Health Assessment Questionnaire-Disability Index scores.

The FDA and the developer of lesinurad, Ardea Biosciences, agreed before the advisory committee meeting not to consider a 400-mg dose of the drug for marketing because it was associated with an increased incidence of renal adverse events (including serious renal AEs, serum creatinine elevations, and kidney stone AEs), compared with placebo. Although, lesinurad 200 mg was not associated with an increased incidence of serious renal or kidney stone AEs, it was associated with a smaller increase in the incidence of overall renal AE and serum creatinine elevations, which suggested dose-dependent toxicity. An imbalance in major adverse cardiovascular event incidence and exposure-adjusted incidence also was observed with lesinurad 400 mg, compared with 200 mg or placebo, although there were a small number of events.

Overall, the average concentration of lesinurad in the studies was higher with 400 mg, compared with 200 mg, but the exposure for the two doses was largely overlapping, raising questions about whether the safety profile of the 200-mg dose will be consistent if used in a larger population with more variability, the FDA said.

Two of the four pivotal phase III clinical trials of lesinurad involved patients who had been taking at least 300 mg/day allopurinol (200 mg/day in patients with estimated creatinine clearance (CrCl) of less than 60 mL/min at baseline) for at least 8 weeks and still had a sUA level of 6.5 mg/dL or greater at the screening visit (and greater than 6.0 mg/dL at the day 7 visit) and also had at least two gout flares in the preceding 12 months. They were randomized to receive placebo, lesinurad 200 mg, or lesinurad 400 mg daily in addition to their background allopurinol for 12 months.

The third study involved the same doses of lesinurad and placebo over a 12-month time frame but instead had lesinurad added on to a background of febuxostat 80 mg and required that sUA had to be at least 8 mg/dL in patients not taking urate lowering therapy (ULT) and at least 6 mg/dL in patients who were on ULT previously. Patients also had to have at least one measurable tophus on the hands/wrists and/or feet/ankles at least 5 mm in width and up to 20 mm in length.

The fourth study was a 6-month study of lesinurad 400 mg monotherapy, compared with placebo, in subjects with gout who had intolerance or contraindication to treatment with an XOI.

Committee members who voted in favor of recommending approval called for postmarketing studies that showed that the drug did indeed improve clinical outcomes such as reducing gout flares and resolution of tophi; long-term safety studies of renal and cardiovascular adverse events, including studies in patients with comorbidities commonly occurring in patients with gout; and structured, specific guidance to providers on who should receive the drug and how prescribers should handle increases in serum creatinine levels during treatment.

Lesinurad inhibits the function of multiple carrier proteins that transport uric acid in the renal proximal tubule epithelium, including uric acid transporter 1 (URAT1) and organic anion transporters 1, 3 and 4.

The FDA is not obligated to follow the recommendations of its advisory committee panels.

[email protected]

This article was updated on 10/27/15.

Members of the Food and Drug Administration’s Arthritis Advisory Committee have voted in favor of recommending approval of the investigational uricosuric drug lesinurad at 200 mg daily for the proposed indication of treatment of hyperuricemia associated with gout in combination with a xanthine oxidase inhibitor, such as allopurinol or febuxostat.

The committee’s 10-4 vote on recommending approval came with much discussion over the benefit-to-risk analysis of lesinurad. Members voted 14-0 that the data in the four pivotal phase III trials submitted to the FDA contained enough evidence of a clinically meaningful beneficial effect of lesinurad in combination with a xanthine oxidase inhibitor (XOI) in the treatment of hyperuricemia associated with gout. However, committee members were much less certain of lesinurad’s safety profile, which indicated a narrow therapeutic index, and voted 7-6 in favor of adequate safety data to support approval, with 1 abstention.

Lesinurad 200 mg daily lowered serum uric acid (sUA) levels 1.1-1.3 mg/dL on top of what is already achieved with an XOI in its pivotal phase III trials, but it did not consistently improve patient outcomes, such as reducing gout flares, resolving tophi, and improving Health Assessment Questionnaire-Disability Index scores.

The FDA and the developer of lesinurad, Ardea Biosciences, agreed before the advisory committee meeting not to consider a 400-mg dose of the drug for marketing because it was associated with an increased incidence of renal adverse events (including serious renal AEs, serum creatinine elevations, and kidney stone AEs), compared with placebo. Although, lesinurad 200 mg was not associated with an increased incidence of serious renal or kidney stone AEs, it was associated with a smaller increase in the incidence of overall renal AE and serum creatinine elevations, which suggested dose-dependent toxicity. An imbalance in major adverse cardiovascular event incidence and exposure-adjusted incidence also was observed with lesinurad 400 mg, compared with 200 mg or placebo, although there were a small number of events.

Overall, the average concentration of lesinurad in the studies was higher with 400 mg, compared with 200 mg, but the exposure for the two doses was largely overlapping, raising questions about whether the safety profile of the 200-mg dose will be consistent if used in a larger population with more variability, the FDA said.

Two of the four pivotal phase III clinical trials of lesinurad involved patients who had been taking at least 300 mg/day allopurinol (200 mg/day in patients with estimated creatinine clearance (CrCl) of less than 60 mL/min at baseline) for at least 8 weeks and still had a sUA level of 6.5 mg/dL or greater at the screening visit (and greater than 6.0 mg/dL at the day 7 visit) and also had at least two gout flares in the preceding 12 months. They were randomized to receive placebo, lesinurad 200 mg, or lesinurad 400 mg daily in addition to their background allopurinol for 12 months.

