Gout

ADELPHI, MD. – A Food and Drug Administration advisory panel on June 21 voted 11-1 that the data on canakinumab did not support its approval as a treatment for gouty arthritis attacks, in patients who have not responded adequately to nonsteroidal anti-inflammatory drugs or colchicine.

Members of the FDA’s Arthritis Advisory Committee considered canakinumab a promising treatment, and all but one panelist agreed that the 150-mg subcutaneous dose that was studied in two phase III trials was shown to be effective in treating an attack of gouty arthritis in this population.

But, in another vote, the panel unanimously agreed that the safety profile of canakinumab did not support approval for this indication, because of concerns that included the lack of long-term safety data including the potential long-term risk of infections and the lack of data on the effects of recurrent treatment. (Only 43 patients in the studies had received three or more injections and most had been treated only once.)

The need for more data in likely patient candidates who are less healthy than those in the trials, such as those with advanced renal disease, was another concern cited by the panel. Several panelists also expressed concern that unless use was restricted in some way, canakinumab might be used to treat a broader population than described in the proposed indication.

Canakinumab (Ilaris), a monoclonal antibody that neutralizes interleukin-1beta, was approved in June 2009 for the treatment of a rare disorder, cryopyrin-associated periodic syndromes (CAPS). The new indication proposed by the manufacturer, Novartis Pharmaceuticals, is for the treatment of gouty arthritis attacks in patients who cannot obtain an adequate response with NSAIDs or colchicine.

The company described canakinumab as the first targeted anti-inflammatory treatment for gout, which could be used to treat about 6% of the patients with gouty arthritis, an estimated 300,000 patients in the United States.

In the two phase III trials of approximately 450 patients, most of whom were male and white, (mean age was early 50s) with at least three gouty arthritis attacks a year, a single 150-mg injection of canakinumab, was compared with an intramuscular injection of triamcinolone (40 mg) in treating an acute attack.

Those treated with canakinumab had significantly greater reductions in pain intensity of the affected joint, as measured by changes in a visual pain scale (a primary end point) 72 hours after the injection, compared with those treated with triamcinolone. The risk of having another gouty arthritis flare over the 12 weeks after treatment – the other primary end point – was also significantly reduced among those treated with canakinumab, compared with those on triamcinolone.

The rates of adverse events, including serious adverse events, were higher among those treated with canakinumab, compared with those on triamcinolone and included infections (19% vs. 13%, respectively) and serious infections (2% vs. 0%, respectively). Treatment with canakinumab also was associated with an increase in serum triglycerides levels, declines in renal function, and elevations in serum uric acid, and hypertension. There were three cases of renal failure among gout patients treated with canakinumab, who had predisposing factors, according to the company.

Canakinumab is under review in the European Union for the same indication.

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

ADELPHI, MD. – A Food and Drug Administration advisory panel on June 21 voted 11-1 that the data on canakinumab did not support its approval as a treatment for gouty arthritis attacks, in patients who have not responded adequately to nonsteroidal anti-inflammatory drugs or colchicine.

Members of the FDA’s Arthritis Advisory Committee considered canakinumab a promising treatment, and all but one panelist agreed that the 150-mg subcutaneous dose that was studied in two phase III trials was shown to be effective in treating an attack of gouty arthritis in this population.

But, in another vote, the panel unanimously agreed that the safety profile of canakinumab did not support approval for this indication, because of concerns that included the lack of long-term safety data including the potential long-term risk of infections and the lack of data on the effects of recurrent treatment. (Only 43 patients in the studies had received three or more injections and most had been treated only once.)

The need for more data in likely patient candidates who are less healthy than those in the trials, such as those with advanced renal disease, was another concern cited by the panel. Several panelists also expressed concern that unless use was restricted in some way, canakinumab might be used to treat a broader population than described in the proposed indication.

Canakinumab (Ilaris), a monoclonal antibody that neutralizes interleukin-1beta, was approved in June 2009 for the treatment of a rare disorder, cryopyrin-associated periodic syndromes (CAPS). The new indication proposed by the manufacturer, Novartis Pharmaceuticals, is for the treatment of gouty arthritis attacks in patients who cannot obtain an adequate response with NSAIDs or colchicine.

The company described canakinumab as the first targeted anti-inflammatory treatment for gout, which could be used to treat about 6% of the patients with gouty arthritis, an estimated 300,000 patients in the United States.

In the two phase III trials of approximately 450 patients, most of whom were male and white, (mean age was early 50s) with at least three gouty arthritis attacks a year, a single 150-mg injection of canakinumab, was compared with an intramuscular injection of triamcinolone (40 mg) in treating an acute attack.

Those treated with canakinumab had significantly greater reductions in pain intensity of the affected joint, as measured by changes in a visual pain scale (a primary end point) 72 hours after the injection, compared with those treated with triamcinolone. The risk of having another gouty arthritis flare over the 12 weeks after treatment – the other primary end point – was also significantly reduced among those treated with canakinumab, compared with those on triamcinolone.

The rates of adverse events, including serious adverse events, were higher among those treated with canakinumab, compared with those on triamcinolone and included infections (19% vs. 13%, respectively) and serious infections (2% vs. 0%, respectively). Treatment with canakinumab also was associated with an increase in serum triglycerides levels, declines in renal function, and elevations in serum uric acid, and hypertension. There were three cases of renal failure among gout patients treated with canakinumab, who had predisposing factors, according to the company.

Canakinumab is under review in the European Union for the same indication.

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

ADELPHI, MD. – A Food and Drug Administration advisory panel on June 21 voted 11-1 that the data on canakinumab did not support its approval as a treatment for gouty arthritis attacks, in patients who have not responded adequately to nonsteroidal anti-inflammatory drugs or colchicine.

Members of the FDA’s Arthritis Advisory Committee considered canakinumab a promising treatment, and all but one panelist agreed that the 150-mg subcutaneous dose that was studied in two phase III trials was shown to be effective in treating an attack of gouty arthritis in this population.

But, in another vote, the panel unanimously agreed that the safety profile of canakinumab did not support approval for this indication, because of concerns that included the lack of long-term safety data including the potential long-term risk of infections and the lack of data on the effects of recurrent treatment. (Only 43 patients in the studies had received three or more injections and most had been treated only once.)

The need for more data in likely patient candidates who are less healthy than those in the trials, such as those with advanced renal disease, was another concern cited by the panel. Several panelists also expressed concern that unless use was restricted in some way, canakinumab might be used to treat a broader population than described in the proposed indication.

Canakinumab (Ilaris), a monoclonal antibody that neutralizes interleukin-1beta, was approved in June 2009 for the treatment of a rare disorder, cryopyrin-associated periodic syndromes (CAPS). The new indication proposed by the manufacturer, Novartis Pharmaceuticals, is for the treatment of gouty arthritis attacks in patients who cannot obtain an adequate response with NSAIDs or colchicine.

The company described canakinumab as the first targeted anti-inflammatory treatment for gout, which could be used to treat about 6% of the patients with gouty arthritis, an estimated 300,000 patients in the United States.

In the two phase III trials of approximately 450 patients, most of whom were male and white, (mean age was early 50s) with at least three gouty arthritis attacks a year, a single 150-mg injection of canakinumab, was compared with an intramuscular injection of triamcinolone (40 mg) in treating an acute attack.

Those treated with canakinumab had significantly greater reductions in pain intensity of the affected joint, as measured by changes in a visual pain scale (a primary end point) 72 hours after the injection, compared with those treated with triamcinolone. The risk of having another gouty arthritis flare over the 12 weeks after treatment – the other primary end point – was also significantly reduced among those treated with canakinumab, compared with those on triamcinolone.

The rates of adverse events, including serious adverse events, were higher among those treated with canakinumab, compared with those on triamcinolone and included infections (19% vs. 13%, respectively) and serious infections (2% vs. 0%, respectively). Treatment with canakinumab also was associated with an increase in serum triglycerides levels, declines in renal function, and elevations in serum uric acid, and hypertension. There were three cases of renal failure among gout patients treated with canakinumab, who had predisposing factors, according to the company.

Canakinumab is under review in the European Union for the same indication.

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

The Food and Drug Administration is questioning whether the "primarily symptomatic relief" of gout provided by the injectable biologic canakinumab outweighs an increased risk of serious infections.

At a June 21 meeting, the FDA will ask its Arthritis Advisory Committee about acute, recurrent use of canakinumab (Ilaris, Novartis) in gout and the risk of infections and laboratory value abnormalities, according to agency briefing documents.

The committee will be asked to vote on whether canakinumab should be approved merely for second-line treatment of gouty attacks or whether efficacy and safety data support adding a claim for extending the time to next attack and reducing the frequency of subsequent attacks.

"Determining the benefit-risk profile of canakinumab for the treatment of acute gout flares in light of its extended pharmacodynamic effects, both desirable and undesirable, is complicated and will underlie the questions for discussion" at the committee meeting, Dr. Sarah Yim, medical team leader, division of pulmonary, allergy, and rheumatology products, wrote in a memo.

The agency also will ask the panel whether Novartis should explore lower doses of canakinumab and obtain additional data on repeated dosing over time.

"Although a fairly wide range of doses were studied early on, only the 150 mg dose of canakinumab was studied further in the gout clinical development program," Dr. Yim wrote. "Given that some of the safety findings suggest a dose-response, it would have been useful to have additional data from a lower dose, to assess whether adequate efficacy could have been provided with less undesirable effects on susceptibility to infection and laboratory abnormalities. However these data are not available."

Canakinumab, an interleukin-1 beta-inhibitor, won FDA approval 2 years ago for treatment of cryopyrin-associated periodic syndrome, an orphan indication. Canakinumab, also in clinical development for systemic juvenile idiopathic arthritis and cardiovascular disease, has hit snags in clinical evaluations in rheumatoid arthritis and diabetes.

By selectively binding and neutralizing IL-1B, canakinumab interrupts the signaling pathway for crystal-induced inflammation in gouty arthritis, Novartis said in its advisory committee briefing document.

Gout attacks are currently treated with anti-inflammatories such as colchicine (Colcrys, Mutual Pharmaceuticals), NSAIDs, and corticosteroids. The underlying pathology is treated by controlling hyperuricemia with urate-lowering therapies, such as allopurinol, probenecid, febuxostat (Uloric, Takeda Pharmaceuticals), and pegloticase (Krystexxa, Savient Pharmaceuticals).

Novartis is pursuing a second-line gout indication that canakinumab has been shown "to extend the time to next attack and reduce the frequency of subsequent attacks." The proposed indication is for treatment of gouty arthritis attacks in patients who do not respond to NSAIDs and colchicine. In its briefing document, Novartis says the targeted patient population is less than 10% of the approximately 300,000 U.S. patients who receive treatment for gouty arthritis. The second-line indication and the narrow population targeted could help turn the risk/benefit equation by demonstrating that the biologic’s potential adverse events are outweighed by the symptomatic and disease relief benefit it brings to patients who fail on first-line therapy.

Pain Reduction With Reduced Risk of New Flares

The supplemental biologics license application is supported by data from two identically designed phase III trials encompassing 454 patients who were intolerant of, or refractory to, NSAIDS or colchicine. Half of the patients in one study, and one-third in the other, were on urate-lowering therapy.

The studies measured two co-primary end points: mean difference in patient assessment of gout pain from baseline to 72 hours post dose using the Visual Analog Scale, and time to new gout flare. Patients were randomized to a single dose of either canakinumab 150 mg or the corticosteroid triamcinolone 40 mg on day 1 and followed for 12 weeks.

"Overall, both trials ... demonstrated statistically significant decreases in pain intensity measured on VAS for canakinumab, compared to triamcinolone, and statistically significant differences between treatment groups (favoring canakinumab) for the risk of a new gout flare," Dr. Yim wrote.

"Subgroup analyses of the co-primary efficacy endpoints were generally consistent with the overall efficacy results, including results for the subgroup of patients intolerant to, with contraindications for, or lack of efficacy from NSAIDs and/or colchicine; however, differences in the magnitude of the treatment effect in the subgroup of patients taking urate-lowering therapy versus those not taking urate therapy [were] observed."

Do Adverse Events Trump Symptom Relief?

While FDA reviewers describe the benefits as primarily symptomatic and question whether they outweigh the risks of infection and other side effects, particularly since the agent is expected to be used on a recurring basis.

Ilaris’ current labeling includes a warning about the risk of serious infections and says physicians should exercise caution when giving the biologic to patients with infections, a history of recurring infections or underlying conditions that may predispose them to infections.

In gout patients, compared to triamcinolone 40 mg, canakinumab 150 mg was associated with a higher proportion of serious adverse events, at least one adverse event, infection and serious infections.

"The types of adverse events and serious adverse events observed were generally consistent with the underlying patient population, with the exception of infections," Dr. Yim noted. "However, the increase in these (adverse events) is particularly notable in light of the fact that they were observed after a single injection of canakinumab."

FDA reviewers also raised concerns about laboratory abnormalities associated with canakinumab use that could negatively affect gout patients over the long term. These include declines in renal function values, increased triglyceride levels, and elevations in serum uric acid levels.

Although small increases in serum uric acid should be manageable with adequate doses of urate-lowering therapy, "one could also imagine that for certain patients whose serum uric acid is not adequately controlled that a further increase might enhance tophi formation," Dr. Yim commented. "In any case, this finding, as with hypertriglyceridemia and creatinine elevation, raises questions regarding the net impact that canakinumab treatment could have on gout patients and their comorbidities."

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration is questioning whether the "primarily symptomatic relief" of gout provided by the injectable biologic canakinumab outweighs an increased risk of serious infections.

At a June 21 meeting, the FDA will ask its Arthritis Advisory Committee about acute, recurrent use of canakinumab (Ilaris, Novartis) in gout and the risk of infections and laboratory value abnormalities, according to agency briefing documents.

The committee will be asked to vote on whether canakinumab should be approved merely for second-line treatment of gouty attacks or whether efficacy and safety data support adding a claim for extending the time to next attack and reducing the frequency of subsequent attacks.

"Determining the benefit-risk profile of canakinumab for the treatment of acute gout flares in light of its extended pharmacodynamic effects, both desirable and undesirable, is complicated and will underlie the questions for discussion" at the committee meeting, Dr. Sarah Yim, medical team leader, division of pulmonary, allergy, and rheumatology products, wrote in a memo.

The agency also will ask the panel whether Novartis should explore lower doses of canakinumab and obtain additional data on repeated dosing over time.

"Although a fairly wide range of doses were studied early on, only the 150 mg dose of canakinumab was studied further in the gout clinical development program," Dr. Yim wrote. "Given that some of the safety findings suggest a dose-response, it would have been useful to have additional data from a lower dose, to assess whether adequate efficacy could have been provided with less undesirable effects on susceptibility to infection and laboratory abnormalities. However these data are not available."

Canakinumab, an interleukin-1 beta-inhibitor, won FDA approval 2 years ago for treatment of cryopyrin-associated periodic syndrome, an orphan indication. Canakinumab, also in clinical development for systemic juvenile idiopathic arthritis and cardiovascular disease, has hit snags in clinical evaluations in rheumatoid arthritis and diabetes.

By selectively binding and neutralizing IL-1B, canakinumab interrupts the signaling pathway for crystal-induced inflammation in gouty arthritis, Novartis said in its advisory committee briefing document.

Gout attacks are currently treated with anti-inflammatories such as colchicine (Colcrys, Mutual Pharmaceuticals), NSAIDs, and corticosteroids. The underlying pathology is treated by controlling hyperuricemia with urate-lowering therapies, such as allopurinol, probenecid, febuxostat (Uloric, Takeda Pharmaceuticals), and pegloticase (Krystexxa, Savient Pharmaceuticals).

Novartis is pursuing a second-line gout indication that canakinumab has been shown "to extend the time to next attack and reduce the frequency of subsequent attacks." The proposed indication is for treatment of gouty arthritis attacks in patients who do not respond to NSAIDs and colchicine. In its briefing document, Novartis says the targeted patient population is less than 10% of the approximately 300,000 U.S. patients who receive treatment for gouty arthritis. The second-line indication and the narrow population targeted could help turn the risk/benefit equation by demonstrating that the biologic’s potential adverse events are outweighed by the symptomatic and disease relief benefit it brings to patients who fail on first-line therapy.

Pain Reduction With Reduced Risk of New Flares

The supplemental biologics license application is supported by data from two identically designed phase III trials encompassing 454 patients who were intolerant of, or refractory to, NSAIDS or colchicine. Half of the patients in one study, and one-third in the other, were on urate-lowering therapy.

The studies measured two co-primary end points: mean difference in patient assessment of gout pain from baseline to 72 hours post dose using the Visual Analog Scale, and time to new gout flare. Patients were randomized to a single dose of either canakinumab 150 mg or the corticosteroid triamcinolone 40 mg on day 1 and followed for 12 weeks.

"Overall, both trials ... demonstrated statistically significant decreases in pain intensity measured on VAS for canakinumab, compared to triamcinolone, and statistically significant differences between treatment groups (favoring canakinumab) for the risk of a new gout flare," Dr. Yim wrote.

"Subgroup analyses of the co-primary efficacy endpoints were generally consistent with the overall efficacy results, including results for the subgroup of patients intolerant to, with contraindications for, or lack of efficacy from NSAIDs and/or colchicine; however, differences in the magnitude of the treatment effect in the subgroup of patients taking urate-lowering therapy versus those not taking urate therapy [were] observed."

Do Adverse Events Trump Symptom Relief?

While FDA reviewers describe the benefits as primarily symptomatic and question whether they outweigh the risks of infection and other side effects, particularly since the agent is expected to be used on a recurring basis.

Ilaris’ current labeling includes a warning about the risk of serious infections and says physicians should exercise caution when giving the biologic to patients with infections, a history of recurring infections or underlying conditions that may predispose them to infections.

In gout patients, compared to triamcinolone 40 mg, canakinumab 150 mg was associated with a higher proportion of serious adverse events, at least one adverse event, infection and serious infections.

"The types of adverse events and serious adverse events observed were generally consistent with the underlying patient population, with the exception of infections," Dr. Yim noted. "However, the increase in these (adverse events) is particularly notable in light of the fact that they were observed after a single injection of canakinumab."

FDA reviewers also raised concerns about laboratory abnormalities associated with canakinumab use that could negatively affect gout patients over the long term. These include declines in renal function values, increased triglyceride levels, and elevations in serum uric acid levels.

