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From Medscape Rheumatology (free registration required) Expert Interview
Latest Advances in Treatment for Gout: An Expert Interview With Kenneth G. Saag, MD
Editor's Note: The evidence from national and international studies shows that the incidence and severity of gout are increasing and start at an earlier age. Increasing evidence shows that changes in dietary habits can lead to the development of insulin resistance syndrome to which hyperuricemia, and thus gout, relate. Hyperuricemia results from poor renal clearance of uric acid, and low-calorie diets result in improvement of the renal clearance of uric acid, consequently leading to a reduction in serum uric acid levels. Dietary modifications can correct insulin resistance syndrome and thus reduce uricemia by its effect on increasing the renal clearance of urate. Although in most cases gout can be managed through dietary modifications, there are some colloquially referred to as "difficult gout," which can be recalcitrant to treatment.
Traditional pharmacologic treatments include colchicines, anti-inflammatory drugs, or steroids; however, there are serious side effects, particularly at high doses. As the interest in gout continues to grow, there is increasing understanding of its pathophysiology, with new research emerging for improved treatment options.
In this expert interview conducted by Helen Fosam, PhD, Medscape Rheumatology, Kenneth G. Saag, MD, comments on some of the more recent advances presented at the 2005 American College of Rheumatology (ACR) meeting for the treatment of gout. Dr. Saag is Associate Professor, Department of Medicine, Division of Clinical Immunology and Rheumatology at The University of Alabama, Birmingham.
Its probably just not the alcohol, but the general dietary indiscretions that happen during that time of the year that would affect gout incidence then.
"The following foods have higher levels of purines should be restricted or avoided:
Offal foods like liver, kidneys, tripe, sweetbreads and tongue.
Large amounts of red meat.
Peas. lentils and beans.
WHAT THE STUDY ASKED
Is febuxostat more effective than allopurinol
for the prevention of gout flares?
■ WHAT THE STUDY FOUND
Febuxostat is better than allopurinol at lowering
uric acid levels but no better at preventing
gout flares. Despite assurances from the
authors, the four deaths in this study should
give us some pause, as should the greater number
of dropouts in the febuxostat groups and
the almost surely higher cost if the drug is
Level of evidence
1b (individual randomized controlled trial....
New full text from Medscape (free registation required): Recent Developments in Diet and Gout
Purpose of Review: Gout is the most common inflammatory arthritis in men, affecting approximately 1-2% of adult men in Western countries. United States gout prevalence has approximately doubled over the past two decades. In recent years, key prospective epidemiological and open-labeled dietary studies, coupled with recent advances in molecular biology elucidating proximal tubular urate transport, have provided novel insights into roles of diet and alcohol in hyperuricemia and gout. This review focuses on recent developments and their implications for clinical practice, including how we advise patients on appropriate diets and alcoholic beverage consumption.
Recent Findings: Studies have observed an increased risk of gout among those who consumed the highest quintile of meat, seafood and alcohol. Although limited by confounding variables, low-fat dairy products, ascorbic acid and wine consumption appeared to be protective for the development of gout.
Summary: The most effective forms of dietary regimen for both hyperuricemia and gout flares remains to be unidentified. Until confirmed by a large, controlled study, it is prudent to advise patients to consume meat, seafood and alcoholic beverages in moderation, with special attention to food portion size and content of non-complex carbohydrates which are essential for weight loss and improved insulin sensitivity.
Background: It is taken for granted that diuretics may induce gout, but there is a general lack of evidence on this topic.
Objectives: To determine the incidence of gout in patients who use diuretics, taking into account concurrent hypertension and cardiovascular diseases.
Methods: A case-control study was designed. From a primary care population all patients with a first gout registration (59 men, 11 women; mean (SD) age 55.1 (13.5)) were identified as cases. To relate the occurrence of gout to diuretic use a matched reference series of three controls for each case was compiled. Conditional logistic regression analyses were applied to estimate incidence rate ratios (IRRs) of gout, and 95% confidence intervals (CIs), in subjects with and without diuretic treatment, hypertension, and cardiovasculardiseases. Additional stratification analyses were made, particularly in the subjects not using diuretics.
Results: The IRRs of gout in subjects with v those without diuretic treatment, hypertension, heart failure, and myocardial infarction were 2.8 (95% CI 1.2 to 6.6), 2.6 (95% CI 1.2 to 5.6), 20.9 (95% CI 2.5 to 173.8), and 1.9 (95% CI 0.7 to 4.7), respectively. After adjustment, the IRR of gout for diuretic use dropped to 0.6 (95% CI 0.2 to 2.0), while the IRRs of gout for hypertension, heart failure, and myocardial infarction were still >1. This was also the case for subjects with hypertension or myocardial infarction, who had not used diuretics.
Conclusion: The results suggest that diuretics do not actually increase the risk of gout. Cardiovascular indications for treatment may have confounded previous inferences.
ScienceDaily are reporting: Gout Increases Risk Of Heart Attack, According To Study
People with gout are at increased risk of having a heart attack, according to a University of Pittsburgh School of Medicine study published in the August edition of the journal Arthritis & Rheumatism. This is the first study to show that among men with no previous history of coronary artery disease, gout is a significant independent risk factor of heart attack....
