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Latest Research on Gout
     
Adv Drug Deliv Rev. 2008 Jan 3;60(1):59-68. Epub 2007 Aug 14.
PEG-uricase in the management of treatment-resistant gout and hyperuricemia.
Sherman MR, Saifer MG, Perez-Ruiz F.
Mountain View Pharmaceuticals, Inc., 3475-S Edison Way, Menlo Park, CA 94025, USA.

Hyperuricemia results from an imbalance between the rates of production and excretion of uric acid. Longstanding hyperuricemia can lead to gout, which is characterized by the deposition of monosodium urate monohydrate crystals in the joints and periarticular structures. Because such deposits are resolved very slowly by lowering plasma urate with available drugs or other measures, the symptoms of gout may become chronic. Persistent hyperuricemia may also increase the risk of renal and cardiovascular diseases. Unlike most mammals, humans lack the enzyme uricase (urate oxidase) that catalyzes the oxidation of uric acid to a more soluble product. This review describes the development of a poly(ethylene glycol) (PEG) conjugate of recombinant porcine-like uricase with which a substantial and persistent reduction of plasma urate concentrations has been demonstrated in a Phase 2 clinical trial. Two ongoing Phase 3 clinical trials include systematic assessments of gout symptoms, tophus resolution and quality of life, in addition to the primary endpoint of reduced plasma urate concentration.

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Arthritis Rheum. 2007 Dec 28;59(1):109-116 [Epub ahead of print]
Sugar-sweetened soft drinks, diet soft drinks, and serum uric acid level: The third national health and nutrition examination survey.
Choi JW, Ford ES, Gao X, Choi HK.
Arthritis Research Centre of Canada, Vancouver, British Columbia, Canada.

OBJECTIVE: Sugar-sweetened soft drinks contain large amounts of fructose, which may significantly increase serum uric acid levels and the risk of gout. Our objective was to evaluate the relationship between sugar-sweetened soft drink intake, diet soft drink intake, and serum uric acid levels in a nationally representative sample of men and women. METHODS: Using data from 14,761 participants age >/=20 years from the Third National Health and Nutrition Examination Survey (1988-1994), we examined the relationship between soft drink consumption and serum uric acid levels using linear regression. Additionally, we examined the relationship between soft drink consumption and hyperuricemia (serum uric acid level >7.0 mg/dl for men and >5.7 mg/dl for women) using logistic regression. Intake was assessed by a food-frequency questionnaire. RESULTS: Serum uric acid levels increased with increasing sugar-sweetened soft drink intake. After adjusting for covariates, serum uric acid levels associated with sugar-sweetened soft drink consumption categories (<0.5, 0.5-0.9, 1-3.9, and >/=4 servings/day) were greater than those associated with no intake by 0.08, 0.15, 0.33, and 0.42 mg/dl, respectively (95% confidence interval 0.11, 0.73; P < 0.001 for trend). The multivariate odds ratios for hyperuricemia according to the corresponding sweetened soft drink consumption levels were 1.01, 1.34, 1.51, and 1.82, respectively (P = 0.003 for trend). Diet soft drink consumption was not associated with serum uric acid levels or hyperuricemia (multivariate P > 0.13 for trend). CONCLUSION: These findings from a nationally representative sample of US adults suggest that sugar-sweetened soft drink consumption is associated with serum uric acid levels and frequency of hyperuricemia, but diet soft drink consumption is not.

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Surg Obes Relat Dis. 2007 Dec 5 [Epub ahead of print]
Gouty attacks occur frequently in postoperative gastric bypass patients.
Friedman JE, Dallal R, Lord JL.
Sacred Heart Institute for Surgical Weight Loss, Pensacola, Florida.

BACKGROUND: Both obesity and surgery are known risk factors for instigating gouty attacks. We describe the incidence and management of postoperative gouty attacks after bariatric surgery. METHODS: We performed a retrospective, multi-institutional review of 411 consecutive laparoscopic gastric bypass patients and identified all patients with postoperative gouty attacks. RESULTS: Of the 411 patients reviewed, 21 (5.1%) had had a previous diagnosis of gout. Of these 21 patients, 7 (33.3%) had had an acute attack postoperatively. No patient who had never had a preoperative episode developed gout. In 4 of the 7 (57.1%) patients, the attack was severe enough to require treatment with corticosteroids. Monoarticular attacks occurred in 5 (71.4%) of the 7 patients, and polyarticular attacks occurred in 2 (28.6%). The joints involved included the toes, ankles, and wrists. One patient presented with cervical gout and developed polyarticular gout that required a significant rehabilitation stay. CONCLUSION: The morbidity of postoperative gouty attacks in bariatric surgery patients is significant. Patients with a history of gout should given prophylactic treatment and closely monitored.

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Expert Opin Drug Saf. 2007 Nov;6(6):625-9.
Reassessing the safety of intravenous and compounded injectable colchicine in acute gout treatment.
Schlesinger N.
Division of Rheumatology, UMDNJ/Robert Wood Johnson Medical School, New Brunswick, NJ 08901-1977, USA. schlesna@umdnj.edu

Colchicine has been used for over 2000 years. Intravenous (i.v.) colchicine has been used for the treatment of acute gout since the 1950s. I.v. and oral colchicine were 'grandfathered' before the 1969 FDA Phase III trials for drug toxicity became law. Data on toxic reactions are, therefore, based only on passive surveillance. The risk of toxicity with i.v. use depends on the total dose over a period of time, the presence of comorbid conditions and the size of individual dose. Colchicine toxicity has been compared to arsenic poisoning. Symptoms start 2-5 h after the toxic dose has been ingested and not uncommonly lead to death. Injections of compounded colchicine have been implicated in the deaths of several patients, several of which received off-label i.v. colchicine for back pain. Given that colchicine has the smallest benefit to toxicity ratio of the drugs that are used in the management of acute gout and the fact that acute gout is not life-threatening, one could make a strong case for eliminating the use of i.v. colchicine the treatment of acute gout.