Although small increases in serum uric acid should be manageable with adequate doses of urate-lowering therapy, "one could also imagine that for certain patients whose serum uric acid is not adequately controlled that a further increase might enhance tophi formation," Dr. Yim commented. "In any case, this finding, as with hypertriglyceridemia and creatinine elevation, raises questions regarding the net impact that canakinumab treatment could have on gout patients and their comorbidities."

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration is questioning whether the "primarily symptomatic relief" of gout provided by the injectable biologic canakinumab outweighs an increased risk of serious infections.

At a June 21 meeting, the FDA will ask its Arthritis Advisory Committee about acute, recurrent use of canakinumab (Ilaris, Novartis) in gout and the risk of infections and laboratory value abnormalities, according to agency briefing documents.

The committee will be asked to vote on whether canakinumab should be approved merely for second-line treatment of gouty attacks or whether efficacy and safety data support adding a claim for extending the time to next attack and reducing the frequency of subsequent attacks.

"Determining the benefit-risk profile of canakinumab for the treatment of acute gout flares in light of its extended pharmacodynamic effects, both desirable and undesirable, is complicated and will underlie the questions for discussion" at the committee meeting, Dr. Sarah Yim, medical team leader, division of pulmonary, allergy, and rheumatology products, wrote in a memo.

The agency also will ask the panel whether Novartis should explore lower doses of canakinumab and obtain additional data on repeated dosing over time.

"Although a fairly wide range of doses were studied early on, only the 150 mg dose of canakinumab was studied further in the gout clinical development program," Dr. Yim wrote. "Given that some of the safety findings suggest a dose-response, it would have been useful to have additional data from a lower dose, to assess whether adequate efficacy could have been provided with less undesirable effects on susceptibility to infection and laboratory abnormalities. However these data are not available."

Canakinumab, an interleukin-1 beta-inhibitor, won FDA approval 2 years ago for treatment of cryopyrin-associated periodic syndrome, an orphan indication. Canakinumab, also in clinical development for systemic juvenile idiopathic arthritis and cardiovascular disease, has hit snags in clinical evaluations in rheumatoid arthritis and diabetes.

By selectively binding and neutralizing IL-1B, canakinumab interrupts the signaling pathway for crystal-induced inflammation in gouty arthritis, Novartis said in its advisory committee briefing document.

Gout attacks are currently treated with anti-inflammatories such as colchicine (Colcrys, Mutual Pharmaceuticals), NSAIDs, and corticosteroids. The underlying pathology is treated by controlling hyperuricemia with urate-lowering therapies, such as allopurinol, probenecid, febuxostat (Uloric, Takeda Pharmaceuticals), and pegloticase (Krystexxa, Savient Pharmaceuticals).

Novartis is pursuing a second-line gout indication that canakinumab has been shown "to extend the time to next attack and reduce the frequency of subsequent attacks." The proposed indication is for treatment of gouty arthritis attacks in patients who do not respond to NSAIDs and colchicine. In its briefing document, Novartis says the targeted patient population is less than 10% of the approximately 300,000 U.S. patients who receive treatment for gouty arthritis. The second-line indication and the narrow population targeted could help turn the risk/benefit equation by demonstrating that the biologic’s potential adverse events are outweighed by the symptomatic and disease relief benefit it brings to patients who fail on first-line therapy.

Pain Reduction With Reduced Risk of New Flares

The supplemental biologics license application is supported by data from two identically designed phase III trials encompassing 454 patients who were intolerant of, or refractory to, NSAIDS or colchicine. Half of the patients in one study, and one-third in the other, were on urate-lowering therapy.

The studies measured two co-primary end points: mean difference in patient assessment of gout pain from baseline to 72 hours post dose using the Visual Analog Scale, and time to new gout flare. Patients were randomized to a single dose of either canakinumab 150 mg or the corticosteroid triamcinolone 40 mg on day 1 and followed for 12 weeks.

"Overall, both trials ... demonstrated statistically significant decreases in pain intensity measured on VAS for canakinumab, compared to triamcinolone, and statistically significant differences between treatment groups (favoring canakinumab) for the risk of a new gout flare," Dr. Yim wrote.

"Subgroup analyses of the co-primary efficacy endpoints were generally consistent with the overall efficacy results, including results for the subgroup of patients intolerant to, with contraindications for, or lack of efficacy from NSAIDs and/or colchicine; however, differences in the magnitude of the treatment effect in the subgroup of patients taking urate-lowering therapy versus those not taking urate therapy [were] observed."

Do Adverse Events Trump Symptom Relief?

While FDA reviewers describe the benefits as primarily symptomatic and question whether they outweigh the risks of infection and other side effects, particularly since the agent is expected to be used on a recurring basis.

Ilaris’ current labeling includes a warning about the risk of serious infections and says physicians should exercise caution when giving the biologic to patients with infections, a history of recurring infections or underlying conditions that may predispose them to infections.

In gout patients, compared to triamcinolone 40 mg, canakinumab 150 mg was associated with a higher proportion of serious adverse events, at least one adverse event, infection and serious infections.

"The types of adverse events and serious adverse events observed were generally consistent with the underlying patient population, with the exception of infections," Dr. Yim noted. "However, the increase in these (adverse events) is particularly notable in light of the fact that they were observed after a single injection of canakinumab."

FDA reviewers also raised concerns about laboratory abnormalities associated with canakinumab use that could negatively affect gout patients over the long term. These include declines in renal function values, increased triglyceride levels, and elevations in serum uric acid levels.

Although small increases in serum uric acid should be manageable with adequate doses of urate-lowering therapy, "one could also imagine that for certain patients whose serum uric acid is not adequately controlled that a further increase might enhance tophi formation," Dr. Yim commented. "In any case, this finding, as with hypertriglyceridemia and creatinine elevation, raises questions regarding the net impact that canakinumab treatment could have on gout patients and their comorbidities."

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

LONDON – Use of canakinumab led to greater reductions in pain among patients with acute gouty arthritis flares after 3 days, and superior prevention of new flares during 12 weeks of follow-up, compared with triamcinolone acetonide in a pair of phase III trials that together enrolled 456 patients.

"Canakinumab is a potential new therapeutic option for acute flares in frequently flaring gouty arthritis patients with limited treatment options," Dr. Naomi Schlesinger said at the annual European Congress of Rheumatology.

Canakinumab is a fully human monoclonal antibody to interleukin (IL)-1 beta that selectively binds to and inhibits the proinflammatory molecule IL-1 beta, and already has Food and Drug Administration approval for treating CAPS (cryopyrin-associated periodic syndromes).

Based in part on the efficacy and safety data from the two reported phase III trials, Novartis, the company the markets canakinumab (Ilaris), filed an application with the FDA earlier this year for a supplemental indication for treating gouty arthritis flares. The FDA’s Arthritis Advisory Committee plans to discuss this application on June 21.

In the two new gouty arthritis trials, canakinumab’s safety profile during the first 12 weeks of treatment "appeared consistent with longer-term safety data from CAPS patients; there were no safety signals related to specific organ class," said Dr. Schlesinger, chief of the division of rheumatology and connective tissue research at the Robert Wood Johnson Medical School in New Brunswick, N.J. The most notable safety observation she made from the new results centered on "a modest increase in infections, mostly mild to moderate, with no opportunistic infections reported," she said.

Despite this promising safety and efficacy, one expert viewed canakinumab as an agent for a "niche population, patients [with gout] who flare and you can’t do anything about it" using standard drugs, commented Dr. Dinesh Khanna, a rheumatologist specializing in gout at the University of California, Los Angeles.

Goutologists see a lot of patients with diabetes, kidney disease, and hypertension who can’t take NSAIDs or colchicine. "You also can’t give them a steroid monthly, so these patients flare because of their high uric acid level and you’re stuck. These are the patients who can be treated with an anti-IL-1 beta to prevent gout attacks," he said in an interview.

The Beta-RELIEVED (Response in Acute Flare and in Prevention of Episodes of Reflare in Gout) and Beta-RELIEVED II trials enrolled patients within 5 days of an acute flare of gouty arthritis who had at least three flares during the prior year and were contraindicated for, intolerant of, or unresponsive to NSAIDs and colchicine. All patients met the American College of Rheumatology’s diagnostic criteria for gouty arthritis, and had pain intensity of at least 50 mm on a visual analog scale of 0–100 mm.

The researchers randomized patients to receive a subcutaneous injection of 150-mg canakinumab or an intramuscular injection of 40-mg triamcinolone acetonide. Patients who reflared during the subsequent 12 weeks during the first phase of the study qualified to receive an additional dose of their assigned drug with each flare.

The study had two primary end points. One was pain resolution at 72 hours after initial treatment. At that time, patients who were treated with canakinumab in the Beta-RELIEVED study had an average pain score that was 11 mm lower than that of patients in the comparator group, a statistically significant difference, reported Dr. Alexander So, a coinvestigator on the study and professor of rheumatology at the University of Lausanne (Switzerland).

Patients who were treated with canakinumab began to show significantly better pain reduction, compared with those who got triamcinolone within 12 hours after their first dose, and the advantage in pain relief continued each time the investigators measured pain during the first 7 days after treatment, Dr. So said. Neither Dr. So nor Dr. Schlesinger reported the results for this end point from the Beta-RELIEVED II trial.

The second primary end point was the percentage of patients having new flares during the first 12 weeks following their initial therapy. In the Beta-RELIEVED trial, 19% of the 115 patients who were treated with canakinumab and 37% of the 115 patients treated with triamcinolone had a new flare, a 55% relative risk reduction with canakinumab that was statistically significant. In the second trial, canakinumab use led to a 68% relative reduction in new flares, also a statistically significant difference in the study that randomized 226 patients, Dr. Schlesinger reported.

The canakinumab-treated patients also showed other signs of superior response in several secondary efficacy measures. Patients in the canakinumab group had a significant reduction in their mean number of flares, significantly less inflammation and swelling, and better suppression of inflammatory markers after 12 weeks, the researchers said.

In the safety analysis, canakinumab was associated with similar rates of all adverse events, a similar low rate of serious adverse events, and a similar low rate of adverse events leading to discontinuation, compared with patients who received triamcinolone.

The Beta-RELIEVED trials were sponsored by Novartis, which markets canakinumab (Ilaris). Dr. Schlesinger said that she is a on the advisory board of Novartis, Enzyme Rx, Takeda, URL Pharma, and Savient. She is a consultant to and has received research grants from Novartis, and is on the speakers bureau of Takeda and Savient. Dr. So said that he is a consultant to Novartis, Bristol-Myers Squibb, Merck, Pfizer, and UCB Pharma. Dr. Khanna said that he is a consultant to Novartis, Takeda, Savient, and UCB Pharma.

LONDON – Use of canakinumab led to greater reductions in pain among patients with acute gouty arthritis flares after 3 days, and superior prevention of new flares during 12 weeks of follow-up, compared with triamcinolone acetonide in a pair of phase III trials that together enrolled 456 patients.

"Canakinumab is a potential new therapeutic option for acute flares in frequently flaring gouty arthritis patients with limited treatment options," Dr. Naomi Schlesinger said at the annual European Congress of Rheumatology.

Canakinumab is a fully human monoclonal antibody to interleukin (IL)-1 beta that selectively binds to and inhibits the proinflammatory molecule IL-1 beta, and already has Food and Drug Administration approval for treating CAPS (cryopyrin-associated periodic syndromes).

Based in part on the efficacy and safety data from the two reported phase III trials, Novartis, the company the markets canakinumab (Ilaris), filed an application with the FDA earlier this year for a supplemental indication for treating gouty arthritis flares. The FDA’s Arthritis Advisory Committee plans to discuss this application on June 21.

In the two new gouty arthritis trials, canakinumab’s safety profile during the first 12 weeks of treatment "appeared consistent with longer-term safety data from CAPS patients; there were no safety signals related to specific organ class," said Dr. Schlesinger, chief of the division of rheumatology and connective tissue research at the Robert Wood Johnson Medical School in New Brunswick, N.J. The most notable safety observation she made from the new results centered on "a modest increase in infections, mostly mild to moderate, with no opportunistic infections reported," she said.

Despite this promising safety and efficacy, one expert viewed canakinumab as an agent for a "niche population, patients [with gout] who flare and you can’t do anything about it" using standard drugs, commented Dr. Dinesh Khanna, a rheumatologist specializing in gout at the University of California, Los Angeles.

Goutologists see a lot of patients with diabetes, kidney disease, and hypertension who can’t take NSAIDs or colchicine. "You also can’t give them a steroid monthly, so these patients flare because of their high uric acid level and you’re stuck. These are the patients who can be treated with an anti-IL-1 beta to prevent gout attacks," he said in an interview.

The Beta-RELIEVED (Response in Acute Flare and in Prevention of Episodes of Reflare in Gout) and Beta-RELIEVED II trials enrolled patients within 5 days of an acute flare of gouty arthritis who had at least three flares during the prior year and were contraindicated for, intolerant of, or unresponsive to NSAIDs and colchicine. All patients met the American College of Rheumatology’s diagnostic criteria for gouty arthritis, and had pain intensity of at least 50 mm on a visual analog scale of 0–100 mm.

The researchers randomized patients to receive a subcutaneous injection of 150-mg canakinumab or an intramuscular injection of 40-mg triamcinolone acetonide. Patients who reflared during the subsequent 12 weeks during the first phase of the study qualified to receive an additional dose of their assigned drug with each flare.

The study had two primary end points. One was pain resolution at 72 hours after initial treatment. At that time, patients who were treated with canakinumab in the Beta-RELIEVED study had an average pain score that was 11 mm lower than that of patients in the comparator group, a statistically significant difference, reported Dr. Alexander So, a coinvestigator on the study and professor of rheumatology at the University of Lausanne (Switzerland).

Patients who were treated with canakinumab began to show significantly better pain reduction, compared with those who got triamcinolone within 12 hours after their first dose, and the advantage in pain relief continued each time the investigators measured pain during the first 7 days after treatment, Dr. So said. Neither Dr. So nor Dr. Schlesinger reported the results for this end point from the Beta-RELIEVED II trial.

The second primary end point was the percentage of patients having new flares during the first 12 weeks following their initial therapy. In the Beta-RELIEVED trial, 19% of the 115 patients who were treated with canakinumab and 37% of the 115 patients treated with triamcinolone had a new flare, a 55% relative risk reduction with canakinumab that was statistically significant. In the second trial, canakinumab use led to a 68% relative reduction in new flares, also a statistically significant difference in the study that randomized 226 patients, Dr. Schlesinger reported.

The canakinumab-treated patients also showed other signs of superior response in several secondary efficacy measures. Patients in the canakinumab group had a significant reduction in their mean number of flares, significantly less inflammation and swelling, and better suppression of inflammatory markers after 12 weeks, the researchers said.

In the safety analysis, canakinumab was associated with similar rates of all adverse events, a similar low rate of serious adverse events, and a similar low rate of adverse events leading to discontinuation, compared with patients who received triamcinolone.

The Beta-RELIEVED trials were sponsored by Novartis, which markets canakinumab (Ilaris). Dr. Schlesinger said that she is a on the advisory board of Novartis, Enzyme Rx, Takeda, URL Pharma, and Savient. She is a consultant to and has received research grants from Novartis, and is on the speakers bureau of Takeda and Savient. Dr. So said that he is a consultant to Novartis, Bristol-Myers Squibb, Merck, Pfizer, and UCB Pharma. Dr. Khanna said that he is a consultant to Novartis, Takeda, Savient, and UCB Pharma.

LONDON – Use of canakinumab led to greater reductions in pain among patients with acute gouty arthritis flares after 3 days, and superior prevention of new flares during 12 weeks of follow-up, compared with triamcinolone acetonide in a pair of phase III trials that together enrolled 456 patients.

"Canakinumab is a potential new therapeutic option for acute flares in frequently flaring gouty arthritis patients with limited treatment options," Dr. Naomi Schlesinger said at the annual European Congress of Rheumatology.

Canakinumab is a fully human monoclonal antibody to interleukin (IL)-1 beta that selectively binds to and inhibits the proinflammatory molecule IL-1 beta, and already has Food and Drug Administration approval for treating CAPS (cryopyrin-associated periodic syndromes).

Based in part on the efficacy and safety data from the two reported phase III trials, Novartis, the company the markets canakinumab (Ilaris), filed an application with the FDA earlier this year for a supplemental indication for treating gouty arthritis flares. The FDA’s Arthritis Advisory Committee plans to discuss this application on June 21.

In the two new gouty arthritis trials, canakinumab’s safety profile during the first 12 weeks of treatment "appeared consistent with longer-term safety data from CAPS patients; there were no safety signals related to specific organ class," said Dr. Schlesinger, chief of the division of rheumatology and connective tissue research at the Robert Wood Johnson Medical School in New Brunswick, N.J. The most notable safety observation she made from the new results centered on "a modest increase in infections, mostly mild to moderate, with no opportunistic infections reported," she said.

Despite this promising safety and efficacy, one expert viewed canakinumab as an agent for a "niche population, patients [with gout] who flare and you can’t do anything about it" using standard drugs, commented Dr. Dinesh Khanna, a rheumatologist specializing in gout at the University of California, Los Angeles.

Goutologists see a lot of patients with diabetes, kidney disease, and hypertension who can’t take NSAIDs or colchicine. "You also can’t give them a steroid monthly, so these patients flare because of their high uric acid level and you’re stuck. These are the patients who can be treated with an anti-IL-1 beta to prevent gout attacks," he said in an interview.

The Beta-RELIEVED (Response in Acute Flare and in Prevention of Episodes of Reflare in Gout) and Beta-RELIEVED II trials enrolled patients within 5 days of an acute flare of gouty arthritis who had at least three flares during the prior year and were contraindicated for, intolerant of, or unresponsive to NSAIDs and colchicine. All patients met the American College of Rheumatology’s diagnostic criteria for gouty arthritis, and had pain intensity of at least 50 mm on a visual analog scale of 0–100 mm.

The researchers randomized patients to receive a subcutaneous injection of 150-mg canakinumab or an intramuscular injection of 40-mg triamcinolone acetonide. Patients who reflared during the subsequent 12 weeks during the first phase of the study qualified to receive an additional dose of their assigned drug with each flare.

The study had two primary end points. One was pain resolution at 72 hours after initial treatment. At that time, patients who were treated with canakinumab in the Beta-RELIEVED study had an average pain score that was 11 mm lower than that of patients in the comparator group, a statistically significant difference, reported Dr. Alexander So, a coinvestigator on the study and professor of rheumatology at the University of Lausanne (Switzerland).