Gout is an autoinflammatory disorder associated with deposition of monosodium urate (MSU) crystals in joints and periarticular tissues. Recent advances suggest that the innate immune system may drive the gouty inflammatory response to MSU. These findings prompt questions concerning how the innate immune system recognizes MSU and the identities of the receptors involved. In this issue of the JCI, Chen et al. show that the IL-1 receptor and its signaling protein myeloid differentiation primary response protein 88 (MyD88) but not the "classical" innate immune receptors, TLRs, are central for MSU-induced inflammation
For over 100 years we have known that the intensely painful disease gout is caused by the accumulation of monosodium urate crystals (MSU) in joints. Now, in a study appearing in the August issue of the Journal of Clinical Investigation, Kenneth Rock and colleagues from University of Massachusetts Medical School uncover how these crystal deposits are recognized by the immune system and trigger acute and painful inflammation.
Gout patients usually produce too much uric acid or are unable to efficiently excrete the uric acid excess. Rock and colleagues had previously shown that uric acid released from "damaged cells" in the body forms MSU crystals, which act as a "danger signal" that stimulates the immune response into action. The same group now shows that, in mice, MSU crystals are internalized by monocytes, resulting in the processing and maturation of the molecule pro-IL-1beta to its biologically active form IL-1beta. IL-1beta activates the IL-1beta receptor on cells around the MSU crystal-laden joints, which recruits the protein MyD88. This triggers the production of inflammatory molecules, resulting in painful joint inflammation. Surprisingly, the inflammatory reaction does not involve Toll-like receptors, which usually recognize foreign pathogens and trigger immune cell responses. In an accompanying commentary, Laurie Glimcher from Harvard Medical School comments that, "the study of the physiological function of IL-1beta in human gouty inflammation will undoubtedly provide new therapeutic tools to better manage the acute inflammation episode in patients with gout."
The investigational gout medication febuxostat consistently maintained serum urate levels below 6 mg/dL while markedly reducing gout flares in a 4-year study, Dr. H. Ralph Schumacher Jr. said at the annual European Congress of Rheumatology.
Dr. Schumacher reported on 116 patients with chronic gout who participated in the ongoing Febuxostat Open-Label Clinical Trial of Urate-Lowering Efficacy and Safety (FOCUS). The study was conducted predominantly by primary care physicians, reflecting the expectation of TAP Pharmaceutical Products Inc. that febuxostat represents such an advance over standard therapies in terms of safety, efficacy, and ease of use that internists and family physicians will take on a more active primary role in gout management, he said. Nearly two-thirds of the 26 study patients who had palpable tophi at baseline had no detectable tophus after 4 years, in the longest trial involving the novel nonpurine selective xanthine oxidase inhibitor, he reported.
“Maintaining serum urate at that level of less than 6 mg/dL looks like it's going to be able to resorb tophi,” observed Dr. Schumacher, professor of medicine at the University of Pennsylvania and director of rheumatology at the Veterans Affairs Medical Center, Philadelphia.
Food and Drug Administration approval of febuxostat is expected imminently. The drug should be on pharmacy shelves later this year, according to Dr. Schumacher. If so, it would be the first new drug approved for gout in 40 years.
FOCUS participants started on once-daily febuxostat at 80 mg. During weeks 4–24 they were allowed to titrate to 40 or 120 mg/day in an effort to maintain serum urate levels in the target range or to address adverse reactions. Patients remained on their week-28 dose for the rest of the 4 years.
The majority of patients reduced their serum urate level to below 6 mg/dL—the generally accepted saturation point, and a level at which crystals would be expected to dissolve—within 7 days. The proportion of patients with a serum urate level below 6 mg/dL climbed from 78% at year 1 to 90% at year 4. Even among the handful of patients on 40 mg/day, which isn't expected to be a recommended dose, 86% had a serum urate below 6 mg/dL.
However, nobody on 40 mg/day got their serum urate level to less than 4 mg/dL, a range in which tophi dissolve more rapidly. In contrast, 30% of patients on 80 or 120 mg of febuxostat once daily had serum urate levels consistently falling below 4 mg/dL.
The mean number of gout flares per year declined sharply over time: an average of 2.22 in year 1, 0.44 in year 2, 0.26 in year 3, and 0.18 in year 4.
Prophylaxis against gout flares was provided by concomitant colchicine at 6 mg/day for the first 4 weeks of FOCUS. Upon discontinuation of the drug, however, the flare rate temporarily went up. This suggests that maintaining prophylaxis for longer than 4 weeks is warranted in clinical practice, Dr. Schumacher said.
Allopurinol, the only FDA-approved serum urate-lowering drug, is a problematic agent with numerous side effects, particularly in patients with renal insufficiency, a common comorbidity. Several studies have demonstrated that patient compliance with allopurinol is “abysmal,” he said.
Fifty-five patients quit FOCUS, most due to disenchantment with the paperwork and frequent office visits.
No serious adverse events were attributed to febuxostat. The most common adverse event was transient, mild to moderate elevation of liver function test results. This occurred in 14 patients; however, 3 were alcohol abusers and 9 others were on concomitant medications having hepatotoxic effects, including acetaminophen, colchicine, and NSAIDs.
Alcohol consumption has long been considered a trigger for recurrent gout attacks; however, this hypothesis has not been formally tested.
We conducted an Internet-based case-crossover study to assess several putative risk factors, including alcohol consumption, thought to trigger recurrent gout attacks. Subjects who had an attack within the past year were recruited online and asked to provide access to medical records pertaining to their gout. Data were obtained on the amount and type of alcoholic beverage consumed on each day over the 2-day period before a gout attack and on each day over a 2-day period during the intercritical period. We examined the amount and type of alcohol consumption and the risk of recurrent gout attacks using a conditional logistic regression adjusting for diuretic use and purine intake.