The third study involved the same doses of lesinurad and placebo over a 12-month time frame but instead had lesinurad added on to a background of febuxostat 80 mg and required that sUA had to be at least 8 mg/dL in patients not taking urate lowering therapy (ULT) and at least 6 mg/dL in patients who were on ULT previously. Patients also had to have at least one measurable tophus on the hands/wrists and/or feet/ankles at least 5 mm in width and up to 20 mm in length.

The fourth study was a 6-month study of lesinurad 400 mg monotherapy, compared with placebo, in subjects with gout who had intolerance or contraindication to treatment with an XOI.

Committee members who voted in favor of recommending approval called for postmarketing studies that showed that the drug did indeed improve clinical outcomes such as reducing gout flares and resolution of tophi; long-term safety studies of renal and cardiovascular adverse events, including studies in patients with comorbidities commonly occurring in patients with gout; and structured, specific guidance to providers on who should receive the drug and how prescribers should handle increases in serum creatinine levels during treatment.

Lesinurad inhibits the function of multiple carrier proteins that transport uric acid in the renal proximal tubule epithelium, including uric acid transporter 1 (URAT1) and organic anion transporters 1, 3 and 4.

The FDA is not obligated to follow the recommendations of its advisory committee panels.

[email protected]

This article was updated on 10/27/15.

Members of the Food and Drug Administration’s Arthritis Advisory Committee have voted in favor of recommending approval of the investigational uricosuric drug lesinurad at 200 mg daily for the proposed indication of treatment of hyperuricemia associated with gout in combination with a xanthine oxidase inhibitor, such as allopurinol or febuxostat.

The committee’s 10-4 vote on recommending approval came with much discussion over the benefit-to-risk analysis of lesinurad. Members voted 14-0 that the data in the four pivotal phase III trials submitted to the FDA contained enough evidence of a clinically meaningful beneficial effect of lesinurad in combination with a xanthine oxidase inhibitor (XOI) in the treatment of hyperuricemia associated with gout. However, committee members were much less certain of lesinurad’s safety profile, which indicated a narrow therapeutic index, and voted 7-6 in favor of adequate safety data to support approval, with 1 abstention.

Lesinurad 200 mg daily lowered serum uric acid (sUA) levels 1.1-1.3 mg/dL on top of what is already achieved with an XOI in its pivotal phase III trials, but it did not consistently improve patient outcomes, such as reducing gout flares, resolving tophi, and improving Health Assessment Questionnaire-Disability Index scores.

The FDA and the developer of lesinurad, Ardea Biosciences, agreed before the advisory committee meeting not to consider a 400-mg dose of the drug for marketing because it was associated with an increased incidence of renal adverse events (including serious renal AEs, serum creatinine elevations, and kidney stone AEs), compared with placebo. Although, lesinurad 200 mg was not associated with an increased incidence of serious renal or kidney stone AEs, it was associated with a smaller increase in the incidence of overall renal AE and serum creatinine elevations, which suggested dose-dependent toxicity. An imbalance in major adverse cardiovascular event incidence and exposure-adjusted incidence also was observed with lesinurad 400 mg, compared with 200 mg or placebo, although there were a small number of events.

Overall, the average concentration of lesinurad in the studies was higher with 400 mg, compared with 200 mg, but the exposure for the two doses was largely overlapping, raising questions about whether the safety profile of the 200-mg dose will be consistent if used in a larger population with more variability, the FDA said.

Two of the four pivotal phase III clinical trials of lesinurad involved patients who had been taking at least 300 mg/day allopurinol (200 mg/day in patients with estimated creatinine clearance (CrCl) of less than 60 mL/min at baseline) for at least 8 weeks and still had a sUA level of 6.5 mg/dL or greater at the screening visit (and greater than 6.0 mg/dL at the day 7 visit) and also had at least two gout flares in the preceding 12 months. They were randomized to receive placebo, lesinurad 200 mg, or lesinurad 400 mg daily in addition to their background allopurinol for 12 months.

The third study involved the same doses of lesinurad and placebo over a 12-month time frame but instead had lesinurad added on to a background of febuxostat 80 mg and required that sUA had to be at least 8 mg/dL in patients not taking urate lowering therapy (ULT) and at least 6 mg/dL in patients who were on ULT previously. Patients also had to have at least one measurable tophus on the hands/wrists and/or feet/ankles at least 5 mm in width and up to 20 mm in length.

The fourth study was a 6-month study of lesinurad 400 mg monotherapy, compared with placebo, in subjects with gout who had intolerance or contraindication to treatment with an XOI.

Committee members who voted in favor of recommending approval called for postmarketing studies that showed that the drug did indeed improve clinical outcomes such as reducing gout flares and resolution of tophi; long-term safety studies of renal and cardiovascular adverse events, including studies in patients with comorbidities commonly occurring in patients with gout; and structured, specific guidance to providers on who should receive the drug and how prescribers should handle increases in serum creatinine levels during treatment.

Lesinurad inhibits the function of multiple carrier proteins that transport uric acid in the renal proximal tubule epithelium, including uric acid transporter 1 (URAT1) and organic anion transporters 1, 3 and 4.

The FDA is not obligated to follow the recommendations of its advisory committee panels.

[email protected]