Patients who were treated with canakinumab began to show significantly better pain reduction, compared with those who got triamcinolone within 12 hours after their first dose, and the advantage in pain relief continued each time the investigators measured pain during the first 7 days after treatment, Dr. So said. Neither Dr. So nor Dr. Schlesinger reported the results for this end point from the Beta-RELIEVED II trial.

The second primary end point was the percentage of patients having new flares during the first 12 weeks following their initial therapy. In the Beta-RELIEVED trial, 19% of the 115 patients who were treated with canakinumab and 37% of the 115 patients treated with triamcinolone had a new flare, a 55% relative risk reduction with canakinumab that was statistically significant. In the second trial, canakinumab use led to a 68% relative reduction in new flares, also a statistically significant difference in the study that randomized 226 patients, Dr. Schlesinger reported.

The canakinumab-treated patients also showed other signs of superior response in several secondary efficacy measures. Patients in the canakinumab group had a significant reduction in their mean number of flares, significantly less inflammation and swelling, and better suppression of inflammatory markers after 12 weeks, the researchers said.

In the safety analysis, canakinumab was associated with similar rates of all adverse events, a similar low rate of serious adverse events, and a similar low rate of adverse events leading to discontinuation, compared with patients who received triamcinolone.

The Beta-RELIEVED trials were sponsored by Novartis, which markets canakinumab (Ilaris). Dr. Schlesinger said that she is a on the advisory board of Novartis, Enzyme Rx, Takeda, URL Pharma, and Savient. She is a consultant to and has received research grants from Novartis, and is on the speakers bureau of Takeda and Savient. Dr. So said that he is a consultant to Novartis, Bristol-Myers Squibb, Merck, Pfizer, and UCB Pharma. Dr. Khanna said that he is a consultant to Novartis, Takeda, Savient, and UCB Pharma.

LONDON – Prophylactic treatment with the potent interleukin-1 inhibitor rilonacept significantly reduced the incidence of acute gout flares triggered by the initiation of urate-lowering therapy, according to data from a global phase III study reported at the annual European Congress of Rheumatology.

Patients in the 16-week trial who were randomized to receive weekly subcutaneous injections of either 80 mg or 160 mg of rilonacept (Acralyst) at the outset of standard uric acid–reducing treatment with allopurinol had significantly fewer gout flares and significantly fewer days per flare than did patients randomized to placebo, said principal investigator Dr. Essack Mitha of Newtown Clinical Research in Johannesburg, South Africa.

Further, treatment with the fusion protein, which interrupts the inflammatory cascade by attaching to and neutralizing interleukin-1, demonstrated acceptable safety and tolerability, he said.

The findings are consistent with those of a sister phase III trial in North America reported at the 2010 annual meeting of the American College of Rheumatology, he said.

The phase III, double-blind Preventive Study Against Urate-Lowering Drug-Induced Gout Exacerbations (PRE-SURGE 2) was conducted in South Africa, Germany, and Asia, and included 248 patients with gout, serum uric acid levels of 7.5 mg/dL or higher, and a history of at least two gout flares in the prior year. All of the patients were initiated on 300 mg of allopurinol daily (except those with documented renal dysfunction, who were initiated on a lower dose), and subsequently titrated to achieve target urate levels of less than 6 mg/dL, Dr. Mitha stated.

After the initial allopurinol dose, which was continued for 20 weeks, including a 4-week safety follow-up period, patients were randomized to receive 16 weekly subcutaneous injections of placebo (82 patients), 80 mg of rilonacept with a double dosing on day 1 (82 patients), or 160 mg of rilonacept with a double dosing on day 1 (84 patients). During the study, nonsteroidal anti-inflammatory drugs and oral steroids were allowed for the treatment but not for prevention of gout flares, said Dr. Mitha.

"The primary end point was the mean number of gout flares per patient through week 16. The secondary end points were the proportion of patients experiencing two or more gout flares during this period and the number of flare-days per patient," he said, adding that safety and tolerability were also assessed.

At baseline, the characteristics of the predominantly male (93%) study population were similar across all three groups, with a mean age of 51 years, a mean serum uric acid level of 9.4 mg/dL, a mean of seven gout flares in the prior year, and a mean gout flare duration of 3.8 days. A similar number of patients in the placebo and rilonacept groups completed the treatment period, Dr. Mitha reported.

With respect to the primary end point, the mean number of gout flares per patient was 101 in the placebo group, 29 in the 80-mg rilonacept group, and 28 in the 160-mg rilonacept group, which represent a significant reduction in gout flares relative to placebo, said Dr. Mitha.

"Compared with placebo, the proportion of patients who experienced more than one gout flare through week 16 was reduced by 54% in the 80-mg group and 63% in the 160-mg group," he said. The respective reductions relative to placebo in the proportion of patients experiencing two or more flares were 74% and 82%. "The mean number of gout flare days per patient was also significantly lower in the rilonacept subjects, at 4.3 and 1.9 for the 80-mg and 160-mg groups, respectively, compared with 11.2 for placebo," and significantly fewer patients in the treatment arms had flares lasting 5 days or longer, he said.

In terms of adverse events, the overall incidence was similar across the groups, and although there were more injection-site reactions in the rilonacept groups, "the reactions were generally mild, and none of the patients withdrew for that reason," Dr. Mitha said. Three patients did withdraw from the higher-dose rilonacept group for other reasons – one each for neutropenia, gout flare, and gastric cancer – "but there were no deaths and no serious adverse events related to the product," he stressed.

Together with the results of the North American PRE-SURGE 1 trial, the findings of this study are an important step in the clinical development program for rilonacept, which the U.S. Food and Drug Administration approved in February 2008 for the treatment of cryopyrin-associated periodic syndromes and Muckle-Wells syndrome in adults and children older than 12 years.

"Our results suggest that concomitant use of rilonacept during the first several months of allopurinol therapy may help avoid the acute gout flares that make it difficult for patients to maintain urate-lowering therapy," according to Dr. Mitha. Currently, standard practice includes the use of colchicine or anti-inflammatory drugs to reduce the risk of flares associated with early allopurinol, but the gastrointestinal side effects associated with colchicine in particular can be prohibitive, he said.

Because rilonacept is "very expensive" compared with standard treatment for acute gout flares, studies looking at the relative efficacy of the various treatment options are warranted before the drug should be widely used for this indication, Dr. Mitha stressed.

Dr. Mitha and his coinvestigators disclosed receiving grant/research support from Regeneron Pharmaceuticals, which manufactures rilonacept.

LONDON – Prophylactic treatment with the potent interleukin-1 inhibitor rilonacept significantly reduced the incidence of acute gout flares triggered by the initiation of urate-lowering therapy, according to data from a global phase III study reported at the annual European Congress of Rheumatology.

Patients in the 16-week trial who were randomized to receive weekly subcutaneous injections of either 80 mg or 160 mg of rilonacept (Acralyst) at the outset of standard uric acid–reducing treatment with allopurinol had significantly fewer gout flares and significantly fewer days per flare than did patients randomized to placebo, said principal investigator Dr. Essack Mitha of Newtown Clinical Research in Johannesburg, South Africa.

Further, treatment with the fusion protein, which interrupts the inflammatory cascade by attaching to and neutralizing interleukin-1, demonstrated acceptable safety and tolerability, he said.

The findings are consistent with those of a sister phase III trial in North America reported at the 2010 annual meeting of the American College of Rheumatology, he said.

The phase III, double-blind Preventive Study Against Urate-Lowering Drug-Induced Gout Exacerbations (PRE-SURGE 2) was conducted in South Africa, Germany, and Asia, and included 248 patients with gout, serum uric acid levels of 7.5 mg/dL or higher, and a history of at least two gout flares in the prior year. All of the patients were initiated on 300 mg of allopurinol daily (except those with documented renal dysfunction, who were initiated on a lower dose), and subsequently titrated to achieve target urate levels of less than 6 mg/dL, Dr. Mitha stated.

After the initial allopurinol dose, which was continued for 20 weeks, including a 4-week safety follow-up period, patients were randomized to receive 16 weekly subcutaneous injections of placebo (82 patients), 80 mg of rilonacept with a double dosing on day 1 (82 patients), or 160 mg of rilonacept with a double dosing on day 1 (84 patients). During the study, nonsteroidal anti-inflammatory drugs and oral steroids were allowed for the treatment but not for prevention of gout flares, said Dr. Mitha.

"The primary end point was the mean number of gout flares per patient through week 16. The secondary end points were the proportion of patients experiencing two or more gout flares during this period and the number of flare-days per patient," he said, adding that safety and tolerability were also assessed.

At baseline, the characteristics of the predominantly male (93%) study population were similar across all three groups, with a mean age of 51 years, a mean serum uric acid level of 9.4 mg/dL, a mean of seven gout flares in the prior year, and a mean gout flare duration of 3.8 days. A similar number of patients in the placebo and rilonacept groups completed the treatment period, Dr. Mitha reported.

With respect to the primary end point, the mean number of gout flares per patient was 101 in the placebo group, 29 in the 80-mg rilonacept group, and 28 in the 160-mg rilonacept group, which represent a significant reduction in gout flares relative to placebo, said Dr. Mitha.

"Compared with placebo, the proportion of patients who experienced more than one gout flare through week 16 was reduced by 54% in the 80-mg group and 63% in the 160-mg group," he said. The respective reductions relative to placebo in the proportion of patients experiencing two or more flares were 74% and 82%. "The mean number of gout flare days per patient was also significantly lower in the rilonacept subjects, at 4.3 and 1.9 for the 80-mg and 160-mg groups, respectively, compared with 11.2 for placebo," and significantly fewer patients in the treatment arms had flares lasting 5 days or longer, he said.

In terms of adverse events, the overall incidence was similar across the groups, and although there were more injection-site reactions in the rilonacept groups, "the reactions were generally mild, and none of the patients withdrew for that reason," Dr. Mitha said. Three patients did withdraw from the higher-dose rilonacept group for other reasons – one each for neutropenia, gout flare, and gastric cancer – "but there were no deaths and no serious adverse events related to the product," he stressed.

Together with the results of the North American PRE-SURGE 1 trial, the findings of this study are an important step in the clinical development program for rilonacept, which the U.S. Food and Drug Administration approved in February 2008 for the treatment of cryopyrin-associated periodic syndromes and Muckle-Wells syndrome in adults and children older than 12 years.

"Our results suggest that concomitant use of rilonacept during the first several months of allopurinol therapy may help avoid the acute gout flares that make it difficult for patients to maintain urate-lowering therapy," according to Dr. Mitha. Currently, standard practice includes the use of colchicine or anti-inflammatory drugs to reduce the risk of flares associated with early allopurinol, but the gastrointestinal side effects associated with colchicine in particular can be prohibitive, he said.

Because rilonacept is "very expensive" compared with standard treatment for acute gout flares, studies looking at the relative efficacy of the various treatment options are warranted before the drug should be widely used for this indication, Dr. Mitha stressed.

Dr. Mitha and his coinvestigators disclosed receiving grant/research support from Regeneron Pharmaceuticals, which manufactures rilonacept.

LONDON – Prophylactic treatment with the potent interleukin-1 inhibitor rilonacept significantly reduced the incidence of acute gout flares triggered by the initiation of urate-lowering therapy, according to data from a global phase III study reported at the annual European Congress of Rheumatology.

Patients in the 16-week trial who were randomized to receive weekly subcutaneous injections of either 80 mg or 160 mg of rilonacept (Acralyst) at the outset of standard uric acid–reducing treatment with allopurinol had significantly fewer gout flares and significantly fewer days per flare than did patients randomized to placebo, said principal investigator Dr. Essack Mitha of Newtown Clinical Research in Johannesburg, South Africa.

Further, treatment with the fusion protein, which interrupts the inflammatory cascade by attaching to and neutralizing interleukin-1, demonstrated acceptable safety and tolerability, he said.

The findings are consistent with those of a sister phase III trial in North America reported at the 2010 annual meeting of the American College of Rheumatology, he said.

The phase III, double-blind Preventive Study Against Urate-Lowering Drug-Induced Gout Exacerbations (PRE-SURGE 2) was conducted in South Africa, Germany, and Asia, and included 248 patients with gout, serum uric acid levels of 7.5 mg/dL or higher, and a history of at least two gout flares in the prior year. All of the patients were initiated on 300 mg of allopurinol daily (except those with documented renal dysfunction, who were initiated on a lower dose), and subsequently titrated to achieve target urate levels of less than 6 mg/dL, Dr. Mitha stated.

After the initial allopurinol dose, which was continued for 20 weeks, including a 4-week safety follow-up period, patients were randomized to receive 16 weekly subcutaneous injections of placebo (82 patients), 80 mg of rilonacept with a double dosing on day 1 (82 patients), or 160 mg of rilonacept with a double dosing on day 1 (84 patients). During the study, nonsteroidal anti-inflammatory drugs and oral steroids were allowed for the treatment but not for prevention of gout flares, said Dr. Mitha.

"The primary end point was the mean number of gout flares per patient through week 16. The secondary end points were the proportion of patients experiencing two or more gout flares during this period and the number of flare-days per patient," he said, adding that safety and tolerability were also assessed.

At baseline, the characteristics of the predominantly male (93%) study population were similar across all three groups, with a mean age of 51 years, a mean serum uric acid level of 9.4 mg/dL, a mean of seven gout flares in the prior year, and a mean gout flare duration of 3.8 days. A similar number of patients in the placebo and rilonacept groups completed the treatment period, Dr. Mitha reported.

With respect to the primary end point, the mean number of gout flares per patient was 101 in the placebo group, 29 in the 80-mg rilonacept group, and 28 in the 160-mg rilonacept group, which represent a significant reduction in gout flares relative to placebo, said Dr. Mitha.

"Compared with placebo, the proportion of patients who experienced more than one gout flare through week 16 was reduced by 54% in the 80-mg group and 63% in the 160-mg group," he said. The respective reductions relative to placebo in the proportion of patients experiencing two or more flares were 74% and 82%. "The mean number of gout flare days per patient was also significantly lower in the rilonacept subjects, at 4.3 and 1.9 for the 80-mg and 160-mg groups, respectively, compared with 11.2 for placebo," and significantly fewer patients in the treatment arms had flares lasting 5 days or longer, he said.

In terms of adverse events, the overall incidence was similar across the groups, and although there were more injection-site reactions in the rilonacept groups, "the reactions were generally mild, and none of the patients withdrew for that reason," Dr. Mitha said. Three patients did withdraw from the higher-dose rilonacept group for other reasons – one each for neutropenia, gout flare, and gastric cancer – "but there were no deaths and no serious adverse events related to the product," he stressed.

Together with the results of the North American PRE-SURGE 1 trial, the findings of this study are an important step in the clinical development program for rilonacept, which the U.S. Food and Drug Administration approved in February 2008 for the treatment of cryopyrin-associated periodic syndromes and Muckle-Wells syndrome in adults and children older than 12 years.

"Our results suggest that concomitant use of rilonacept during the first several months of allopurinol therapy may help avoid the acute gout flares that make it difficult for patients to maintain urate-lowering therapy," according to Dr. Mitha. Currently, standard practice includes the use of colchicine or anti-inflammatory drugs to reduce the risk of flares associated with early allopurinol, but the gastrointestinal side effects associated with colchicine in particular can be prohibitive, he said.

Because rilonacept is "very expensive" compared with standard treatment for acute gout flares, studies looking at the relative efficacy of the various treatment options are warranted before the drug should be widely used for this indication, Dr. Mitha stressed.

Dr. Mitha and his coinvestigators disclosed receiving grant/research support from Regeneron Pharmaceuticals, which manufactures rilonacept.

LONDON – Gout is an independent risk factor for acute myocardial infarction, even among younger patients and those without cardiovascular risk factors, according to Dr. Chang-Fu Kuo, who presented a late-breaking report at the Annual European Congress of Rheumatology.

The risk for acute MI was 23% higher among gout patients than the general population, judging from an analysis of a large Taiwanese database. Among individuals aged 20-44 years old and those without additional cardiovascular risk factors, the risk of acute MI was increased by 59% and 76%, respectively, reported Dr. Kuo of Chang Gung Memorial Hospital, Taipei, Taiwan.

To investigate the risk of acute MI associated with gout, Dr. Kuo and colleagues analyzed the 2000 Taiwan National Health Insurance database, which is a representative sampling cohort of the general population. Specifically, the investigators compared rates of first hospital admission for acute MI among gout and nongout patients aged 20 years or older. Of the 704,503 individuals included in the cohort (mean age, 42.73 years), 26,566 were diagnosed and treated for gout in 1996-1999, Dr. Kuo said. Compared with the nongout patients, "the gout patients were significantly older, with a mean age of 55.4 years, and they were significantly more likely to have diabetes and hypertension," he said.

The investigators followed the cohort from January 2000 through December 2008, for a total of 5.6 million patient-years of follow-up. During this period, 3,718 patients were hospitalized for acute MI, including 463 patients with gout. Of these events, 299 were fatal, including 35 in gout patients, Dr. Kuo said. "The incidence of acute [MI] in gout patients was 2.20 per 1,000 patient years and was significantly higher than in nongout patients, which was 0.60," he said.

In the multivariate model adjusted for age, sex, diabetes, hypertension, coronary heart disease, stroke, and end-stage renal disease, the respective hazard ratios for all acute MI and nonfatal acute MI in gout patients were 1.23 and 1.26, Dr. Kuo reported. "In patients without cardiovascular risk factors, the hazard ratio for all acute [MI] was 1.84, and for nonfatal acute [MI] was 1.80," he said, and when assessed by age, the respective hazard ratios for gout patients aged 20-44 years, 45-59 years, and 60 years or older were 1.59, 1.24, and 1.11.

The multivariate model was not adjusted for hyperlipidemia, which has been associated with gout, Dr. Kuo said, acknowledging that elevated lipid levels could play an important role in the increased cardiovascular risks observed in the gout patients.

Although the increased risk of acute MI associated with gout has been previously reported, "the risk in younger patients and those with low risk profiles hasn’t previously been established," Dr. Kuo explained. The finding that gout is an independent risk factor for the occurrence of acute MI – particularly nonfatal acute MI – among young, low-risk patients suggests the need for "vigilant cardiovascular monitoring" of these patients, he stressed.

Dr. Kuo reported having no conflicts of interest to disclose.

LONDON – Gout is an independent risk factor for acute myocardial infarction, even among younger patients and those without cardiovascular risk factors, according to Dr. Chang-Fu Kuo, who presented a late-breaking report at the Annual European Congress of Rheumatology.