A total of 197 subjects were recruited online over a 10-month period. Of those, 179 (91%) fulfilled the American College of Rheumatology Criteria for gout. Compared with no alcohol consumption, odds ratios for recurrent gout attacks were 1.1, 0.9, 2.0, and 2.5 for 1 to 2, 3 to 4, 5 to 6, and 7 or more drinks consumed over the 2-day period, respectively (P<.005). A dose-response relationship of risk of gout attacks was more evident for alcohol consumed over the last 24 hours. An increased risk of recurrent gout attacks was found for each type of beverage consumed.
Alcohol consumption triggers recurrent gout attacks. This effect was likely to occur within 24 hours after its consumption.
Press Release: Extreme Pain Of Gout Is Detrimental To Quality Of Life & Work , New Poll Shows11 Nov 2006
Results of a new survey show that two-thirds (65 percent) of gout patients ranked their typical gout flares -- defined as a sudden, intense pain -- as either close to, or the worst pain possible and say that the flares last an average of eight days. Seventy-two percent reported having experienced at least one flare within the last 12 months. The online survey of 321 gout patients was conducted by Harris Interactive(R) on behalf of Savient Pharmaceuticals, Inc. (Nasdaq: SVNT), whose drug Puricase(R) (PEG-uricase), is currently in Phase 3 development in symptomatic gout patients who have failed previous therapies. The survey results were released today just prior to the 2006 American College of Rheumatology Annual Scientific Meeting in Washington, D.C.
The majority of surveyed gout patients reported that a gout flare has a major or extreme impact on walking (75 percent), putting on shoes (71 percent), and participating in recreational sports and activities (70 percent). About one in five (21 percent) employed gout patients say that they have missed work in the last year due to a gout flare, with 23 percent of those respondents saying they missed seven work days or more.(1) While more than half (57 percent) of gout sufferers see a doctor for treatment, only 13 percent reported seeing a rheumatologist, the type of physician who specializes in rheumatic disorders such as gout, whereas 80 percent see a primary care physician.
"These survey findings confirm that gout is an excruciating and debilitating form of arthritis that can negatively affect daily activities, lifestyle and work productivity," said N. Lawrence Edwards, MD, Professor of Medicine, Rheumatology and Clinical Immunology, University of Florida College of Medicine, and Chairman and CEO of the newly launched Gout & Uric Acid Education Society, a non-profit, patient advocacy organization created to educate patients and healthcare providers about gout and the related consequences of hyperuricemia (http://www.gouteducation.org). "The prevalence of gout has steadily increased in recent decades due to a variety of dietary and lifestyle changes, obesity, greater use of medications that can cause high uric acid levels, and the aging population. Fortunately for patients, the first new prescription treatments for gout in 40 years are being developed."
There are an estimated 5 million Americans with gout, including over 100,000 patients for whom conventional therapy is contraindicated or has been ineffective. Gout results from deposits of needle-like crystals of uric acid in connective tissue and in the joints. These deposits lead to inflammatory arthritis, which causes joint swelling, redness, heat, pain, and stiffness and damage to the affected joints. In patients for whom conventional therapy is contraindicated or has been ineffective, the disease can become chronic, progressively worsen and cause debilitating flares of pain and swelling, development of tophi, loss of joint functionality, renal disease and kidney stones. Over 2 million gout patients are treated for their hyperuricemia with the urate lowering drug, allopurinol, a xanthine oxidase inhibitor, which may take a period of years to achieve meaningful clinical outcomes, if ever.
About the Survey
The survey, conducted on behalf of Savient Pharmaceuticals, also found:
-- Although gout flares are more likely to occur in the big toe (62 percent), many also had a flare in a joint other than the big toe (52 percent).
-- The majority of gout sufferers (71 percent) report that they are currently taking prescription medication from their doctor to treat gout.
-- A vast majority of gout sufferers (95 percent) report they get gout information from their doctor.
This survey was conducted online within the United States by Harris Interactive(R) on behalf of Savient Pharmaceuticals, Inc. between October 2 and October 9, 2006 among 321 gout patients (aged 18 and over) who have experienced a gout flare, of which 98 are employed. Harris Interactive recruited the survey respondents via email through the Harris Interactive Chronic Illness Panel. Figures for age by sex, race/ethnicity, education, region and household income were weighted where necessary to bring them into line with their actual proportions in the population. Propensity score weighting was also used to adjust for respondents' propensity to be online.
With a pure probability sample of 321 one could say with a ninety-five percent probability that the overall results would have a sampling error of +/- 5.5 percentage points. Sampling error for data based on sub-samples would be higher and would vary. However, that does not take other sources of error into account. This online survey is not based on a probability sample and therefore no theoretical sampling error can be calculated.
About Puricase (PEG-uricase)
Although therapy for gout has not improved dramatically in 3 decades, this is now changing, particularly for those patients with difficult disease, with the development of Puricase (PEG-uricase), a recombinant, pegylated formulation of urate oxidase, an enzyme present in almost all mammals -- but not in humans -- that eliminates uric acid from the blood and tissues. Savient Pharmaceuticals is developing this Phase 3 compound for the control of hyperuricemia in treatment failure gout.
About Puricase (PEG-uricase) Phase 3 Clinical Studies
Savient is conducting phase 3 clinical studies with Puricase (PEG-uricase) in symptomatic gout patients who cannot benefit from conventional therapies. There is currently no available treatment option for this subset of gout patients. The Phase 3 program is designed to compare the safety and efficacy of Puricase (PEG-uricase) administered by two-hour intravenous infusion every two weeks or every four weeks versus placebo infusion, over a six-month period. Eligible patients must have hyperuricemia and symptomatic gout, and have been unresponsive to or intolerant of conventional therapy. All patients who complete the placebo-controlled trials will be invited to participate in a long-term open label extension.
Efficacy endpoints will include the level of uric acid control, an assessment of the reduction in burden of gout tophi using digital photography, reduction in the frequency of gout flares, improvement in the count of swollen and tender joints, and improvements in patient reported outcomes using the Short Form 36 (SF-36) and the Health Assessment Questionnaire-Disability Index (HAQ-DI).
Savient licensed exclusive, worldwide rights to the technologies related to Puricase (PEG-uricase) from Duke University (Duke) of North Carolina and Mountain View Pharmaceuticals, Inc. (MVP), a California corporation. Duke developed the recombinant porcine uricase enzyme and MVP developed the PEGylation technology. MVP and Duke were granted U.S. and foreign patents covering the licensed technology. Puricase is a registered trademark of Mountain View Pharmaceuticals, Inc. About Savient Pharmaceuticals, Inc.
Savient Pharmaceuticals is a biopharmaceutical company engaged in developing and marketing pharmaceutical products that target unmet medical needs in both niche and broader markets. The Company's lead product development candidate, Puricase (PEG-uricase) for treatment failure gout, has reported positive Phase 1 and 2 clinical data; patient dosing in Phase 3 clinical studies began in May 2006. Savient's experienced management team is committed to advancing its pipeline and expanding its product portfolio by in- licensing late-stage compounds and exploring co-promotion and co-development opportunities that fit the Company's expertise in specialty pharmaceuticals and biopharmaceuticals with an initial focus in rheumatology. Savient also markets Oxandrin(R) (oxandrolone tablets, USP) CIII in the U.S. Puricase is a registered trademark of Mountain View Pharmaceuticals, Inc.
This news release contains forward-looking statements that are subject to certain risks, trends and uncertainties that could cause actual results and achievements to differ materially from those expressed in such statements. These risks, trends and uncertainties are in some instances beyond Savient's control.
Words such as "anticipate," "believe," "estimate," "expect," "intend," "plan," "will" and other similar expressions help identify forward-looking statements, although not all forward-looking statements contain these identifying words. These forward-looking statements involve substantial risks and uncertainties and are based on current expectations, assumptions, estimates and projections about Savient's business and the biopharmaceutical and specialty pharmaceutical industries in which Savient operates. Such risks and uncertainties include, but are not limited to, Savient's stock price and market conditions, delay or failure in developing Puricase (PEG-uricase) and other product candidates, difficulties of expanding Savient's product portfolio through in-licensing, introduction of generic competition for Oxandrin, fluctuations in buying patterns of wholesalers, potential future returns of Oxandrin or other products, Savient's continuing to incur substantial net losses for the foreseeable future, difficulties in obtaining financing, potential development of alternative technologies or more effective products by competitors, reliance on third-parties to manufacture, market and distribute many of Savient's products, economic, political and other risks associated with foreign operations, risks of maintaining protection for Savient's intellectual property, risks of an adverse determination in ongoing or future intellectual property litigation, and risks associated with stringent government regulation of the biopharmaceutical industry. Savient may not actually achieve the plans, intentions or expectations disclosed in Savient's forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements that Savient makes. Stockholders should not place undue reliance on the forward-looking statements, which speak only as to the date of this press release. Savient's forward-looking statements do not reflect the potential impact of any future acquisitions, mergers, dispositions, joint ventures or investments that Savient may make. Except as required by law, Savient does not assume any obligation to update any forward-looking statements.
(1) Due to a small sample sizes, data should only be used directionally.
It's The Heat And The Humidity: How Each Worsens Gout Symptoms
It's The Heat And The Humidity: How Each Worsens Gout Symptoms
13 Nov 2006
Climatic factors such as heat and humidity that lead to dehydration can signal a future attack for gout sufferers, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Washington DC.
Gout, caused by deposits of monosodium uric crystals, causes severe pain and swelling of the joints. The attacks, which typically affect one joint over a period of a few days, most often the big toe, can also generate fever, chills, a general feeling of malaise and rapid heartbeat. Depleting the body of fluids through perspiration has been long considered a potential trigger for recurrent gout attacks.
To test the suspected effects of humidity and temperature on the chances of recurrent attacks, researchers recruited 197 individuals who had experienced a gout attack within the past year. Participants were asked to log onto a study Web site when they experienced a gout attack and complete a questionnaire on the risk factors they had experienced the two days prior (known as the hazard period). They also were asked to complete the same questionnaire on experiences over a two-day control period. Climatic data on temperature, barometric pressure, humidity and precipitation for each participant's zip code, obtained from the National Oceanic and Atmospheric Administration, was then compared between hazard period and control period with adjustments made for alcohol consumption, purine intake and diuretic use.
Results indicated that high temperature and high humidity were strongly associated with increased risk of a recurrent gout attack. The risk of recurrent attacks increased by almost two-fold when the maximum daily temperature increased from 0-53° F to 87-105° F. A similar magnitude of increased risk also was found when the humidity increased from the dew point of 4-32°F to 64-77°F. Barometric pressure and precipitation appeared to have no influence.
"Our data indicate that both high temperature and high humidity are associated with an increased risk of recurrent gout attacks," explains Yuquing Zhang, D.Sc., Professor of Medicine and Epidemiology, Boston University School of Medicine; Boston, Massachusetts and an investigator in the study. "Thus, when it's hot and humid, those with gout should consider drinking more fluids to avoid potentially painful gout attacks."