The risk for acute MI was 23% higher among gout patients than the general population, judging from an analysis of a large Taiwanese database. Among individuals aged 20-44 years old and those without additional cardiovascular risk factors, the risk of acute MI was increased by 59% and 76%, respectively, reported Dr. Kuo of Chang Gung Memorial Hospital, Taipei, Taiwan.

To investigate the risk of acute MI associated with gout, Dr. Kuo and colleagues analyzed the 2000 Taiwan National Health Insurance database, which is a representative sampling cohort of the general population. Specifically, the investigators compared rates of first hospital admission for acute MI among gout and nongout patients aged 20 years or older. Of the 704,503 individuals included in the cohort (mean age, 42.73 years), 26,566 were diagnosed and treated for gout in 1996-1999, Dr. Kuo said. Compared with the nongout patients, "the gout patients were significantly older, with a mean age of 55.4 years, and they were significantly more likely to have diabetes and hypertension," he said.

The investigators followed the cohort from January 2000 through December 2008, for a total of 5.6 million patient-years of follow-up. During this period, 3,718 patients were hospitalized for acute MI, including 463 patients with gout. Of these events, 299 were fatal, including 35 in gout patients, Dr. Kuo said. "The incidence of acute [MI] in gout patients was 2.20 per 1,000 patient years and was significantly higher than in nongout patients, which was 0.60," he said.

In the multivariate model adjusted for age, sex, diabetes, hypertension, coronary heart disease, stroke, and end-stage renal disease, the respective hazard ratios for all acute MI and nonfatal acute MI in gout patients were 1.23 and 1.26, Dr. Kuo reported. "In patients without cardiovascular risk factors, the hazard ratio for all acute [MI] was 1.84, and for nonfatal acute [MI] was 1.80," he said, and when assessed by age, the respective hazard ratios for gout patients aged 20-44 years, 45-59 years, and 60 years or older were 1.59, 1.24, and 1.11.

The multivariate model was not adjusted for hyperlipidemia, which has been associated with gout, Dr. Kuo said, acknowledging that elevated lipid levels could play an important role in the increased cardiovascular risks observed in the gout patients.

Although the increased risk of acute MI associated with gout has been previously reported, "the risk in younger patients and those with low risk profiles hasn’t previously been established," Dr. Kuo explained. The finding that gout is an independent risk factor for the occurrence of acute MI – particularly nonfatal acute MI – among young, low-risk patients suggests the need for "vigilant cardiovascular monitoring" of these patients, he stressed.

Dr. Kuo reported having no conflicts of interest to disclose.

LONDON – Gout is an independent risk factor for acute myocardial infarction, even among younger patients and those without cardiovascular risk factors, according to Dr. Chang-Fu Kuo, who presented a late-breaking report at the Annual European Congress of Rheumatology.

The risk for acute MI was 23% higher among gout patients than the general population, judging from an analysis of a large Taiwanese database. Among individuals aged 20-44 years old and those without additional cardiovascular risk factors, the risk of acute MI was increased by 59% and 76%, respectively, reported Dr. Kuo of Chang Gung Memorial Hospital, Taipei, Taiwan.

To investigate the risk of acute MI associated with gout, Dr. Kuo and colleagues analyzed the 2000 Taiwan National Health Insurance database, which is a representative sampling cohort of the general population. Specifically, the investigators compared rates of first hospital admission for acute MI among gout and nongout patients aged 20 years or older. Of the 704,503 individuals included in the cohort (mean age, 42.73 years), 26,566 were diagnosed and treated for gout in 1996-1999, Dr. Kuo said. Compared with the nongout patients, "the gout patients were significantly older, with a mean age of 55.4 years, and they were significantly more likely to have diabetes and hypertension," he said.

The investigators followed the cohort from January 2000 through December 2008, for a total of 5.6 million patient-years of follow-up. During this period, 3,718 patients were hospitalized for acute MI, including 463 patients with gout. Of these events, 299 were fatal, including 35 in gout patients, Dr. Kuo said. "The incidence of acute [MI] in gout patients was 2.20 per 1,000 patient years and was significantly higher than in nongout patients, which was 0.60," he said.

In the multivariate model adjusted for age, sex, diabetes, hypertension, coronary heart disease, stroke, and end-stage renal disease, the respective hazard ratios for all acute MI and nonfatal acute MI in gout patients were 1.23 and 1.26, Dr. Kuo reported. "In patients without cardiovascular risk factors, the hazard ratio for all acute [MI] was 1.84, and for nonfatal acute [MI] was 1.80," he said, and when assessed by age, the respective hazard ratios for gout patients aged 20-44 years, 45-59 years, and 60 years or older were 1.59, 1.24, and 1.11.

The multivariate model was not adjusted for hyperlipidemia, which has been associated with gout, Dr. Kuo said, acknowledging that elevated lipid levels could play an important role in the increased cardiovascular risks observed in the gout patients.

Although the increased risk of acute MI associated with gout has been previously reported, "the risk in younger patients and those with low risk profiles hasn’t previously been established," Dr. Kuo explained. The finding that gout is an independent risk factor for the occurrence of acute MI – particularly nonfatal acute MI – among young, low-risk patients suggests the need for "vigilant cardiovascular monitoring" of these patients, he stressed.

Dr. Kuo reported having no conflicts of interest to disclose.

SAN DIEGO – Allopurinol should remain the first-line agent for gout prophylaxis, despite some competition from a newer drug, febuxostat, according to Dr. John Pendleton.

Allopurinol is generally very effective, can be safely titrated for those with renal impairment, and is the most cost-effective option, he said at the annual meeting of the American College of Physicians.

Photo credit: ©craftvision/iStockphoto.com

"I still recommend allopurinol as the initial treatment, because you don’t need a 24-hour urine collection to give it; it’s effective in both overproducers and underexcretors [of uric acid]; it can be taken just once a day; and it’s safe and effective for those with mild renal insufficiency when the dose is adjusted," said Dr. Pendleton, an internist in Roanoke, Va.

Price is also an important factor, he noted. "Generic allopurinol costs about $15 per month. The brand name costs about $43 per month. But the price for febuxostat comes in at about $156 per month."

With either drug, the treatment goal should be to lower uric acid levels to be 6 mg/dL, said Dr. Pendleton, referring to a retrospective study of 276 patients with recurrent gout attacks. "This study noted that among the 81 patients with a uric acid of less than 6 mg/dL, 88% had no recurrent attacks during the 3-year observational period" (Arthritis Rheum. 2004;51:321-5).

Allopurinol has been the "standby drug" for gouty arthritis for 60 years, and still performs admirably, Dr. Pendleton said. Although most initial doses range from 50 to 300 mg/day, "some recent studies suggest that only 25% of patients will reach the uric acid target on that regimen. For many patients, we need to increase the dose to get that level down."

The dose should be incrementally increased every 3-4 weeks to reach the uric acid target level; doses of up to 800 mg/day are approved for this indication. "But if you’re not able to achieve this desired level by pushing the dose close to 800 mg, I would consider trying febuxostat."

Febuxostat, a xanthine oxidase inhibitor, is more selective and potent than allopurinol. "It’s metabolized in the liver and very little of the active drug is excreted renally, raising the possibility that it might be safer in patients with mild to moderate renal insufficiency," Dr. Pendleton said.

It’s not easy to fully compare the two, because all three of the studies on the basis of which febuxostat was approved used a fixed-dose allopurinol regimen. "None of them allowed the total upward titration of allopurinol for a fair comparison," Dr. Pendleton pointed out.

The studies concluded that 40 mg of febuxostat was as effective as 300 mg of allopurinol. "The higher dose [of febuxostat 80 mg] seemed to be more effective than 400 mg allopurinol, but again, the studies did not allow for an upward titration" of the comparator, he said.

Although none of the patients in those trials had a creatinine level of more than 2.5 mg/dL, "a short-term study suggests that febuxostat dosing would not need to be adjusted even with a very low creatinine clearance [of 10-29 mL/min]. But just the same I would be very careful in that setting," Dr. Pendleton said (Am. J. Ther. 2005;12:22-34).

Febuxostat also appears to be safe for patients with mild hepatic dysfunction, with an adverse event profile similar to that of allopurinol. However, febuxostat is contraindicated in patients who are taking azathioprine, mercaptopurine, and theophylline.

Probenecid could be another option for some patients, especially those who underexcrete uric acid. Although probenecid has a somewhat better adverse event profile than allopurinol, it requires a 24-hour urine collection to rule out overproduction of uric acid and it seems to increase the risk of kidney stones. The drug is not as effective in patients with a low creatinine clearance (less than 60 mL/min), and "seems to have no effect at all at a creatinine level of 30 mL/min or lower," Dr. Pendleton said. Probenecid also must be taken three times a day – another drawback, in his opinion.

Dr. Pendleton said that he had no relevant financial disclosures.

SAN DIEGO – Allopurinol should remain the first-line agent for gout prophylaxis, despite some competition from a newer drug, febuxostat, according to Dr. John Pendleton.

Allopurinol is generally very effective, can be safely titrated for those with renal impairment, and is the most cost-effective option, he said at the annual meeting of the American College of Physicians.

Photo credit: ©craftvision/iStockphoto.com

"I still recommend allopurinol as the initial treatment, because you don’t need a 24-hour urine collection to give it; it’s effective in both overproducers and underexcretors [of uric acid]; it can be taken just once a day; and it’s safe and effective for those with mild renal insufficiency when the dose is adjusted," said Dr. Pendleton, an internist in Roanoke, Va.

Price is also an important factor, he noted. "Generic allopurinol costs about $15 per month. The brand name costs about $43 per month. But the price for febuxostat comes in at about $156 per month."

With either drug, the treatment goal should be to lower uric acid levels to be 6 mg/dL, said Dr. Pendleton, referring to a retrospective study of 276 patients with recurrent gout attacks. "This study noted that among the 81 patients with a uric acid of less than 6 mg/dL, 88% had no recurrent attacks during the 3-year observational period" (Arthritis Rheum. 2004;51:321-5).

Allopurinol has been the "standby drug" for gouty arthritis for 60 years, and still performs admirably, Dr. Pendleton said. Although most initial doses range from 50 to 300 mg/day, "some recent studies suggest that only 25% of patients will reach the uric acid target on that regimen. For many patients, we need to increase the dose to get that level down."

The dose should be incrementally increased every 3-4 weeks to reach the uric acid target level; doses of up to 800 mg/day are approved for this indication. "But if you’re not able to achieve this desired level by pushing the dose close to 800 mg, I would consider trying febuxostat."

Febuxostat, a xanthine oxidase inhibitor, is more selective and potent than allopurinol. "It’s metabolized in the liver and very little of the active drug is excreted renally, raising the possibility that it might be safer in patients with mild to moderate renal insufficiency," Dr. Pendleton said.

It’s not easy to fully compare the two, because all three of the studies on the basis of which febuxostat was approved used a fixed-dose allopurinol regimen. "None of them allowed the total upward titration of allopurinol for a fair comparison," Dr. Pendleton pointed out.

The studies concluded that 40 mg of febuxostat was as effective as 300 mg of allopurinol. "The higher dose [of febuxostat 80 mg] seemed to be more effective than 400 mg allopurinol, but again, the studies did not allow for an upward titration" of the comparator, he said.

Although none of the patients in those trials had a creatinine level of more than 2.5 mg/dL, "a short-term study suggests that febuxostat dosing would not need to be adjusted even with a very low creatinine clearance [of 10-29 mL/min]. But just the same I would be very careful in that setting," Dr. Pendleton said (Am. J. Ther. 2005;12:22-34).

Febuxostat also appears to be safe for patients with mild hepatic dysfunction, with an adverse event profile similar to that of allopurinol. However, febuxostat is contraindicated in patients who are taking azathioprine, mercaptopurine, and theophylline.

Probenecid could be another option for some patients, especially those who underexcrete uric acid. Although probenecid has a somewhat better adverse event profile than allopurinol, it requires a 24-hour urine collection to rule out overproduction of uric acid and it seems to increase the risk of kidney stones. The drug is not as effective in patients with a low creatinine clearance (less than 60 mL/min), and "seems to have no effect at all at a creatinine level of 30 mL/min or lower," Dr. Pendleton said. Probenecid also must be taken three times a day – another drawback, in his opinion.

Dr. Pendleton said that he had no relevant financial disclosures.

SAN DIEGO – Allopurinol should remain the first-line agent for gout prophylaxis, despite some competition from a newer drug, febuxostat, according to Dr. John Pendleton.

Allopurinol is generally very effective, can be safely titrated for those with renal impairment, and is the most cost-effective option, he said at the annual meeting of the American College of Physicians.

Photo credit: ©craftvision/iStockphoto.com

"I still recommend allopurinol as the initial treatment, because you don’t need a 24-hour urine collection to give it; it’s effective in both overproducers and underexcretors [of uric acid]; it can be taken just once a day; and it’s safe and effective for those with mild renal insufficiency when the dose is adjusted," said Dr. Pendleton, an internist in Roanoke, Va.

Price is also an important factor, he noted. "Generic allopurinol costs about $15 per month. The brand name costs about $43 per month. But the price for febuxostat comes in at about $156 per month."

With either drug, the treatment goal should be to lower uric acid levels to be 6 mg/dL, said Dr. Pendleton, referring to a retrospective study of 276 patients with recurrent gout attacks. "This study noted that among the 81 patients with a uric acid of less than 6 mg/dL, 88% had no recurrent attacks during the 3-year observational period" (Arthritis Rheum. 2004;51:321-5).

Allopurinol has been the "standby drug" for gouty arthritis for 60 years, and still performs admirably, Dr. Pendleton said. Although most initial doses range from 50 to 300 mg/day, "some recent studies suggest that only 25% of patients will reach the uric acid target on that regimen. For many patients, we need to increase the dose to get that level down."

The dose should be incrementally increased every 3-4 weeks to reach the uric acid target level; doses of up to 800 mg/day are approved for this indication. "But if you’re not able to achieve this desired level by pushing the dose close to 800 mg, I would consider trying febuxostat."

Febuxostat, a xanthine oxidase inhibitor, is more selective and potent than allopurinol. "It’s metabolized in the liver and very little of the active drug is excreted renally, raising the possibility that it might be safer in patients with mild to moderate renal insufficiency," Dr. Pendleton said.

It’s not easy to fully compare the two, because all three of the studies on the basis of which febuxostat was approved used a fixed-dose allopurinol regimen. "None of them allowed the total upward titration of allopurinol for a fair comparison," Dr. Pendleton pointed out.

The studies concluded that 40 mg of febuxostat was as effective as 300 mg of allopurinol. "The higher dose [of febuxostat 80 mg] seemed to be more effective than 400 mg allopurinol, but again, the studies did not allow for an upward titration" of the comparator, he said.

Although none of the patients in those trials had a creatinine level of more than 2.5 mg/dL, "a short-term study suggests that febuxostat dosing would not need to be adjusted even with a very low creatinine clearance [of 10-29 mL/min]. But just the same I would be very careful in that setting," Dr. Pendleton said (Am. J. Ther. 2005;12:22-34).

Febuxostat also appears to be safe for patients with mild hepatic dysfunction, with an adverse event profile similar to that of allopurinol. However, febuxostat is contraindicated in patients who are taking azathioprine, mercaptopurine, and theophylline.

Probenecid could be another option for some patients, especially those who underexcrete uric acid. Although probenecid has a somewhat better adverse event profile than allopurinol, it requires a 24-hour urine collection to rule out overproduction of uric acid and it seems to increase the risk of kidney stones. The drug is not as effective in patients with a low creatinine clearance (less than 60 mL/min), and "seems to have no effect at all at a creatinine level of 30 mL/min or lower," Dr. Pendleton said. Probenecid also must be taken three times a day – another drawback, in his opinion.

Dr. Pendleton said that he had no relevant financial disclosures.

NEW YORK – Evidence is emerging that treating hyperuricemia and gout could help control comorbid cardiovascular disease, according to Dr. Michael H. Pillinger, director of the rheumatology fellowship program at New York University and director of rheumatology at the Manhattan VA Hospital, New York.

Patients with gout tend to have an average of three to four comorbidities, including hypertension, hyperlipidemia, kidney disease, diabetes, and coronary artery disease.

Now there is some limited evidence indicating that lowering uric acid may help to reduce cardiovascular mortality, Dr. Pillinger said at the meeting.

Data presented at last year's American College of Rheumatology's annual meeting show that cardiovascular mortality dropped by nearly half among patients taking urate-lowering therapy.

The study, which looked at a database of about 45,000 Taiwanese hyperuricemia patients, also showed that stroke mortality decreased significantly when urate levels were lowered.

And the researchers observed a larger decrease in mortality when patients on the drug actually achieved urate lowering than when they did not.

“This would suggest that there really is a relationship between uric acid and cardiovascular disease,” Dr. Pillinger said.

More research will be needed to know for sure whether lowering uric acid could benefit cardiovascular disease, he said.

And other questions remain as well: For example, is it hyperuricemia or gout that conveys the risk for coronary artery disease?

That's unclear, because most of the current studies have been done comparing only hyperuricemia to cardiac outcomes, he said.

Another Taiwanese database study, published last year, compared patients with hyperuricemia and those with gout vs. control patients.

After adjusting for comorbidities, the researchers concluded that only gout was a risk for cardiovascular mortality (Rheumatology [Oxford] 2010;49:141–6). But Dr. Pillinger said he's not convinced that the data should have been adjusted, because if gout or hyperuricemia themselves contribute to the comorbidities, then such an adjustment may lead to an underestimation of the impact of uric acid.

To shed more light on the role of gout and hyperuricemia in cardiovascular disease, researchers at NYU have been recruiting patients to a study assessing coronary artery disease in men with hyperuricemia, in those with gout, and in control patients.

Preliminary data from the prospective cohort study indicate that coronary artery disease increases in a stepwise fashion from hyperuricemia to gout, according to Dr. Pillinger.

The researchers are also starting to look at how hyperuricemic patients with lower levels of uric acid (6.9–9.0 mg/dL), compared with those who have higher levels (greater than 9.0 mg/dL).

In that preliminary subanalysis, patients with the highest levels of uric acid had the highest risk for coronary artery disease and MI.

“I think this is beginning to suggest that there's at least an intermediate risk from having elevated uric acid,” Dr. Pillinger said.

Some studies have also shown that treatment of the inflammation associated with gout could help in cardiovascular disease.