Gout afflicts about 1 in 100 people and as many as 6 - 7 percent of older men. This condition and its complications occur more often in men, women after menopause, and people with kidney disease. Gout is strongly associated with obesity, hypertension, hyperlipidemia and diabetes. Because of genetic factors, gout tends to run in some families.
The American College of Rheumatology is the professional organization for rheumatologists and health professionals who share a dedication to healing, preventing disability and curing arthritis and related rheumatic and musculoskeletal diseases. For more information on the ACR's annual meeting, see http://www.rheumatology.org/annual.
Presentation Number: 707
High Humidity and High Temperature Increase the Risk of Recurrent Gout Attacks: The Online Case-crossover Gout Study
YQ Zhang1, CE Chaisson1, CA Chen1, TE McAlindon2, DJ Hunter1. 1BUSM, Boston, MA; 2NEMC, Boston, MA
While dehydration has long been considered a potential trigger for recurrent gout attacks, few studies have examined the relation of risk factors that may cause dehydration to the risk of recurrent gout attacks. In hot and humid weather individuals can lose body fluids through perspiration. Thus, serum uric acid levels may increase due to reduced uric acid excretion.
We conducted a case-crossover study to assess a set of putative risk factors, including climatic factors, triggering recurrent gout attacks. Subjects who had experienced a gout attack within the past year were recruited online and followed-up prospectively. Participants were asked to log onto a study website when they experienced a gout attack. Risk factors on each day over the two-day period prior to an acute gout attack (hazard period) were assessed using the online questionnaire. The same questionnaire was used over each of two days during an intercritical period (control period). We obtained climatic data (i.e., temperature, barometric pressure, humidity, precipitation) from the National Oceanic and Atmospheric Administration website for the corresponding hazard and control periods according to the zip code provided by the participant. We examined the relation of each climatic factor to the risk of recurrent gout attacks using conditional logistic regression model adjusting for alcohol consumption, purine intake and diuretic use.
197 subjects completed both control and hazard period questionnaires during the follow-up period. 94% of the subjects had a confirmed history of gout according to ACR criteria. Participants were predominantly male (80.2%) and White (88.0%). Most participants had a college education (57.3%). The median time between the onset of a gout attack and logging on to the website was 2 days. High temperature and high humidity were both strongly associated with an increased risk of recurrent gout attacks (Table). Compared to the lowest quintile of maximum daily temperature (0-53 °F) over the last 2 days, the odds ratio for recurrent gout attacks for the highest quintile of maximum daily temperature (87-105 °F) was 2.0 (95% CI: 1.1-3.5) (P for trend =0.033). Compared to the lowest quintile of humidity (dew point:-4-32°F), the odds ratio for recurrent gout attacks for the highest quintile of humidity (dew point: 64-77°F) was 2.1 (95% CI: 1.2-3.7). (P for trend = 0.018). No such relation was observed for barometric pressure or precipitation.
Our results demonstrate that high temperature and high humidity are both associated with an increased risk of recurrent gout attacks. Under such weather conditions, subjects with gout may need to increase fluid intake to replace volume depletion.
Aim: The aim is to determine whether response to topical ice versus heat differentiates between patients with gout versus other arthritides.
Methods: The first 150 patients seen in our clinic with joint pain from February 2004 onward were asked to fill out questionnaires regarding their response to heat and ice. Patients who responded that topical ice eased their pain and who did not have a diagnosis of crystal-induced arthritis were asked to have a joint aspiration if they had active synovitis on presentation to the clinic.
Results: Of 150 completed questionnaires, 26 patients never tried heat or cold as adjuvant treatment for their arthritis. The remaining 124 patients were divided into 6 groups: patients with crystal-proven gout (n = 20), rheumatoid arthritis (RA; n = 32), osteoarthritis (OA; n = 32), other forms of inflammatory arthritis (n = 18), and soft tissue conditions (n = 22). None of the patients with gout benefited from topical heating of their affected joints and all preferred topical ice (P < 0.001). Most patients with RA preferred heat (n = 24). Of 4 patients with RA who preferred topical ice, 3 had effusions and arthrocentesis was performed. Intracellular monosodium urate (MSU) crystals were seen in 2 and intracellular calcium pyrophosphate dihydrate (CPPD) crystals were seen in one patient raising questions about coexistence of 2 diseases or previous misdiagnoses. Most patients with OA preferred heat (n = 28). A significantly higher percentage of the patients with gouty arthritis found that topical ice helped relieve their joint pain as compared with patients with RA (P = 8 x 10-11) and other inflammatory arthritides (P = 3 x 10-8).
Discussion: Heat and cold are adjuvant treatments for arthritis. In gouty arthritis, cold applications are a useful adjunct to treatment and may help discriminate patients with gout from other forms of inflammatory arthritis.
OBJECTIVES: To determine whether joints affected by gout are also affected by osteoarthritis (OA).
METHODS: A postal questionnaire was sent to all adults aged over 30 years registered with two general practices. The questionnaire assessed a history of gout (doctor diagnosed, or episodes suggestive of acute crystal synovitis) and medication use. Possible cases of gout attended for clinical assessment in order to verify the diagnosis on clinical grounds and assess the distribution of joints affected by acute attacks of gout and OA. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were calculated between the history of an acute attack of gout and the presence of OA at an individual joint adjusting for age, gender, BMI and prior diuretic use in a binary logistic regression model.
RESULTS: 4249 completed questionnaires were returned (32%). From 359 attendees, 164 clinically confirmed cases of gout were identified. A highly significant association existed between the site of acute attacks of gout and the presence of OA (aOR 7.94; 95% CI 6.27, 10.05). Analysis at individual joint sites revealed a significant association at the 1st MTPJ (aOR 2.06; 95% CI 1.28, 3.30), mid-foot (aOR 2.85; 95% CI 1.34, 6.03), knee (aOR 3.07; 95% CI 1.05, 8.96) and distal interphalangeal joints (aOR 12.67; 95% CI 1.46, 109.91).
CONCLUSION: Acute attacks of gout at individual joint sites are associated with the presence of clinically assessed OA at that joint suggesting that OA may predispose to the localised deposition of MSU crystals.
May 25, 2007 — Long-term consumption of coffee is associated with reduced risk for gout in men older than 40 years, according to the results of a prospective study reported in the June issue of Arthritis & Rheumatism.
"Coffee is one of the most widely consumed beverages in the world and may affect the risk of gout via various mechanisms," write Hyon K. Choi, MD, DrPH, from the University of British Columbia in Vancouver, Canada, and colleagues. "A study of a nationally representative sample of US adults showed that coffee consumption was associated with a lower serum level of uric acid and a lower frequency of hyperuricemia."
The study cohort from the Health Professionals Follow-Up Study consisted of 45,869 men with no history of gout at baseline. Validated questionnaires were used to measure intake of coffee, decaffeinated coffee, tea, and total caffeine every 4 years for 12 years, and a supplementary questionnaire was used to determine whether participants met the American College of Rheumatology survey criteria for gout.
During the 12-year study, there were 757 confirmed incident cases of gout. Increasing coffee intake was inversely associated with the risk for gout, with multivariate relative risks (RRs) for incident gout of 1.00, 0.97, 0.92, 0.60 (95% confidence interval [CI], 0.41 - 0.87), and 0.41 (95% CI, 0.19 - 0.88) for coffee consumption categories of 0, less than 1, 1 to 3, 4 to 5, and 6 or more cups per day, respectively (P for trend = .009).
For decaffeinated coffee, the multivariate RRs for 0, less than 1, 1 to 3, and 4 or more cups per day were 1.00, 0.83, 0.67 (95% CI, 0.54 - 0.82), and 0.73 (95% CI, 0.46 - 1.17), respectively (P for trend = .002).
These associations were independent of dietary and other risk factors for gout such as body mass index, age, hypertension, diuretic use, alcohol consumption, and chronic renal failure. Total caffeine from all sources and tea intake were not associated with the risk for gout.
"These prospective data suggest that long-term coffee consumption is associated with a lower risk of incident gout," the authors write.
Study limitations include self-report of coffee consumption, restriction to male healthcare professionals in the cohort, observational design, and inability to rule out the possibility that unmeasured factors might contribute to the observed associations.
The National Institutes of Health and TAP Pharmaceuticals supported this study. Some of the authors have disclosed various financial relationships with TAP and/or Savient Pharmaceuticals.
Firstly gout just does not appear by deposition of crystals of uric acid.
The pH between the joints and blood play a major role. The presence of super saturated solutions, remember growing copper sulphate crystals at school? the same principle.
A major cause is due to gut disease. Classically a stressful time, eg long surgical operation to sever chest infection can change the gut to make you wheat intolerant/gluten intolerant. So begins the gout cycle.
A patient of mine has wheat intolerance developed after a stressful period in his life. Just to eat a jellybean that contains wheat dust (common) he gets the best bout of gout you can imagine.
Worth getting them tested especially if gout starts out of the blue.
Objectives. To compare quality of life (QOL) between gout cases and controls in a primary care population and to investigate whether impaired QOL in gout is secondary to co-morbid factors or to intrinsic factors related to gout itself.
Methods. A postal questionnaire was sent to all adults aged over 30 yrs registered with two general practices. The questionnaire assessed a history of gout (doctor diagnosed, or episodes suggestive of acute crystal synovitis) and medical and musculoskeletal co-morbidities. QOL was assessed using the WHOQoL-Bref instrument. Possible cases of gout attended for clinical assessment where the diagnosis was verified on clinical grounds. Overall QOL, satisfaction with health and QOL across four domains were compared between gout cases and controls and then entered into a linear regression model adjusting for gout, age, gender, body mass index and medical and musculoskeletal co-morbidities.
Results. Of 13 684 questionnaires mailed, 3082 completed questionnaires were returned (23%). From 289 suggested cases of gout, 137 cases were confirmed by clinical assessment. Compared with controls, cases had impaired overall QOL (15.67 vs 16.41, P = 0.003), satisfaction with health (13.16 vs 14.45, P < 0.001) and physical health-related QOL (14.08 vs 15.95, P < 0.001). On multi-variate analysis, gout remained associated with impaired physical health-related QOL (ß = –0.059, P = 0.001) but not overall QOL (ß = –0.024, P = 0.198) or satisfaction with health (ß = –0.028, P = 0.142).
Conclusions. Gout associates with poor overall QOL mainly resulting from associated co-morbidity. Physical health-related QOL, however, remains impaired after adjustment for co-morbidities.