Researchers performed an analysis of nearly 1,300 patients in the New York VA gout cohort.

About half of the patients were on chronic colchicine therapy and half were not taking colchicine.

The cross-sectional study, which was presented at the 2010 ACR annual meeting, found that patients who took colchicine had more than a 50% decrease in MI rates, compared with those who were not on the drug.

Patients also had a lower risk of death and a lower C-reactive protein level, but these results did not achieve statistical significance. “This is very provocative,” Dr. Pillinger said.

A recent study based on data from National Health and Nutrition Examination Survey shows that an estimated 32 million Americans, one-fifth of the U.S. population, have hyperuricemia, which precedes gout.

Gout rates also are increasing in the U.S. NHANES data show a 1.2% increase in gout among U.S. adults, from 2.7% during 1988–1994 to 3.9% during 2007–2008. Men and older adults were the most likely to be at increased risk for gout (

Dr. Pillinger said that he had no relevant financial conflicts of interest to report.

Patients with the highest levels of uric acid had the highest risk for coronary artery disease and MI.

Source DR. PILLINGER

NEW YORK – Evidence is emerging that treating hyperuricemia and gout could help control comorbid cardiovascular disease, according to Dr. Michael H. Pillinger, director of the rheumatology fellowship program at New York University and director of rheumatology at the Manhattan VA Hospital, New York.

Patients with gout tend to have an average of three to four comorbidities, including hypertension, hyperlipidemia, kidney disease, diabetes, and coronary artery disease.

Now there is some limited evidence indicating that lowering uric acid may help to reduce cardiovascular mortality, Dr. Pillinger said at the meeting.

Data presented at last year's American College of Rheumatology's annual meeting show that cardiovascular mortality dropped by nearly half among patients taking urate-lowering therapy.

The study, which looked at a database of about 45,000 Taiwanese hyperuricemia patients, also showed that stroke mortality decreased significantly when urate levels were lowered.

And the researchers observed a larger decrease in mortality when patients on the drug actually achieved urate lowering than when they did not.

“This would suggest that there really is a relationship between uric acid and cardiovascular disease,” Dr. Pillinger said.

More research will be needed to know for sure whether lowering uric acid could benefit cardiovascular disease, he said.

And other questions remain as well: For example, is it hyperuricemia or gout that conveys the risk for coronary artery disease?

That's unclear, because most of the current studies have been done comparing only hyperuricemia to cardiac outcomes, he said.

Another Taiwanese database study, published last year, compared patients with hyperuricemia and those with gout vs. control patients.

After adjusting for comorbidities, the researchers concluded that only gout was a risk for cardiovascular mortality (Rheumatology [Oxford] 2010;49:141–6). But Dr. Pillinger said he's not convinced that the data should have been adjusted, because if gout or hyperuricemia themselves contribute to the comorbidities, then such an adjustment may lead to an underestimation of the impact of uric acid.

To shed more light on the role of gout and hyperuricemia in cardiovascular disease, researchers at NYU have been recruiting patients to a study assessing coronary artery disease in men with hyperuricemia, in those with gout, and in control patients.

Preliminary data from the prospective cohort study indicate that coronary artery disease increases in a stepwise fashion from hyperuricemia to gout, according to Dr. Pillinger.

The researchers are also starting to look at how hyperuricemic patients with lower levels of uric acid (6.9–9.0 mg/dL), compared with those who have higher levels (greater than 9.0 mg/dL).

In that preliminary subanalysis, patients with the highest levels of uric acid had the highest risk for coronary artery disease and MI.

“I think this is beginning to suggest that there's at least an intermediate risk from having elevated uric acid,” Dr. Pillinger said.

Some studies have also shown that treatment of the inflammation associated with gout could help in cardiovascular disease.

Researchers performed an analysis of nearly 1,300 patients in the New York VA gout cohort.

About half of the patients were on chronic colchicine therapy and half were not taking colchicine.

The cross-sectional study, which was presented at the 2010 ACR annual meeting, found that patients who took colchicine had more than a 50% decrease in MI rates, compared with those who were not on the drug.

Patients also had a lower risk of death and a lower C-reactive protein level, but these results did not achieve statistical significance. “This is very provocative,” Dr. Pillinger said.

A recent study based on data from National Health and Nutrition Examination Survey shows that an estimated 32 million Americans, one-fifth of the U.S. population, have hyperuricemia, which precedes gout.

Gout rates also are increasing in the U.S. NHANES data show a 1.2% increase in gout among U.S. adults, from 2.7% during 1988–1994 to 3.9% during 2007–2008. Men and older adults were the most likely to be at increased risk for gout (

Dr. Pillinger said that he had no relevant financial conflicts of interest to report.

Patients with the highest levels of uric acid had the highest risk for coronary artery disease and MI.

Source DR. PILLINGER

NEW YORK – Evidence is emerging that treating hyperuricemia and gout could help control comorbid cardiovascular disease, according to Dr. Michael H. Pillinger, director of the rheumatology fellowship program at New York University and director of rheumatology at the Manhattan VA Hospital, New York.

Patients with gout tend to have an average of three to four comorbidities, including hypertension, hyperlipidemia, kidney disease, diabetes, and coronary artery disease.

Now there is some limited evidence indicating that lowering uric acid may help to reduce cardiovascular mortality, Dr. Pillinger said at the meeting.

Data presented at last year's American College of Rheumatology's annual meeting show that cardiovascular mortality dropped by nearly half among patients taking urate-lowering therapy.

The study, which looked at a database of about 45,000 Taiwanese hyperuricemia patients, also showed that stroke mortality decreased significantly when urate levels were lowered.

And the researchers observed a larger decrease in mortality when patients on the drug actually achieved urate lowering than when they did not.

“This would suggest that there really is a relationship between uric acid and cardiovascular disease,” Dr. Pillinger said.

More research will be needed to know for sure whether lowering uric acid could benefit cardiovascular disease, he said.

And other questions remain as well: For example, is it hyperuricemia or gout that conveys the risk for coronary artery disease?

That's unclear, because most of the current studies have been done comparing only hyperuricemia to cardiac outcomes, he said.

Another Taiwanese database study, published last year, compared patients with hyperuricemia and those with gout vs. control patients.

After adjusting for comorbidities, the researchers concluded that only gout was a risk for cardiovascular mortality (Rheumatology [Oxford] 2010;49:141–6). But Dr. Pillinger said he's not convinced that the data should have been adjusted, because if gout or hyperuricemia themselves contribute to the comorbidities, then such an adjustment may lead to an underestimation of the impact of uric acid.

To shed more light on the role of gout and hyperuricemia in cardiovascular disease, researchers at NYU have been recruiting patients to a study assessing coronary artery disease in men with hyperuricemia, in those with gout, and in control patients.

Preliminary data from the prospective cohort study indicate that coronary artery disease increases in a stepwise fashion from hyperuricemia to gout, according to Dr. Pillinger.

The researchers are also starting to look at how hyperuricemic patients with lower levels of uric acid (6.9–9.0 mg/dL), compared with those who have higher levels (greater than 9.0 mg/dL).

In that preliminary subanalysis, patients with the highest levels of uric acid had the highest risk for coronary artery disease and MI.

“I think this is beginning to suggest that there's at least an intermediate risk from having elevated uric acid,” Dr. Pillinger said.

Some studies have also shown that treatment of the inflammation associated with gout could help in cardiovascular disease.

Researchers performed an analysis of nearly 1,300 patients in the New York VA gout cohort.

About half of the patients were on chronic colchicine therapy and half were not taking colchicine.

The cross-sectional study, which was presented at the 2010 ACR annual meeting, found that patients who took colchicine had more than a 50% decrease in MI rates, compared with those who were not on the drug.

Patients also had a lower risk of death and a lower C-reactive protein level, but these results did not achieve statistical significance. “This is very provocative,” Dr. Pillinger said.

A recent study based on data from National Health and Nutrition Examination Survey shows that an estimated 32 million Americans, one-fifth of the U.S. population, have hyperuricemia, which precedes gout.

Gout rates also are increasing in the U.S. NHANES data show a 1.2% increase in gout among U.S. adults, from 2.7% during 1988–1994 to 3.9% during 2007–2008. Men and older adults were the most likely to be at increased risk for gout (

Dr. Pillinger said that he had no relevant financial conflicts of interest to report.

Patients with the highest levels of uric acid had the highest risk for coronary artery disease and MI.

Source DR. PILLINGER

The prevalence of gout has increased in the United States, especially among the eldest population, according to the latest national data. That means that nursing home staff are caring for more hot, swollen, and inflamed joints than ever, said several experts on the topic.

In interviews, they added that clinicians' potential success in preventing, diagnosing, and treating the disease in long-term care residents lies largely in fundamental practices and an individualized approach to medications.

Data from the National Health and Nutrition Examination Survey (NHANES) show an increase in gout prevalence among U.S. adults from 2.7% in the survey's 1994–1998 reporting periods to 3.9% in 2007–2008. Meanwhile, the prevalence in adults aged 80 years and older jumped from 5.9% to 12.6%.

The prevalence of hyperuricemia, which usually precedes gout, was 31% in adults aged 65 years or older and 37% among those aged 80 years and older, according to the latest NHANES data.

The increase in actual gout occurred mainly among men in NHANES. Other studies, however, have documented an increased prevalence of the disease among older women as well. Studies cited in a review of “Crystal-Associated Arthritis in the Elderly” showed women making up at least half of the cases in which gout first strikes after age 60 years. Among individuals who have a first episode after age 80, women seem to predominate (Rheum. Dis. Clin. N. Am. 2007;33:33–55).

The presentation of the disease, as well as its prevalence, is changing, said Dr. Arthur Weinstein, professor of medicine at Georgetown University, Washington, and director of rheumatology at the Washington Hospital Center. “We're seeing more and more polyarticular gout in older patients, for instance, either as an initial presentation or years after just a single monoarticular episode” with no subsequent recurrences, he said in an interview.

He and others said they believe that the common use of thiazide diuretics in older patients is a major driver of gout's changing profile. Other factors could include genetic predispositions to hyperuricemia and gout and increasing obesity, insulin resistance, and metabolic syndrome in the aging population.

While often the best choice for hypertension management, thiazide diuretics can contribute to the development of chronic hyperuricemia, as can low-dose aspirin and cyclosporine. Also, increasing numbers of elderly people have chronic cardiac and renal disease – factors that have been associated with hyperuricemia and gout.

Other changes in gout's presentation in the elderly include earlier and often-atypical development of the soft tissue masses known as tophi and more frequent and earlier involvement of the small joints of the fingers.

Diagnosis, Empiric Therapy

The differential diagnosis of a swollen, inflamed joint often involves ruling out the likelihood of septic arthritis, fracture, or other injury, and pseudogout – the other main form of crystal-induced arthritis.

Patients experiencing an acute gout attack can have a low-grade fever. “But with a fever of 101 or higher, you have to consider that it's something that's not crystal induced,” said Dr. John W. Rachow, a geriatrician and rheumatologist at the University of Iowa, Iowa City.

Septic arthritis should also be suspected when patients have joint pain and tachycardia, hypotension, or signs of other acute illness. “And if there is hardware in the joint, even without a fever, patients should be evaluated at a higher level,” said Dr. Rachow, who also serves as an attending physician in numerous nursing homes in the Iowa City area.

While the diagnostic standard for gout – synovial fluid or tophus aspiration with the identification of monosodium urate crystals under polarizing microscopy – can seem even more important in the older population, it is also more untenable given the stresses of transporting nursing home patients to hospitals.

A good long-term care mind-set can preclude the need for crystal confirmation in every case, said clinicians interviewed for this story.

“In health care, we tend to turn things into acute episodes when they're really acute exacerbations of chronic conditions,” said Dr. George Taler, director of long-term care in the department of medicine at the Washington Hospital Center and medical director of the Capitol Hill Nursing Center, both in Washington.

Diagnosing and treating goutsmean “remembering that our patients have a history,” said Dr. Taler. He advised “making sure that when the nurse calls about a swollen knee, he or she has reviewed the medical record.”

A host of factors can indicate the likelihood that joint pain is a gout attack. These include a history of gout, persistent elevated uric acid levels, and the use of medications or existence of medical conditions associated with gout. Blood testing at the time of an attack is not informative, said Dr. Rachow. While most patients with gout have chronically elevated uric acid levels, serum uric acid levels at the time of an attack are frequently normal, he explained.

Gout should also be considered in elderly patients when attacks of acute pain and swelling are seen in osteoarthritic joints of the fingers, especially in patients who have renal disease or are on chronic diuretic therapy.

An older patient without a history of gout and without any obvious risk for gout or sign of a septic joint probably has pseudogout, which is caused by the deposition of calcium pyrophosphate dihydrate rather than monosodium urate. Pseudogout often strikes the wrist or the knee and does not commonly involve polyarticular attacks, as gout does.

With a suspicion of either gout or pseudogout, a short empiric course of anti-inflammatory treatment should be considered, said Dr. Rachow. “If it really is crystal induced, you'll know in 12 hours and definitely within 24 hours” because the pain will begin to subside, he said.

“And, at that point, if you've started with a nonsteroidal anti-inflammatory and it's working well, you can add a gastroprotective agent and continue the NSAID, reducing the dose once symptoms begin to improve. Or you can switch to colchicine.”

If the anti-inflammatory treatment is “not working spectacularly well within 24 hours, you need to put the brakes on, close your office door, and think things over again,” he said.

Facilities that have a sizable number of patients with frequent flares probably should have a nurse practitioner or a physician assistant trained to aspirate joints and arrange the logistics for sending out samples, Dr. Taler said.

The Longer Term

With a correct approach, “gout is eminently preventable and treatable in 90% of nursing home residents,” said Dr. Weinstein. “The principles are studied, reported, and well described,” he said. The American College of Rheumatology plans to release its first practice guidelines on the management of gout in 2012.

Decisions about managing acute attacks – whether to use NSAIDs, glucocorticoids, or oral colchicine – are rightly driven by the severity of gout and consideration of the patient's coexisting illnesses and the drugs' side effects. While NSAID use carries the risk of gastropathy, colchicine can cause diarrhea and other potentially serious side effects and should be avoided in patients who have renal or hepatic insufficiency.

Many clinicians consider colchicine a second-line therapy for acute gout, after NSAIDs or corticosteroids. In very elderly people, however, the treatment decision might be different. Dr. Weinstein said he worries about possible cardiac risks with the use of NSAIDs in very old patients. He has had success with the early use of low-dose colchicine in very elderly patients with reasonable kidney function, and he said that the drug “works best in the first 48–72 hours.”

Parenteral corticosteroids, intra-articular injections, or even an oral prednisone taper are good options, he emphasized. Issues of whether and how to move from acute management of gout attacks to long-term urate-lowering therapy are taking on added significance in nursing homes as the prevalence of gout increases there.

Dr. Rachow recommended hypouricemic therapy for patients with documented hyperuricemia and a history of multiple attacks, and for patients who have developed tophi. It can even be considered for a frail, ill nursing home resident for whom a second gout attack would be unusually complicating and traumatic, said Dr. Rachow.

When it is deemed beneficial, the urate-lowering therapy must be undertaken with care, he emphasized.

Hypouricemic therapy should start only after an acute attack is completely resolved (or even 2–4 weeks after flare resolution), with cautious dosing and careful monitoring for adverse effects and, when possible, under the cover of a prophylactic anti-inflammatory drug. Low-dose colchicine has long been used to prevent flares associated with the lowering of urate.

Allopurinol, the xanthine oxidase inhibitor most often prescribed to lower urate levels, should be “started low and increased slowly” in older patients with renal impairment, Dr. Weinstein said.

A xanthine oxidase inhibitor called febuxostat (Uloric) was approved in 2009 for treatment of hyperuricemia in patients with gout, but its efficacy and safety compared with allopurinol is not fully established (N. Engl. J. Med. 2011;364: 443–52).

Also on the medication front is a newly approved drug called pegloticase (Krystexxa), which might be a good option for patients who cannot use allopurinol, said Dr. Weinstein.

Dr. Rachow and Dr. Taler said they had no conflicts of interest to disclose on this topic. Dr. Weinstein disclosed that he has received research grants from Savient Pharmaceuticals, the maker of pegloticase, for a clinical study, but not for any therapeutic studies.

The presentation of gout, as well as its prevalence, has been changing.

Source ©craftvision/iStockphoto.com

The prevalence of gout has increased in the United States, especially among the eldest population, according to the latest national data. That means that nursing home staff are caring for more hot, swollen, and inflamed joints than ever, said several experts on the topic.

In interviews, they added that clinicians' potential success in preventing, diagnosing, and treating the disease in long-term care residents lies largely in fundamental practices and an individualized approach to medications.

Data from the National Health and Nutrition Examination Survey (NHANES) show an increase in gout prevalence among U.S. adults from 2.7% in the survey's 1994–1998 reporting periods to 3.9% in 2007–2008. Meanwhile, the prevalence in adults aged 80 years and older jumped from 5.9% to 12.6%.

The prevalence of hyperuricemia, which usually precedes gout, was 31% in adults aged 65 years or older and 37% among those aged 80 years and older, according to the latest NHANES data.

The increase in actual gout occurred mainly among men in NHANES. Other studies, however, have documented an increased prevalence of the disease among older women as well. Studies cited in a review of “Crystal-Associated Arthritis in the Elderly” showed women making up at least half of the cases in which gout first strikes after age 60 years. Among individuals who have a first episode after age 80, women seem to predominate (Rheum. Dis. Clin. N. Am. 2007;33:33–55).

The presentation of the disease, as well as its prevalence, is changing, said Dr. Arthur Weinstein, professor of medicine at Georgetown University, Washington, and director of rheumatology at the Washington Hospital Center. “We're seeing more and more polyarticular gout in older patients, for instance, either as an initial presentation or years after just a single monoarticular episode” with no subsequent recurrences, he said in an interview.

He and others said they believe that the common use of thiazide diuretics in older patients is a major driver of gout's changing profile. Other factors could include genetic predispositions to hyperuricemia and gout and increasing obesity, insulin resistance, and metabolic syndrome in the aging population.

While often the best choice for hypertension management, thiazide diuretics can contribute to the development of chronic hyperuricemia, as can low-dose aspirin and cyclosporine. Also, increasing numbers of elderly people have chronic cardiac and renal disease – factors that have been associated with hyperuricemia and gout.

Other changes in gout's presentation in the elderly include earlier and often-atypical development of the soft tissue masses known as tophi and more frequent and earlier involvement of the small joints of the fingers.