Arthritis caused by gout (i.e., gouty arthritis) accounts for millions of outpatient visits annually, and the prevalence is increasing. Gout is caused by monosodium urate crystal deposition in tissues leading to arthritis, soft tissue masses (i.e., tophi), nephrolithiasis, and urate nephropathy. The biologic precursor to gout is elevated serum uric acid levels (i.e., hyperuricemia). Asymptomatic hyperuricemia is common and usually does not progress to clinical gout. Acute gout most often presents as attacks of pain, erythema, and swelling of one or a few joints in the lower extremities. The diagnosis is confirmed if monosodium urate crystals are present in synovial fluid. First-line therapy for acute gout is nonsteroidal anti-inflammatory drugs or corticosteroids, depending on comorbidities; colchicine is second-line therapy. After the first gout attack, modifiable risk factors (e.g., high-purine diet, alcohol use, obesity, diuretic therapy) should be addressed. Urate-lowering therapy for gout is initiated after multiple attacks or after the development of tophi or urate nephrolithiasis. Allopurinol is the most common therapy for chronic gout. Uricosuric agents are alternative therapies in patients with preserved renal function and no history of nephrolithiasis. During urate-lowering therapy, the dose should be titrated upward until the serum uric acid level is less than 6 mg per dL (355 µmol per L). When initiating urate-lowering therapy, concurrent prophylactic therapy with low-dose colchicine for three to six months may reduce flare-ups.
Savient Pharmaceuticals, Inc. (NASDAQ: SVNT) announced the completion of the in-life portion of its two pivotal Phase 3 clinical trials for Puricase® (pegloticase) in patients with treatment-failure gout, an orphan indication. Puricase is a pegylated recombinant mammalian urate oxidase that is being developed to control hyperuricemia and its clinical consequences in patients for whom conventional therapy is contraindicated or has been ineffective. At this time there is no alternative therapeutic option for the management of treatment-failure gout patients other than symptomatic relief.
"The completion of the in-life portion of the Phase 3 studies is an important milestone for both the Company and for treatment-failure gout patients," commented Christopher Clement, President and Chief Executive Officer. "We believe the level of patient commitment during the study period and the high rate of enrollment in our open label extension protocol underscores the critical void in treatment options for patients who suffer from this condition that Puricase may uniquely address. As we move forward over the next several weeks, we will focus our resources on assembling and analyzing the Phase 3 data. We remain on track to make our next public statement regarding the Phase 3 studies when we report top-line results in December."
The two Phase 3 pivotal trials assessed the safety and efficacy of a six-month course of Puricase therapy in patients with treatment-failure gout, under the auspices of a Special Protocol Assessment from the U.S. Food and Drug Administration. The two Phase 3 studies included over 200 patients at more than 50 clinical sites across the United States, Canada and Mexico. The studies consisted of two replicate protocols; each a randomized, double-blinded, placebo controlled study of six months duration in which Puricase or placebo was administered by a two-hour intravenous infusion. Approximately 110 patients were randomized into each study and a total of 212 patients received at least one dose of study medication (Puricase or placebo). Each study had three arms: placebo, Puricase 8 mg administered every two weeks, or Puricase 8 mg administered every four weeks. In order to maintain blind to the treatment assignment, all patients received an intravenous infusion every two weeks.
On a rolling basis, as patients completed their participation in the Phase 3 studies, all completed patients were invited to enroll in a twelve-month open label extension protocol offering a choice among three options: observation, in which patients could use any gout drug except Puricase; Puricase 8 mg every two weeks; or Puricase 8mg every four weeks. After six months in the open label extension protocol, patients are allowed to switch arms. Nearly all patients who completed the Phase 3 trials have opted to enroll in the open label extension, selecting either the every two week, or the every four week 8 mg Puricase treatment arms. The open label extension protocol is ongoing. A follow-on open label extension protocol for another twelve months is planned, regardless of whether patients choose to continue to receive Puricase or whether they enter the observation arm of the study.
"We are very pleased with the completion of the Phase 3 program and we look forward to studying the data set," said Zeb Horowitz, M.D., Sr. Vice President and Chief Medical Officer. "In parallel, we will continue to closely observe our patients in the open label extension protocol to learn as much as we can about the safety and efficacy of long term use of Puricase, and to monitor the clinical outcomes for patients who have chosen to discontinue Puricase dose administration. It is our hope that if clinical benefit beyond control of uric acid has been attained through Puricase treatment, such clinical benefit could prove to be durable. This would be a wonderful outcome for patients who currently have limited or no therapeutic options."
Separately, the Company announced that pegloticase has become the official generic name for Puricase assigned by the USAN Council, replacing the previously used name of PEG-uricase.
The polymorphism -863C/A in tumour necrosis factor- gene contributes an independent association to gout
S.-J. Chang, P.-C. Tsai, C.-J. Chen, H.-M. Lai and Y.-C. Ko Rheumatology 2007 46(11):1662-1666
Objective. To investigate the associations between polymorphisms in the promoter of the tumour necrosis factor- (TNF-) gene and gout.
Methods. The polymorphisms -308G/A and -863C/A in the TNF- gene were determined in 106 gout patients and 159 healthy controls among male Taiwanese using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. The biochemical markers, including Glutamic-oxaloacetic transaminase (GOT), Glutamic-pyruvic transaminase (GPT), uric acid, creatinine, total cholesterol (TC), triglycerides (TG), body mass index (BMI) and hypertension, as well as alcohol consumption were measured.
Results. The gout patients had 9.43% (10/106) with genotype AA at polymorphism -863C/A showing a significantly higher fraction than controls (0.63%; 1/159, P < 0.001). The crude results also showed that the gout patients had significantly higher portions of abnormal GOT, GPT, creatinine, TC, TG, alcohol consumption, hypertension and hyperuricaemia than controls (P < 0.05), but the -308G/A, BMI and genotype CA at -863C/A did not show the same significant difference (P > 0.05). After adjustment by a stepwise logistic regression method, the hyperuricaemia, creatinine, GPT, TG and alcohol consumption as well as genotype AA at polymorphism -863C/A were found to be significantly associated with gout.
Conclusion. The genotype AA at polymorphism -863C/A in a recessive model showed a significant association with developing gout independent of hyperuricaemia, abnormal creatinine, higher TG, GPT and alcohol consumption.
Although diet has long been assumed to be associated with hyperuricemia, the association between diet and hyperuricemia remains to be verified.
The Nutrition and Health Survey in Taiwan (NAHSIT) implemented between 1993 and 1996 was a nationwide survey using a stratified multistage sampling design. A food frequency questionnaire (FFQ), 24-hour diet recall, and blood samples were utilized. Hyperuricemia was defined as serum urate >7.7 mg/dL for men and >6.6 mg/dL for women.
In total, 2176 adults, 987 (45%) men and 1189 (55%) women, were recruited. Mean serum urate was 6.81 ± 1.66 mg/dL (range, 2.5-16.8 mg/dL) and 5.47 ± 1.55 mg/dL (range, 1.4-11.5 mg/dL) for men and women, respectively. Multiple logistic regression analysis indicated that beer consumption in both the FFQ and the 24-hour diet recall were significantly associated with hyperuricemia in men after adjusting for age, total caloric intake, body mass index, and geographic area. In FFQ, the adjusted odds ratio was 1.49 for men who imbibed 0.1 to 11.6 g ethanol (<1 standard drink) daily and 1.56 for men who imbibed ≥11.7 g ethanol (≥1 standard drink) daily, when compared with that for men who did not drink beer (P = 0.035). In the 24-hour diet recall, the adjusted odds ratio for men who drank <5 cans of beer daily was 1.13, and for men who drank ≥5 cans daily was 1.28 when compared with that for men who did not drink beer (P = 0.003).
Conclusions This cross-sectional survey demonstrated that beer intake is independently associated with increased risk of hyperuricemia in men. Restricted beer intake may help prevent hyperuricemia in the population. The finding of elevated mean serum urate levels over recent decades warrants further study.
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Update on Crystal-Induced Arthritis and Hyperuricemia From ACR 2007
A remarkable set of convergent factors has contributed to the increased prevalence and clinical complexity of gout in the United States in the last 15 years. These factors include increased population longevity, broad use of thiazide and loop diuretics and of low-dose aspirin that promote hyperuricemia, surges in the prevalence of hypertension, metabolic syndrome, obesity, and end-stage renal disease. Concurrently, there has been a shortfall in new US Food and Drug Administration (FDA)-approved therapies for treatment of hyperuricemia and gouty inflammation.The 2007 American College of Rheumatology (ACR) meeting featured a variety of studies pertinent to clinical practice via refinements in understanding of the impact of hyperuricemia and gout and evolving antihyperuricemic and anti-inflammatory treatments, which are discussed below.
Objective. To describe the ambulatory care utilization by patients with gouty arthritis (gout) in the United States using a nationally representative sample.
Methods. A cross-sectional survey design based on the ambulatory care data from the 2002 US National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey was used to examine the ambulatory care burden for gout, the characteristics of gout patients, the types of providers who see gout patients, and prescribing patterns associated with the management of gout. Weighted analyses were performed to estimate the effect of age, sex, and ethnicity on the association with gout and prescription of allopurinol.
Results. Of the 973 million ambulatory care visits in the United States, 3.9 million were for gout. The majority of visits were for men. The average age for men with gout was lower than that for women with gout (65 vs 70 years of age). Over two-thirds of these gout visits were attended to by primary care providers, whereas visits to rheumatologists constituted only a very small proportion of these visits (1.3%). There were 2.8 million prescriptions for allopurinol, 700,000 prescriptions for nonsteroidal antiinflammatory drugs, 381,000 prescriptions for colchicine, and 341,000 prescriptions for prednisone. After adjusting for age and sex, Asians were 2.7 times more likely than Caucasians to have a gout visit. Yet these patients had lower probability of receiving allopurinol (odds ratio 0.04, 95% confidence interval 0.01-0.27).
Conclusion. The majority of patients with gout are seen by generalist physicians. Asian ethnicity is associated with higher number of visits for gout, but a lower frequency of allopurinol treatment.
Objective To examine the relation between intake of sugar sweetened soft drinks and fructose and the risk of incident gout in men.
Design Prospective cohort over 12 years.
Setting Health professionals follow-up study.
Participants 46 393 men with no history of gout at baseline who provided information on intake of soft drinks and fructose through validated food frequency questionnaires.
Main outcome measure Incident cases of gout meeting the American College of Rheumatology survey criteria for gout.
Results During the 12 years of follow-up 755 confirmed incident cases of gout were reported. Increasing intake of sugar sweetened soft drinks was associated with an increasing risk of gout. Compared with consumption of less than one serving of sugar sweetened soft drinks a month the multivariate relative risk of gout for 5-6 servings a week was 1.29 (95% confidence interval 1.00 to 1.68), for one serving a day was 1.45 (1.02 to 2.08), and for two or more servings a day was 1.85 (1.08 to 3.16; P for trend=0.002). Diet soft drinks were not associated with risk of gout (P for trend=0.99). The multivariate relative risk of gout according to increasing fifths of fructose intake were 1.00, 1.29, 1.41, 1.84, and 2.02 (1.49 to 2.75; P for trend <0.001). Other major contributors to fructose intake such as total fruit juice or fructose rich fruits (apples and oranges) were also associated with a higher risk of gout (P values for trend <0.05).
Conclusions Prospective data suggest that consumption of sugar sweetened soft drinks and fructose is strongly associated with an increased risk of gout in men. Furthermore, fructose rich fruits and fruit juices may also increase the risk. Diet soft drinks were not associated with the risk of gout.