Diagnosis, Empiric Therapy

The differential diagnosis of a swollen, inflamed joint often involves ruling out the likelihood of septic arthritis, fracture, or other injury, and pseudogout – the other main form of crystal-induced arthritis.

Patients experiencing an acute gout attack can have a low-grade fever. “But with a fever of 101 or higher, you have to consider that it's something that's not crystal induced,” said Dr. John W. Rachow, a geriatrician and rheumatologist at the University of Iowa, Iowa City.

Septic arthritis should also be suspected when patients have joint pain and tachycardia, hypotension, or signs of other acute illness. “And if there is hardware in the joint, even without a fever, patients should be evaluated at a higher level,” said Dr. Rachow, who also serves as an attending physician in numerous nursing homes in the Iowa City area.

While the diagnostic standard for gout – synovial fluid or tophus aspiration with the identification of monosodium urate crystals under polarizing microscopy – can seem even more important in the older population, it is also more untenable given the stresses of transporting nursing home patients to hospitals.

A good long-term care mind-set can preclude the need for crystal confirmation in every case, said clinicians interviewed for this story.

“In health care, we tend to turn things into acute episodes when they're really acute exacerbations of chronic conditions,” said Dr. George Taler, director of long-term care in the department of medicine at the Washington Hospital Center and medical director of the Capitol Hill Nursing Center, both in Washington.

Diagnosing and treating goutsmean “remembering that our patients have a history,” said Dr. Taler. He advised “making sure that when the nurse calls about a swollen knee, he or she has reviewed the medical record.”

A host of factors can indicate the likelihood that joint pain is a gout attack. These include a history of gout, persistent elevated uric acid levels, and the use of medications or existence of medical conditions associated with gout. Blood testing at the time of an attack is not informative, said Dr. Rachow. While most patients with gout have chronically elevated uric acid levels, serum uric acid levels at the time of an attack are frequently normal, he explained.

Gout should also be considered in elderly patients when attacks of acute pain and swelling are seen in osteoarthritic joints of the fingers, especially in patients who have renal disease or are on chronic diuretic therapy.

An older patient without a history of gout and without any obvious risk for gout or sign of a septic joint probably has pseudogout, which is caused by the deposition of calcium pyrophosphate dihydrate rather than monosodium urate. Pseudogout often strikes the wrist or the knee and does not commonly involve polyarticular attacks, as gout does.

With a suspicion of either gout or pseudogout, a short empiric course of anti-inflammatory treatment should be considered, said Dr. Rachow. “If it really is crystal induced, you'll know in 12 hours and definitely within 24 hours” because the pain will begin to subside, he said.

“And, at that point, if you've started with a nonsteroidal anti-inflammatory and it's working well, you can add a gastroprotective agent and continue the NSAID, reducing the dose once symptoms begin to improve. Or you can switch to colchicine.”

If the anti-inflammatory treatment is “not working spectacularly well within 24 hours, you need to put the brakes on, close your office door, and think things over again,” he said.

Facilities that have a sizable number of patients with frequent flares probably should have a nurse practitioner or a physician assistant trained to aspirate joints and arrange the logistics for sending out samples, Dr. Taler said.

The Longer Term

With a correct approach, “gout is eminently preventable and treatable in 90% of nursing home residents,” said Dr. Weinstein. “The principles are studied, reported, and well described,” he said. The American College of Rheumatology plans to release its first practice guidelines on the management of gout in 2012.

Decisions about managing acute attacks – whether to use NSAIDs, glucocorticoids, or oral colchicine – are rightly driven by the severity of gout and consideration of the patient's coexisting illnesses and the drugs' side effects. While NSAID use carries the risk of gastropathy, colchicine can cause diarrhea and other potentially serious side effects and should be avoided in patients who have renal or hepatic insufficiency.

Many clinicians consider colchicine a second-line therapy for acute gout, after NSAIDs or corticosteroids. In very elderly people, however, the treatment decision might be different. Dr. Weinstein said he worries about possible cardiac risks with the use of NSAIDs in very old patients. He has had success with the early use of low-dose colchicine in very elderly patients with reasonable kidney function, and he said that the drug “works best in the first 48–72 hours.”

Parenteral corticosteroids, intra-articular injections, or even an oral prednisone taper are good options, he emphasized. Issues of whether and how to move from acute management of gout attacks to long-term urate-lowering therapy are taking on added significance in nursing homes as the prevalence of gout increases there.

Dr. Rachow recommended hypouricemic therapy for patients with documented hyperuricemia and a history of multiple attacks, and for patients who have developed tophi. It can even be considered for a frail, ill nursing home resident for whom a second gout attack would be unusually complicating and traumatic, said Dr. Rachow.

When it is deemed beneficial, the urate-lowering therapy must be undertaken with care, he emphasized.

Hypouricemic therapy should start only after an acute attack is completely resolved (or even 2–4 weeks after flare resolution), with cautious dosing and careful monitoring for adverse effects and, when possible, under the cover of a prophylactic anti-inflammatory drug. Low-dose colchicine has long been used to prevent flares associated with the lowering of urate.

Allopurinol, the xanthine oxidase inhibitor most often prescribed to lower urate levels, should be “started low and increased slowly” in older patients with renal impairment, Dr. Weinstein said.

A xanthine oxidase inhibitor called febuxostat (Uloric) was approved in 2009 for treatment of hyperuricemia in patients with gout, but its efficacy and safety compared with allopurinol is not fully established (N. Engl. J. Med. 2011;364: 443–52).

Also on the medication front is a newly approved drug called pegloticase (Krystexxa), which might be a good option for patients who cannot use allopurinol, said Dr. Weinstein.

Dr. Rachow and Dr. Taler said they had no conflicts of interest to disclose on this topic. Dr. Weinstein disclosed that he has received research grants from Savient Pharmaceuticals, the maker of pegloticase, for a clinical study, but not for any therapeutic studies.

The presentation of gout, as well as its prevalence, has been changing.

Source ©craftvision/iStockphoto.com

The prevalence of gout has increased in the United States, especially among the eldest population, according to the latest national data. That means that nursing home staff are caring for more hot, swollen, and inflamed joints than ever, said several experts on the topic.

In interviews, they added that clinicians' potential success in preventing, diagnosing, and treating the disease in long-term care residents lies largely in fundamental practices and an individualized approach to medications.

Data from the National Health and Nutrition Examination Survey (NHANES) show an increase in gout prevalence among U.S. adults from 2.7% in the survey's 1994–1998 reporting periods to 3.9% in 2007–2008. Meanwhile, the prevalence in adults aged 80 years and older jumped from 5.9% to 12.6%.

The prevalence of hyperuricemia, which usually precedes gout, was 31% in adults aged 65 years or older and 37% among those aged 80 years and older, according to the latest NHANES data.

The increase in actual gout occurred mainly among men in NHANES. Other studies, however, have documented an increased prevalence of the disease among older women as well. Studies cited in a review of “Crystal-Associated Arthritis in the Elderly” showed women making up at least half of the cases in which gout first strikes after age 60 years. Among individuals who have a first episode after age 80, women seem to predominate (Rheum. Dis. Clin. N. Am. 2007;33:33–55).

The presentation of the disease, as well as its prevalence, is changing, said Dr. Arthur Weinstein, professor of medicine at Georgetown University, Washington, and director of rheumatology at the Washington Hospital Center. “We're seeing more and more polyarticular gout in older patients, for instance, either as an initial presentation or years after just a single monoarticular episode” with no subsequent recurrences, he said in an interview.

He and others said they believe that the common use of thiazide diuretics in older patients is a major driver of gout's changing profile. Other factors could include genetic predispositions to hyperuricemia and gout and increasing obesity, insulin resistance, and metabolic syndrome in the aging population.

While often the best choice for hypertension management, thiazide diuretics can contribute to the development of chronic hyperuricemia, as can low-dose aspirin and cyclosporine. Also, increasing numbers of elderly people have chronic cardiac and renal disease – factors that have been associated with hyperuricemia and gout.

Other changes in gout's presentation in the elderly include earlier and often-atypical development of the soft tissue masses known as tophi and more frequent and earlier involvement of the small joints of the fingers.

Diagnosis, Empiric Therapy

The differential diagnosis of a swollen, inflamed joint often involves ruling out the likelihood of septic arthritis, fracture, or other injury, and pseudogout – the other main form of crystal-induced arthritis.

Patients experiencing an acute gout attack can have a low-grade fever. “But with a fever of 101 or higher, you have to consider that it's something that's not crystal induced,” said Dr. John W. Rachow, a geriatrician and rheumatologist at the University of Iowa, Iowa City.

Septic arthritis should also be suspected when patients have joint pain and tachycardia, hypotension, or signs of other acute illness. “And if there is hardware in the joint, even without a fever, patients should be evaluated at a higher level,” said Dr. Rachow, who also serves as an attending physician in numerous nursing homes in the Iowa City area.

While the diagnostic standard for gout – synovial fluid or tophus aspiration with the identification of monosodium urate crystals under polarizing microscopy – can seem even more important in the older population, it is also more untenable given the stresses of transporting nursing home patients to hospitals.

A good long-term care mind-set can preclude the need for crystal confirmation in every case, said clinicians interviewed for this story.

“In health care, we tend to turn things into acute episodes when they're really acute exacerbations of chronic conditions,” said Dr. George Taler, director of long-term care in the department of medicine at the Washington Hospital Center and medical director of the Capitol Hill Nursing Center, both in Washington.

Diagnosing and treating goutsmean “remembering that our patients have a history,” said Dr. Taler. He advised “making sure that when the nurse calls about a swollen knee, he or she has reviewed the medical record.”

A host of factors can indicate the likelihood that joint pain is a gout attack. These include a history of gout, persistent elevated uric acid levels, and the use of medications or existence of medical conditions associated with gout. Blood testing at the time of an attack is not informative, said Dr. Rachow. While most patients with gout have chronically elevated uric acid levels, serum uric acid levels at the time of an attack are frequently normal, he explained.

Gout should also be considered in elderly patients when attacks of acute pain and swelling are seen in osteoarthritic joints of the fingers, especially in patients who have renal disease or are on chronic diuretic therapy.

An older patient without a history of gout and without any obvious risk for gout or sign of a septic joint probably has pseudogout, which is caused by the deposition of calcium pyrophosphate dihydrate rather than monosodium urate. Pseudogout often strikes the wrist or the knee and does not commonly involve polyarticular attacks, as gout does.

With a suspicion of either gout or pseudogout, a short empiric course of anti-inflammatory treatment should be considered, said Dr. Rachow. “If it really is crystal induced, you'll know in 12 hours and definitely within 24 hours” because the pain will begin to subside, he said.

“And, at that point, if you've started with a nonsteroidal anti-inflammatory and it's working well, you can add a gastroprotective agent and continue the NSAID, reducing the dose once symptoms begin to improve. Or you can switch to colchicine.”

If the anti-inflammatory treatment is “not working spectacularly well within 24 hours, you need to put the brakes on, close your office door, and think things over again,” he said.

Facilities that have a sizable number of patients with frequent flares probably should have a nurse practitioner or a physician assistant trained to aspirate joints and arrange the logistics for sending out samples, Dr. Taler said.

The Longer Term

With a correct approach, “gout is eminently preventable and treatable in 90% of nursing home residents,” said Dr. Weinstein. “The principles are studied, reported, and well described,” he said. The American College of Rheumatology plans to release its first practice guidelines on the management of gout in 2012.

Decisions about managing acute attacks – whether to use NSAIDs, glucocorticoids, or oral colchicine – are rightly driven by the severity of gout and consideration of the patient's coexisting illnesses and the drugs' side effects. While NSAID use carries the risk of gastropathy, colchicine can cause diarrhea and other potentially serious side effects and should be avoided in patients who have renal or hepatic insufficiency.

Many clinicians consider colchicine a second-line therapy for acute gout, after NSAIDs or corticosteroids. In very elderly people, however, the treatment decision might be different. Dr. Weinstein said he worries about possible cardiac risks with the use of NSAIDs in very old patients. He has had success with the early use of low-dose colchicine in very elderly patients with reasonable kidney function, and he said that the drug “works best in the first 48–72 hours.”

Parenteral corticosteroids, intra-articular injections, or even an oral prednisone taper are good options, he emphasized. Issues of whether and how to move from acute management of gout attacks to long-term urate-lowering therapy are taking on added significance in nursing homes as the prevalence of gout increases there.

Dr. Rachow recommended hypouricemic therapy for patients with documented hyperuricemia and a history of multiple attacks, and for patients who have developed tophi. It can even be considered for a frail, ill nursing home resident for whom a second gout attack would be unusually complicating and traumatic, said Dr. Rachow.

When it is deemed beneficial, the urate-lowering therapy must be undertaken with care, he emphasized.

Hypouricemic therapy should start only after an acute attack is completely resolved (or even 2–4 weeks after flare resolution), with cautious dosing and careful monitoring for adverse effects and, when possible, under the cover of a prophylactic anti-inflammatory drug. Low-dose colchicine has long been used to prevent flares associated with the lowering of urate.

Allopurinol, the xanthine oxidase inhibitor most often prescribed to lower urate levels, should be “started low and increased slowly” in older patients with renal impairment, Dr. Weinstein said.

A xanthine oxidase inhibitor called febuxostat (Uloric) was approved in 2009 for treatment of hyperuricemia in patients with gout, but its efficacy and safety compared with allopurinol is not fully established (N. Engl. J. Med. 2011;364: 443–52).

Also on the medication front is a newly approved drug called pegloticase (Krystexxa), which might be a good option for patients who cannot use allopurinol, said Dr. Weinstein.

Dr. Rachow and Dr. Taler said they had no conflicts of interest to disclose on this topic. Dr. Weinstein disclosed that he has received research grants from Savient Pharmaceuticals, the maker of pegloticase, for a clinical study, but not for any therapeutic studies.

The presentation of gout, as well as its prevalence, has been changing.

Source ©craftvision/iStockphoto.com

NEW YORK – Evidence is emerging that treating hyperuricemia and gout could help control comorbid cardiovascular disease, according to Dr. Michael H. Pillinger, director of the rheumatology fellowship program at New York University and director of rheumatology at the Manhattan VA Hospital, New York.

Patients with gout tend to have an average of three to four comorbidities, including hypertension, hyperlipidemia, kidney disease, diabetes, and coronary artery disease. Now there is some limited evidence indicating that lowering uric acid may help to reduce cardiovascular mortality, Dr. Pillinger said at a rheumatology meeting sponsored by New York University.

Data presented at last year’s American College of Rheumatology’s annual meeting show that cardiovascular mortality dropped by nearly half among patients taking urate-lowering therapy. The study, which looked at a database of about 45,000 Taiwanese hyperuricemia patients, also showed that stroke mortality decreased significantly when urate levels were lowered. And the researchers observed a larger decrease in mortality when patients on the drug actually achieved urate lowering than when they did not. "This would suggest that there really is a relationship between uric acid and cardiovascular disease," Dr. Pillinger said.

More research will be needed to know for sure whether lowering uric acid could benefit cardiovascular disease, he said. And other questions remain as well: For example, is it hyperuricemia or gout that conveys the risk for coronary artery disease? That’s unclear, because most of the current studies have been done comparing only hyperuricemia to cardiac outcomes, he said.

Another Taiwanese database study, published last year, compared patients with hyperuricemia and those with gout vs. control patients. After adjusting for comorbidities, the researchers concluded that only gout was a risk for cardiovascular mortality (Rheumatology [Oxford] 2010;49:141-6). But Dr. Pillinger said he’s not convinced that the data should have been adjusted, because if gout or hyperuricemia themselves contribute to the comorbidities, then such an adjustment may lead to an underestimation of the impact of uric acid.

To shed more light on the role of gout and hyperuricemia in cardiovascular disease, researchers at NYU have been recruiting patients to a study assessing coronary artery disease in men with hyperuricemia, in those with gout, and in control patients. Preliminary data from the prospective cohort study indicate that coronary artery disease increases in a stepwise fashion from hyperuricemia to gout, Dr. Pillinger said.

The researchers are also starting to look at how hyperuricemic patients with lower levels of uric acid (6.9-9.0 mg/dL), compared with those who have higher levels (greater than 9.0 mg/dL). In that preliminary subanalysis, patients with the highest levels of uric acid had the highest risk for coronary artery disease and MI. "I think this is beginning to suggest that there’s at least an intermediate risk from having elevated uric acid," Dr. Pillinger said.

Some studies have also shown that treatment of the inflammation associated with gout could help in cardiovascular disease. Researchers performed an analysis of nearly 1,300 patients in the New York VA gout cohort. About half of the patients were on chronic colchicine therapy and half were not taking colchicine. The cross-sectional study, which was presented at the 2010 ACR annual meeting, found that patients who took colchicine had more than a 50% decrease in MI rates, compared with those who were not on the drug. Patients also had a lower risk of death and a lower C-reactive protein level, but these results did not achieve statistical significance. "This is very provocative," Dr. Pillinger said.

Dr. Pillinger said that he had no relevant conflicts of interest to report.

NEW YORK – Evidence is emerging that treating hyperuricemia and gout could help control comorbid cardiovascular disease, according to Dr. Michael H. Pillinger, director of the rheumatology fellowship program at New York University and director of rheumatology at the Manhattan VA Hospital, New York.

Patients with gout tend to have an average of three to four comorbidities, including hypertension, hyperlipidemia, kidney disease, diabetes, and coronary artery disease. Now there is some limited evidence indicating that lowering uric acid may help to reduce cardiovascular mortality, Dr. Pillinger said at a rheumatology meeting sponsored by New York University.

Data presented at last year’s American College of Rheumatology’s annual meeting show that cardiovascular mortality dropped by nearly half among patients taking urate-lowering therapy. The study, which looked at a database of about 45,000 Taiwanese hyperuricemia patients, also showed that stroke mortality decreased significantly when urate levels were lowered. And the researchers observed a larger decrease in mortality when patients on the drug actually achieved urate lowering than when they did not. "This would suggest that there really is a relationship between uric acid and cardiovascular disease," Dr. Pillinger said.

More research will be needed to know for sure whether lowering uric acid could benefit cardiovascular disease, he said. And other questions remain as well: For example, is it hyperuricemia or gout that conveys the risk for coronary artery disease? That’s unclear, because most of the current studies have been done comparing only hyperuricemia to cardiac outcomes, he said.

Another Taiwanese database study, published last year, compared patients with hyperuricemia and those with gout vs. control patients. After adjusting for comorbidities, the researchers concluded that only gout was a risk for cardiovascular mortality (Rheumatology [Oxford] 2010;49:141-6). But Dr. Pillinger said he’s not convinced that the data should have been adjusted, because if gout or hyperuricemia themselves contribute to the comorbidities, then such an adjustment may lead to an underestimation of the impact of uric acid.

To shed more light on the role of gout and hyperuricemia in cardiovascular disease, researchers at NYU have been recruiting patients to a study assessing coronary artery disease in men with hyperuricemia, in those with gout, and in control patients. Preliminary data from the prospective cohort study indicate that coronary artery disease increases in a stepwise fashion from hyperuricemia to gout, Dr. Pillinger said.

The researchers are also starting to look at how hyperuricemic patients with lower levels of uric acid (6.9-9.0 mg/dL), compared with those who have higher levels (greater than 9.0 mg/dL). In that preliminary subanalysis, patients with the highest levels of uric acid had the highest risk for coronary artery disease and MI. "I think this is beginning to suggest that there’s at least an intermediate risk from having elevated uric acid," Dr. Pillinger said.

Some studies have also shown that treatment of the inflammation associated with gout could help in cardiovascular disease. Researchers performed an analysis of nearly 1,300 patients in the New York VA gout cohort. About half of the patients were on chronic colchicine therapy and half were not taking colchicine. The cross-sectional study, which was presented at the 2010 ACR annual meeting, found that patients who took colchicine had more than a 50% decrease in MI rates, compared with those who were not on the drug. Patients also had a lower risk of death and a lower C-reactive protein level, but these results did not achieve statistical significance. "This is very provocative," Dr. Pillinger said.

Dr. Pillinger said that he had no relevant conflicts of interest to report.

NEW YORK – Evidence is emerging that treating hyperuricemia and gout could help control comorbid cardiovascular disease, according to Dr. Michael H. Pillinger, director of the rheumatology fellowship program at New York University and director of rheumatology at the Manhattan VA Hospital, New York.

Patients with gout tend to have an average of three to four comorbidities, including hypertension, hyperlipidemia, kidney disease, diabetes, and coronary artery disease. Now there is some limited evidence indicating that lowering uric acid may help to reduce cardiovascular mortality, Dr. Pillinger said at a rheumatology meeting sponsored by New York University.

Data presented at last year’s American College of Rheumatology’s annual meeting show that cardiovascular mortality dropped by nearly half among patients taking urate-lowering therapy. The study, which looked at a database of about 45,000 Taiwanese hyperuricemia patients, also showed that stroke mortality decreased significantly when urate levels were lowered. And the researchers observed a larger decrease in mortality when patients on the drug actually achieved urate lowering than when they did not. "This would suggest that there really is a relationship between uric acid and cardiovascular disease," Dr. Pillinger said.

More research will be needed to know for sure whether lowering uric acid could benefit cardiovascular disease, he said. And other questions remain as well: For example, is it hyperuricemia or gout that conveys the risk for coronary artery disease? That’s unclear, because most of the current studies have been done comparing only hyperuricemia to cardiac outcomes, he said.

Another Taiwanese database study, published last year, compared patients with hyperuricemia and those with gout vs. control patients. After adjusting for comorbidities, the researchers concluded that only gout was a risk for cardiovascular mortality (Rheumatology [Oxford] 2010;49:141-6). But Dr. Pillinger said he’s not convinced that the data should have been adjusted, because if gout or hyperuricemia themselves contribute to the comorbidities, then such an adjustment may lead to an underestimation of the impact of uric acid.

To shed more light on the role of gout and hyperuricemia in cardiovascular disease, researchers at NYU have been recruiting patients to a study assessing coronary artery disease in men with hyperuricemia, in those with gout, and in control patients. Preliminary data from the prospective cohort study indicate that coronary artery disease increases in a stepwise fashion from hyperuricemia to gout, Dr. Pillinger said.

The researchers are also starting to look at how hyperuricemic patients with lower levels of uric acid (6.9-9.0 mg/dL), compared with those who have higher levels (greater than 9.0 mg/dL). In that preliminary subanalysis, patients with the highest levels of uric acid had the highest risk for coronary artery disease and MI. "I think this is beginning to suggest that there’s at least an intermediate risk from having elevated uric acid," Dr. Pillinger said.

Some studies have also shown that treatment of the inflammation associated with gout could help in cardiovascular disease. Researchers performed an analysis of nearly 1,300 patients in the New York VA gout cohort. About half of the patients were on chronic colchicine therapy and half were not taking colchicine. The cross-sectional study, which was presented at the 2010 ACR annual meeting, found that patients who took colchicine had more than a 50% decrease in MI rates, compared with those who were not on the drug. Patients also had a lower risk of death and a lower C-reactive protein level, but these results did not achieve statistical significance. "This is very provocative," Dr. Pillinger said.

Dr. Pillinger said that he had no relevant conflicts of interest to report.

The prevalence of gout has increased in the United States, especially among the eldest population, according to the latest national data. That means that nursing home staff are caring for more hot, swollen, and inflamed joints than ever, said several experts on the topic.

In interviews, they added that clinicians’ potential success in preventing, diagnosing, and treating the disease in long-term care residents lies largely in fundamental practices and an individualized approach to medications.

Photo credit: craftvision/Stockphoto.com

Data from the National Health and Nutrition Examination Survey (NHANES) show an increase in gout prevalence among U.S. adults from 2.7% in the survey’s 1994-1998 reporting periods to 3.9% in 2007-2008. Meanwhile, the prevalence in adults aged 80 years and older jumped from 5.9% to 12.6%.

The prevalence of hyperuricemia, which usually precedes gout, was 31% in adults aged 65 years or older and 37% among those aged 80 years and older, according to the latest NHANES data. The increase in actual gout occurred mainly among men in NHANES. Other studies, however, have documented an increased prevalence of the disease among older women as well. Studies cited in a review of "Crystal-Associated Arthritis in the Elderly" showed women making up at least half of the cases in which gout first strikes after age 60 years. Among individuals who have a first episode after age 80, women seem to predominate (Rheum. Dis. Clin. N. Am. 2007;33:33-55).

The presentation of the disease, as well as its prevalence, is changing, said Dr. Arthur Weinstein, professor of medicine at Georgetown University Medical Center and director of rheumatology at Washington Hospital Center. "We’re seeing more and more polyarticular gout in older patients, for instance, either as an initial presentation or years after just a single monoarticular episode" with no subsequent recurrences, said Dr. Weinstein in an interview.

He and others said they believe that the common use of thiazide diuretics in older patients is a major driver of gout’s changing profile. Other factors could include genetic predispositions to hyperuricemia and gout and increasing obesity, insulin resistance, and metabolic syndrome in the aging population.

While often the best choice for hypertension management, thiazide diuretics can contribute to the development of chronic hyperuricemia, as can low-dose aspirin and cyclosporine. Also, increasing numbers of elderly people have chronic cardiac and renal disease – factors that have been associated with hyperuricemia and gout.

Other changes in gout’s presentation in the elderly include earlier and often-atypical development of the soft tissue masses known as tophi and more frequent and earlier involvement of the small joints of the fingers.

Diagnosis, Empiric Therapy

The differential diagnosis of a swollen, inflamed joint often involves ruling out the likelihood of septic arthritis, fracture, or other injury, and pseudogout – the other main form of crystal-induced arthritis.

Patients experiencing an acute gout attack can have a low-grade fever. "But with a fever of 101 or higher, you have to consider that it’s something that’s not crystal induced," said Dr. John W. Rachow, a geriatrician and rheumatologist at the University of Iowa, Iowa City.

Septic arthritis should also be suspected when patients have joint pain and tachycardia, hypotension, or signs of other acute illness. "And if there is hardware in the joint, even without a fever, patients should be evaluated at a higher level," said Dr. Rachow, who also serves as an attending physician in numerous nursing homes in the Iowa City area.

While the diagnostic standard for gout – synovial fluid or tophi aspiration with the identification of monosodium urate crystals under polarizing microscopy – can seem even more important in the older population, it is also more untenable given the stresses of transporting nursing home patients to hospitals.

A good long-term care mindset can preclude the need for crystal diagnosis in every case, said clinicians interviewed for this story.

"In health care, we tend to turn things into acute episodes when they’re really acute exacerbations of chronic conditions," said Dr. George Taler, director of long-term care in the department of medicine at the Washington Hospital Center and medical director of the Capitol Hill Nursing Center, both in Washington.

"Diagnosing and treating gout successfully "means remembering that our patients have a history," said Dr. Taler. He advised "making sure that when the nurse calls about a swollen knee, he or she has reviewed the medical record."

A host of factors can indicate the likelihood that joint pain is a gout attack. These include a history of gout, persistent elevated uric acid levels, and the use of medications or existence of medical conditions associated with gout. Blood testing at the time of an attack is not informative, said Dr. Rachow. While most patients with gout have chronically elevated uric acid levels, serum uric acid levels at the time of an attack are frequently normal, he explained.

Gout should also be considered in elderly patients when attacks of acute pain and swelling are seen in osteoarthritic joints of the fingers, especially in patients who have renal disease or are on chronic diuretic therapy.

An older patient without a history of gout and without any obvious risk for gout or sign of a septic joint probably has pseudogout, which is caused by the deposition of calcium pyrophosphate dihydrate rather than monosodium urate. Pseudogout often strikes the wrist or the knee and does not commonly involve polyarticular attacks, as gout does.

Clinical experience has shown that with a suspicion of either gout or pseudogout, a short empiric course of anti-inflammatory treatment should be considered, said Dr. Rachow. "If it really is crystal induced, you’ll know in 12 hours and definitely within 24 hours" because the pain will begin to subside, he said.

"And, at that point, if you’ve started with a nonsteroidal anti-inflammatory and it’s working well, you can add a gastroprotective agent and continue the NSAID, reducing the dose once symptoms begin to improve. Or you can switch to colchicine."

"At your leisure, you can consider getting an x-ray," Dr. Rachow added, as detectable calcium deposits in the cartilage are typical of pseudogout.

If the anti-inflammatory treatment is "not working spectacularly well within 24 hours, you need to put the brakes on, close your office door, and think things over again," he said.

Facilities that have a sizable number of patients with frequent flares probably should have a nurse practitioner or of physician assistant trained to aspirate joints and arrange the logistics for sending out samples, Dr. Taler said.

The Longer Term

With a correct approach, "gout is eminently preventable and treatable in 90% of nursing home residents," said Dr. Weinstein. "The principles are studied, reported, and well described," he said. The American College of Rheumatology plans to release its first practice guidelines on the management of gout in 2012.

Decisions about managing acute attacks – whether to use NSAIDs, glucocorticoids, or oral colchicine – are rightly driven by the severity of gout and consideration of the patient’s coexisting illnesses and the drugs’ side effects. While NSAID use carries the risk of gastropathy, colchicine can cause diarrhea and other potentially serious side effects and should be avoided in patients who have renal or hepatic insufficiency.

Many clinicians consider colchicine a second-line therapy for acute gout, after NSAIDs or corticosteroids. In very elderly people, however, the treatment decision might be different. Dr. Weinstein said he worries about possible cardiac risks with the use of NSAIDs in very old patients. He has had success with the early use of low-dose colchicine in very elderly patients with reasonable kidney function, and he said that the drug "works best in the first 48-72 hours."

Parenteral corticosteroids, intra-articular injections, or even an oral prednisone taper are good options, he emphasized. Issues of whether and how to move from acute management of gout attacks to long-term urate-lowering therapy are taking on added significance in nursing homes as the prevalence of gout increases there.

Dr. Rachow recommended that hypouricemic therapy be initiated for patients who have documented hyperuricemia and a history of multiple attacks, and for patients who have developed tophi, which the therapy can dissolve.

It can even be considered for a frail, ill nursing home resident for whom a second gout attack would be unusually complicating and traumatic, said Dr. Rachow. "There may be residents who we can’t imagine having to hospitalize in the next year [for another gout attack], for whom we want to take possible recurrence out of the picture once and for all."

When it is deemed beneficial, the urate-lowering therapy must be undertaken with care, he emphasized. Dr. Rachow said that hypouricemic therapy should start only after an acute attack is completely resolved (or even 2-4 weeks after flare resolution), with cautious dosing and careful monitoring for adverse effects and, when possible, under the cover of a prophylactic anti-inflammatory drug. Low-dose colchicine has long been used to prevent flares associated with the lowering of urate.

Allopurinol, the xanthine oxidase inhibitor most commonly prescribed to lower urate levels, should be "started low and increased slowly" in older patients with renal impairment, Dr. Weinstein said. He advised beginning with 100 mg/day and increasing by 100 mg/day each month until the patient’s uric acid level is below 6 mg/dL.

Another xanthine oxidase inhibitor called febuxostat (Uloric) was approved in 2009 by the FDA for treatment of hyperuricemia in patients with gout, but its efficacy and safety compared with allopurinol is not fully established (N. Engl. J. Med. 2011;364:443-52). The new drug may have advantages, however, in that it appears to be safe without dose adjustment in patients with renal insufficiency, Dr. Weinstein said.

Also on the medication front is a newly approved drug called pegloticase (Krystexxa), which might be a good option for lowering serum uric acid levels and preventing gout attacks in patients who cannot use allopurinol, said Dr. Weinstein.

If a gout attack strikes during hypouricemic therapy, Dr. Weinstein cautioned, "Don’t change anything – don’t stop the allopurinol, don’t change the diuretic. ... Just add the steroid or whatever you’ve chosen for an acute attack. Treat the attack like any other."

Colcrys, the Costly Alternative

Physicians who have long had colchicine as part of their armamentarium for the treatment of acute gout and, more important, for gout-flare prophylaxis, are coping with the loss of an array of traditional colchicine products and the current availability of only one, recently approved formulation – Colcrys – which is 50 times the cost of the earlier versions.

The winnowing of options is a result of the Food and Drug Administration’s Unapproved Drugs Initiative of 2006 that aims to bring previously grandfathered prescription drugs in compliance with current FDA approval requirements for safety and efficacy.

In July 2009, the FDA approved URL Pharma to market Colcrys for treatment of acute gout flares and prophylaxis of flares of familial Mediterranean fever. The agency gave the company 3 years of marketing exclusivity for the acute gout indication. The FDA approved an indication for gout flare prophylaxis several months later. Then, in the Oct. 1, 2010, Federal Register, the agency announced its intention to "take enforcement action" against the manufacture and distribution of unapproved single-ingredient oral colchicine products.

The cost of Colcrys caused an uproar in the rheumatology community, and the American College of Rheumatology worked with URL Pharma to cut prices to patients finding it hard to afford the drug.

College officials have also been encouraging manufacturers of unapproved colchicine products to submit new drug applications for the gout prophylaxis indication. According to the college, URL Pharma does not have exclusivity for this indication, and one other manufacturer has filed an application to market its product for this indication.

In the meantime, the FDA has been calling attention to safety concerns identified during its review of Colcrys, namely, a risk for severe drug interactions in certain patients treated with colchicine and concomitant P-gp or strong CYP3A4 inhibitors such as clarithromycin. Also, a dosing study submitted as part of the Colcrys application indicated that low-dose colchicine (1.8 mg over 1 hour) was a better treatment for acute gout than was a high-dose regimen (4.8 mg over 6 hours).

Dr. Rachow and Dr. Taler said they had no conflict of interest to disclose on this topic. Dr. Weinstein disclosed that he has received research grants from Savient Pharmaceuticals, the maker of pegloticase, for a clinical study, but not for any therapeutic studies.

The prevalence of gout has increased in the United States, especially among the eldest population, according to the latest national data. That means that nursing home staff are caring for more hot, swollen, and inflamed joints than ever, said several experts on the topic.

In interviews, they added that clinicians’ potential success in preventing, diagnosing, and treating the disease in long-term care residents lies largely in fundamental practices and an individualized approach to medications.

Photo credit: craftvision/Stockphoto.com

Data from the National Health and Nutrition Examination Survey (NHANES) show an increase in gout prevalence among U.S. adults from 2.7% in the survey’s 1994-1998 reporting periods to 3.9% in 2007-2008. Meanwhile, the prevalence in adults aged 80 years and older jumped from 5.9% to 12.6%.

The prevalence of hyperuricemia, which usually precedes gout, was 31% in adults aged 65 years or older and 37% among those aged 80 years and older, according to the latest NHANES data. The increase in actual gout occurred mainly among men in NHANES. Other studies, however, have documented an increased prevalence of the disease among older women as well. Studies cited in a review of "Crystal-Associated Arthritis in the Elderly" showed women making up at least half of the cases in which gout first strikes after age 60 years. Among individuals who have a first episode after age 80, women seem to predominate (Rheum. Dis. Clin. N. Am. 2007;33:33-55).

The presentation of the disease, as well as its prevalence, is changing, said Dr. Arthur Weinstein, professor of medicine at Georgetown University Medical Center and director of rheumatology at Washington Hospital Center. "We’re seeing more and more polyarticular gout in older patients, for instance, either as an initial presentation or years after just a single monoarticular episode" with no subsequent recurrences, said Dr. Weinstein in an interview.

He and others said they believe that the common use of thiazide diuretics in older patients is a major driver of gout’s changing profile. Other factors could include genetic predispositions to hyperuricemia and gout and increasing obesity, insulin resistance, and metabolic syndrome in the aging population.

While often the best choice for hypertension management, thiazide diuretics can contribute to the development of chronic hyperuricemia, as can low-dose aspirin and cyclosporine. Also, increasing numbers of elderly people have chronic cardiac and renal disease – factors that have been associated with hyperuricemia and gout.

Other changes in gout’s presentation in the elderly include earlier and often-atypical development of the soft tissue masses known as tophi and more frequent and earlier involvement of the small joints of the fingers.

Diagnosis, Empiric Therapy

The differential diagnosis of a swollen, inflamed joint often involves ruling out the likelihood of septic arthritis, fracture, or other injury, and pseudogout – the other main form of crystal-induced arthritis.

Patients experiencing an acute gout attack can have a low-grade fever. "But with a fever of 101 or higher, you have to consider that it’s something that’s not crystal induced," said Dr. John W. Rachow, a geriatrician and rheumatologist at the University of Iowa, Iowa City.

Septic arthritis should also be suspected when patients have joint pain and tachycardia, hypotension, or signs of other acute illness. "And if there is hardware in the joint, even without a fever, patients should be evaluated at a higher level," said Dr. Rachow, who also serves as an attending physician in numerous nursing homes in the Iowa City area.

While the diagnostic standard for gout – synovial fluid or tophi aspiration with the identification of monosodium urate crystals under polarizing microscopy – can seem even more important in the older population, it is also more untenable given the stresses of transporting nursing home patients to hospitals.

A good long-term care mindset can preclude the need for crystal diagnosis in every case, said clinicians interviewed for this story.

"In health care, we tend to turn things into acute episodes when they’re really acute exacerbations of chronic conditions," said Dr. George Taler, director of long-term care in the department of medicine at the Washington Hospital Center and medical director of the Capitol Hill Nursing Center, both in Washington.

"Diagnosing and treating gout successfully "means remembering that our patients have a history," said Dr. Taler. He advised "making sure that when the nurse calls about a swollen knee, he or she has reviewed the medical record."

A host of factors can indicate the likelihood that joint pain is a gout attack. These include a history of gout, persistent elevated uric acid levels, and the use of medications or existence of medical conditions associated with gout. Blood testing at the time of an attack is not informative, said Dr. Rachow. While most patients with gout have chronically elevated uric acid levels, serum uric acid levels at the time of an attack are frequently normal, he explained.

Gout should also be considered in elderly patients when attacks of acute pain and swelling are seen in osteoarthritic joints of the fingers, especially in patients who have renal disease or are on chronic diuretic therapy.

An older patient without a history of gout and without any obvious risk for gout or sign of a septic joint probably has pseudogout, which is caused by the deposition of calcium pyrophosphate dihydrate rather than monosodium urate. Pseudogout often strikes the wrist or the knee and does not commonly involve polyarticular attacks, as gout does.

Clinical experience has shown that with a suspicion of either gout or pseudogout, a short empiric course of anti-inflammatory treatment should be considered, said Dr. Rachow. "If it really is crystal induced, you’ll know in 12 hours and definitely within 24 hours" because the pain will begin to subside, he said.

"And, at that point, if you’ve started with a nonsteroidal anti-inflammatory and it’s working well, you can add a gastroprotective agent and continue the NSAID, reducing the dose once symptoms begin to improve. Or you can switch to colchicine."

"At your leisure, you can consider getting an x-ray," Dr. Rachow added, as detectable calcium deposits in the cartilage are typical of pseudogout.

If the anti-inflammatory treatment is "not working spectacularly well within 24 hours, you need to put the brakes on, close your office door, and think things over again," he said.

Facilities that have a sizable number of patients with frequent flares probably should have a nurse practitioner or of physician assistant trained to aspirate joints and arrange the logistics for sending out samples, Dr. Taler said.

The Longer Term

With a correct approach, "gout is eminently preventable and treatable in 90% of nursing home residents," said Dr. Weinstein. "The principles are studied, reported, and well described," he said. The American College of Rheumatology plans to release its first practice guidelines on the management of gout in 2012.

Decisions about managing acute attacks – whether to use NSAIDs, glucocorticoids, or oral colchicine – are rightly driven by the severity of gout and consideration of the patient’s coexisting illnesses and the drugs’ side effects. While NSAID use carries the risk of gastropathy, colchicine can cause diarrhea and other potentially serious side effects and should be avoided in patients who have renal or hepatic insufficiency.

Many clinicians consider colchicine a second-line therapy for acute gout, after NSAIDs or corticosteroids. In very elderly people, however, the treatment decision might be different. Dr. Weinstein said he worries about possible cardiac risks with the use of NSAIDs in very old patients. He has had success with the early use of low-dose colchicine in very elderly patients with reasonable kidney function, and he said that the drug "works best in the first 48-72 hours."

Parenteral corticosteroids, intra-articular injections, or even an oral prednisone taper are good options, he emphasized. Issues of whether and how to move from acute management of gout attacks to long-term urate-lowering therapy are taking on added significance in nursing homes as the prevalence of gout increases there.

Dr. Rachow recommended that hypouricemic therapy be initiated for patients who have documented hyperuricemia and a history of multiple attacks, and for patients who have developed tophi, which the therapy can dissolve.

It can even be considered for a frail, ill nursing home resident for whom a second gout attack would be unusually complicating and traumatic, said Dr. Rachow. "There may be residents who we can’t imagine having to hospitalize in the next year [for another gout attack], for whom we want to take possible recurrence out of the picture once and for all."

When it is deemed beneficial, the urate-lowering therapy must be undertaken with care, he emphasized. Dr. Rachow said that hypouricemic therapy should start only after an acute attack is completely resolved (or even 2-4 weeks after flare resolution), with cautious dosing and careful monitoring for adverse effects and, when possible, under the cover of a prophylactic anti-inflammatory drug. Low-dose colchicine has long been used to prevent flares associated with the lowering of urate.

Allopurinol, the xanthine oxidase inhibitor most commonly prescribed to lower urate levels, should be "started low and increased slowly" in older patients with renal impairment, Dr. Weinstein said. He advised beginning with 100 mg/day and increasing by 100 mg/day each month until the patient’s uric acid level is below 6 mg/dL.

Another xanthine oxidase inhibitor called febuxostat (Uloric) was approved in 2009 by the FDA for treatment of hyperuricemia in patients with gout, but its efficacy and safety compared with allopurinol is not fully established (N. Engl. J. Med. 2011;364:443-52). The new drug may have advantages, however, in that it appears to be safe without dose adjustment in patients with renal insufficiency, Dr. Weinstein said.

Also on the medication front is a newly approved drug called pegloticase (Krystexxa), which might be a good option for lowering serum uric acid levels and preventing gout attacks in patients who cannot use allopurinol, said Dr. Weinstein.

If a gout attack strikes during hypouricemic therapy, Dr. Weinstein cautioned, "Don’t change anything – don’t stop the allopurinol, don’t change the diuretic. ... Just add the steroid or whatever you’ve chosen for an acute attack. Treat the attack like any other."

Colcrys, the Costly Alternative

Physicians who have long had colchicine as part of their armamentarium for the treatment of acute gout and, more important, for gout-flare prophylaxis, are coping with the loss of an array of traditional colchicine products and the current availability of only one, recently approved formulation – Colcrys – which is 50 times the cost of the earlier versions.

The winnowing of options is a result of the Food and Drug Administration’s Unapproved Drugs Initiative of 2006 that aims to bring previously grandfathered prescription drugs in compliance with current FDA approval requirements for safety and efficacy.

In July 2009, the FDA approved URL Pharma to market Colcrys for treatment of acute gout flares and prophylaxis of flares of familial Mediterranean fever. The agency gave the company 3 years of marketing exclusivity for the acute gout indication. The FDA approved an indication for gout flare prophylaxis several months later. Then, in the Oct. 1, 2010, Federal Register, the agency announced its intention to "take enforcement action" against the manufacture and distribution of unapproved single-ingredient oral colchicine products.

The cost of Colcrys caused an uproar in the rheumatology community, and the American College of Rheumatology worked with URL Pharma to cut prices to patients finding it hard to afford the drug.

College officials have also been encouraging manufacturers of unapproved colchicine products to submit new drug applications for the gout prophylaxis indication. According to the college, URL Pharma does not have exclusivity for this indication, and one other manufacturer has filed an application to market its product for this indication.

In the meantime, the FDA has been calling attention to safety concerns identified during its review of Colcrys, namely, a risk for severe drug interactions in certain patients treated with colchicine and concomitant P-gp or strong CYP3A4 inhibitors such as clarithromycin. Also, a dosing study submitted as part of the Colcrys application indicated that low-dose colchicine (1.8 mg over 1 hour) was a better treatment for acute gout than was a high-dose regimen (4.8 mg over 6 hours).

Dr. Rachow and Dr. Taler said they had no conflict of interest to disclose on this topic. Dr. Weinstein disclosed that he has received research grants from Savient Pharmaceuticals, the maker of pegloticase, for a clinical study, but not for any therapeutic studies.

The prevalence of gout has increased in the United States, especially among the eldest population, according to the latest national data. That means that nursing home staff are caring for more hot, swollen, and inflamed joints than ever, said several experts on the topic.

In interviews, they added that clinicians’ potential success in preventing, diagnosing, and treating the disease in long-term care residents lies largely in fundamental practices and an individualized approach to medications.

Photo credit: craftvision/Stockphoto.com

Data from the National Health and Nutrition Examination Survey (NHANES) show an increase in gout prevalence among U.S. adults from 2.7% in the survey’s 1994-1998 reporting periods to 3.9% in 2007-2008. Meanwhile, the prevalence in adults aged 80 years and older jumped from 5.9% to 12.6%.

The prevalence of hyperuricemia, which usually precedes gout, was 31% in adults aged 65 years or older and 37% among those aged 80 years and older, according to the latest NHANES data. The increase in actual gout occurred mainly among men in NHANES. Other studies, however, have documented an increased prevalence of the disease among older women as well. Studies cited in a review of "Crystal-Associated Arthritis in the Elderly" showed women making up at least half of the cases in which gout first strikes after age 60 years. Among individuals who have a first episode after age 80, women seem to predominate (Rheum. Dis. Clin. N. Am. 2007;33:33-55).

The presentation of the disease, as well as its prevalence, is changing, said Dr. Arthur Weinstein, professor of medicine at Georgetown University Medical Center and director of rheumatology at Washington Hospital Center. "We’re seeing more and more polyarticular gout in older patients, for instance, either as an initial presentation or years after just a single monoarticular episode" with no subsequent recurrences, said Dr. Weinstein in an interview.

He and others said they believe that the common use of thiazide diuretics in older patients is a major driver of gout’s changing profile. Other factors could include genetic predispositions to hyperuricemia and gout and increasing obesity, insulin resistance, and metabolic syndrome in the aging population.

While often the best choice for hypertension management, thiazide diuretics can contribute to the development of chronic hyperuricemia, as can low-dose aspirin and cyclosporine. Also, increasing numbers of elderly people have chronic cardiac and renal disease – factors that have been associated with hyperuricemia and gout.

Other changes in gout’s presentation in the elderly include earlier and often-atypical development of the soft tissue masses known as tophi and more frequent and earlier involvement of the small joints of the fingers.

Diagnosis, Empiric Therapy

The differential diagnosis of a swollen, inflamed joint often involves ruling out the likelihood of septic arthritis, fracture, or other injury, and pseudogout – the other main form of crystal-induced arthritis.

Patients experiencing an acute gout attack can have a low-grade fever. "But with a fever of 101 or higher, you have to consider that it’s something that’s not crystal induced," said Dr. John W. Rachow, a geriatrician and rheumatologist at the University of Iowa, Iowa City.

Septic arthritis should also be suspected when patients have joint pain and tachycardia, hypotension, or signs of other acute illness. "And if there is hardware in the joint, even without a fever, patients should be evaluated at a higher level," said Dr. Rachow, who also serves as an attending physician in numerous nursing homes in the Iowa City area.

While the diagnostic standard for gout – synovial fluid or tophi aspiration with the identification of monosodium urate crystals under polarizing microscopy – can seem even more important in the older population, it is also more untenable given the stresses of transporting nursing home patients to hospitals.

A good long-term care mindset can preclude the need for crystal diagnosis in every case, said clinicians interviewed for this story.

"In health care, we tend to turn things into acute episodes when they’re really acute exacerbations of chronic conditions," said Dr. George Taler, director of long-term care in the department of medicine at the Washington Hospital Center and medical director of the Capitol Hill Nursing Center, both in Washington.

"Diagnosing and treating gout successfully "means remembering that our patients have a history," said Dr. Taler. He advised "making sure that when the nurse calls about a swollen knee, he or she has reviewed the medical record."

A host of factors can indicate the likelihood that joint pain is a gout attack. These include a history of gout, persistent elevated uric acid levels, and the use of medications or existence of medical conditions associated with gout. Blood testing at the time of an attack is not informative, said Dr. Rachow. While most patients with gout have chronically elevated uric acid levels, serum uric acid levels at the time of an attack are frequently normal, he explained.

Gout should also be considered in elderly patients when attacks of acute pain and swelling are seen in osteoarthritic joints of the fingers, especially in patients who have renal disease or are on chronic diuretic therapy.

An older patient without a history of gout and without any obvious risk for gout or sign of a septic joint probably has pseudogout, which is caused by the deposition of calcium pyrophosphate dihydrate rather than monosodium urate. Pseudogout often strikes the wrist or the knee and does not commonly involve polyarticular attacks, as gout does.

Clinical experience has shown that with a suspicion of either gout or pseudogout, a short empiric course of anti-inflammatory treatment should be considered, said Dr. Rachow. "If it really is crystal induced, you’ll know in 12 hours and definitely within 24 hours" because the pain will begin to subside, he said.

"And, at that point, if you’ve started with a nonsteroidal anti-inflammatory and it’s working well, you can add a gastroprotective agent and continue the NSAID, reducing the dose once symptoms begin to improve. Or you can switch to colchicine."

"At your leisure, you can consider getting an x-ray," Dr. Rachow added, as detectable calcium deposits in the cartilage are typical of pseudogout.

If the anti-inflammatory treatment is "not working spectacularly well within 24 hours, you need to put the brakes on, close your office door, and think things over again," he said.

Facilities that have a sizable number of patients with frequent flares probably should have a nurse practitioner or of physician assistant trained to aspirate joints and arrange the logistics for sending out samples, Dr. Taler said.

The Longer Term

With a correct approach, "gout is eminently preventable and treatable in 90% of nursing home residents," said Dr. Weinstein. "The principles are studied, reported, and well described," he said. The American College of Rheumatology plans to release its first practice guidelines on the management of gout in 2012.

Decisions about managing acute attacks – whether to use NSAIDs, glucocorticoids, or oral colchicine – are rightly driven by the severity of gout and consideration of the patient’s coexisting illnesses and the drugs’ side effects. While NSAID use carries the risk of gastropathy, colchicine can cause diarrhea and other potentially serious side effects and should be avoided in patients who have renal or hepatic insufficiency.

Many clinicians consider colchicine a second-line therapy for acute gout, after NSAIDs or corticosteroids. In very elderly people, however, the treatment decision might be different. Dr. Weinstein said he worries about possible cardiac risks with the use of NSAIDs in very old patients. He has had success with the early use of low-dose colchicine in very elderly patients with reasonable kidney function, and he said that the drug "works best in the first 48-72 hours."

Parenteral corticosteroids, intra-articular injections, or even an oral prednisone taper are good options, he emphasized. Issues of whether and how to move from acute management of gout attacks to long-term urate-lowering therapy are taking on added significance in nursing homes as the prevalence of gout increases there.

Dr. Rachow recommended that hypouricemic therapy be initiated for patients who have documented hyperuricemia and a history of multiple attacks, and for patients who have developed tophi, which the therapy can dissolve.

It can even be considered for a frail, ill nursing home resident for whom a second gout attack would be unusually complicating and traumatic, said Dr. Rachow. "There may be residents who we can’t imagine having to hospitalize in the next year [for another gout attack], for whom we want to take possible recurrence out of the picture once and for all."

When it is deemed beneficial, the urate-lowering therapy must be undertaken with care, he emphasized. Dr. Rachow said that hypouricemic therapy should start only after an acute attack is completely resolved (or even 2-4 weeks after flare resolution), with cautious dosing and careful monitoring for adverse effects and, when possible, under the cover of a prophylactic anti-inflammatory drug. Low-dose colchicine has long been used to prevent flares associated with the lowering of urate.

Allopurinol, the xanthine oxidase inhibitor most commonly prescribed to lower urate levels, should be "started low and increased slowly" in older patients with renal impairment, Dr. Weinstein said. He advised beginning with 100 mg/day and increasing by 100 mg/day each month until the patient’s uric acid level is below 6 mg/dL.

Another xanthine oxidase inhibitor called febuxostat (Uloric) was approved in 2009 by the FDA for treatment of hyperuricemia in patients with gout, but its efficacy and safety compared with allopurinol is not fully established (N. Engl. J. Med. 2011;364:443-52). The new drug may have advantages, however, in that it appears to be safe without dose adjustment in patients with renal insufficiency, Dr. Weinstein said.

Also on the medication front is a newly approved drug called pegloticase (Krystexxa), which might be a good option for lowering serum uric acid levels and preventing gout attacks in patients who cannot use allopurinol, said Dr. Weinstein.

If a gout attack strikes during hypouricemic therapy, Dr. Weinstein cautioned, "Don’t change anything – don’t stop the allopurinol, don’t change the diuretic. ... Just add the steroid or whatever you’ve chosen for an acute attack. Treat the attack like any other."

Colcrys, the Costly Alternative

Physicians who have long had colchicine as part of their armamentarium for the treatment of acute gout and, more important, for gout-flare prophylaxis, are coping with the loss of an array of traditional colchicine products and the current availability of only one, recently approved formulation – Colcrys – which is 50 times the cost of the earlier versions.

The winnowing of options is a result of the Food and Drug Administration’s Unapproved Drugs Initiative of 2006 that aims to bring previously grandfathered prescription drugs in compliance with current FDA approval requirements for safety and efficacy.

In July 2009, the FDA approved URL Pharma to market Colcrys for treatment of acute gout flares and prophylaxis of flares of familial Mediterranean fever. The agency gave the company 3 years of marketing exclusivity for the acute gout indication. The FDA approved an indication for gout flare prophylaxis several months later. Then, in the Oct. 1, 2010, Federal Register, the agency announced its intention to "take enforcement action" against the manufacture and distribution of unapproved single-ingredient oral colchicine products.

The cost of Colcrys caused an uproar in the rheumatology community, and the American College of Rheumatology worked with URL Pharma to cut prices to patients finding it hard to afford the drug.

College officials have also been encouraging manufacturers of unapproved colchicine products to submit new drug applications for the gout prophylaxis indication. According to the college, URL Pharma does not have exclusivity for this indication, and one other manufacturer has filed an application to market its product for this indication.

In the meantime, the FDA has been calling attention to safety concerns identified during its review of Colcrys, namely, a risk for severe drug interactions in certain patients treated with colchicine and concomitant P-gp or strong CYP3A4 inhibitors such as clarithromycin. Also, a dosing study submitted as part of the Colcrys application indicated that low-dose colchicine (1.8 mg over 1 hour) was a better treatment for acute gout than was a high-dose regimen (4.8 mg over 6 hours).

Dr. Rachow and Dr. Taler said they had no conflict of interest to disclose on this topic. Dr. Weinstein disclosed that he has received research grants from Savient Pharmaceuticals, the maker of pegloticase, for a clinical study, but not for any therapeutic studies.