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Rheumatol Int. 2007 Nov;28(1):1-6. Epub 2007 Jul 26.
Elderly-onset gout: a review.
De Leonardis F, Govoni M, Colina M, Bruschi M, Trotta F.
Section of Rheumatology, Department of Clinical and Experimental Medicine, University of Ferrara, Corso della Giovecca, 203, 44100, Ferrara, Italy, dlnfnc@unife.it.

Elderly-onset gout (EOG), defined as a disease with onset at age 65 years or over, shows relevant epidemiological, clinical and therapeutic differences from the typical middle-age form. The main differences are the more frequent subacute/chronic polyarticular onset with hand involvement, the unusual localization of tophi on ostheoarthritis (OA) nodes, the increased female/male ratio and the frequent association with drugs that decrease renal urate excretion (diuretics and low-dose aspirin) and/or with primitive renal impairment. EOG has recently been confirmed as the most common inflammatory arthropathy in older people, with important demographic implications and substantial impact on daily clinical practice. Despite the high prevalence, gout, in the elderly, often remains misdiagnosed or diagnosed late in its clinical course. Even when correctly recognized, its treatment is often difficult or unsatisfactory.

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J Am Acad Orthop Surg. 2007 Oct;15(10):625-35.
Gout affecting the hand and wrist.
Fitzgerald BT, Setty A, Mudgal CS.
Naval Medical Center, San Diego, USA.

Tophaceous gout in the hand and wrist often presents de novo as the first sign of the disease process in the elderly. Tophaceous material may present in a liquid, pasty, or chalky/granular state. Treatment may be as simple as aspirating the liquid or squeezing out pasty tophaceous material. Other nonsurgical treatment options include lifestyle and dietary modifications and drug therapy. Surgery is often indicated for the patient with significant tendon and joint compromise as well as skin breakdown and for decompression of compressive peripheral neuropathy.

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Am Fam Physician. 2007 Sep 15;76(6):801-8. Summary for patients in:
Am Fam Physician. 2007 Sep 15;76(6):811-2.
Gout: an update.
Eggebeen AT.
University of Pittsburgh Arthritis Institute, Pittsburgh, Pennsylvania 15261, USA.

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 micromol per L). When initiating urate-lowering therapy, concurrent prophylactic therapy with low-dose colchicine for three to six months may reduce flare-ups.

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Rheumatol Int. 2007 Jul 26; [Epub ahead of print]
Elderly-onset gout: a review.
De Leonardis F, Govoni M, Colina M, Bruschi M, Trotta F.
Section of Rheumatology, Department of Clinical and Experimental Medicine, University of Ferrara, Corso della Giovecca, 203, 44100, Ferrara, Italy, dlnfnc@unife.it.

Elderly-onset gout (EOG), defined as a disease with onset at age 65 years or over, shows relevant epidemiological, clinical and therapeutic differences from the typical middle-age form. The main differences are the more frequent subacute/chronic polyarticular onset with hand involvement, the unusual localization of tophi on ostheoarthritis (OA) nodes, the increased female/male ratio and the frequent association with drugs that decrease renal urate excretion (diuretics and low-dose aspirin) and/or with primitive renal impairment. EOG has recently been confirmed as the most common inflammatory arthropathy in older people, with important demographic implications and substantial impact on daily clinical practice. Despite the high prevalence, gout, in the elderly, often remains misdiagnosed or diagnosed late in its clinical course. Even when correctly recognized, its treatment is often difficult or unsatisfactory.

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J Rheumatol. 2007 Jul;34(7):1566-8. Epub 2007 Jun 15.
Treatment of acute gout in hospitalized patients.
Petersel D, Schlesinger N.
Rheumatology Division, Department of Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903-0019, USA.

OBJECTIVE: To record practice patterns of treatment of acute gout in hospitalized patients. METHODS: We performed a retrospective chart review of hospitalized patients diagnosed with gout. RESULTS: Seventy-nine (43%) patients were diagnosed with acute gout during their hospitalization. Fifty-eight (73%) patients with acute gout were found to have a reduction in their glomerular filtration rate. Twenty patients (25%) underwent arthrocentesis. The most widely used drugs for acute gout were colchicine, n = 42 (53%), and nonsteroidal antiinflammatory drugs (NSAID), n = 40 (51%). Combination therapy was used in 52% of patients with acute gout. Thiry-six (86%) patients treated with colchicine and 32 (80%) patients treated with NSAID had renal failure. DISCUSSION: Crystal analysis, the gold standard for diagnosing gout, was performed in only 25% of patients suspected of acute gout. Combination antiinflammatory agents are used in over 50% of patients despite the absence of evidence t
o support use of such combinations. Renal failure was present in 73% of patients with acute gout. Colchicine and NSAID should therefore be used with caution in these patients. Practice patterns vary widely and often appear to be in conflict with recommended diagnostic and treatment measures for acute gout.

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Rheumatology (Oxford). 2007 Jul;46(7):1126-32. Epub 2007 May 3.
Lumiracoxib 400 mg once daily is comparable to indomethacin 50 mg three times daily for the treatment of acute flares of gout.
Willburger RE, Mysler E, Derbot J, Jung T, Thurston H, Kreiss A, Litschig S, Krammer G, Tate GA.
Orthopaedic University Clinic, Bochum, Germany.

OBJECTIVES: To demonstrate non-inferiority of lumiracoxib 400 mg once daily (o.d.) compared with indomethacin 50 mg three times daily (t.i.d.) in the treatment of acute gout, and to compare the safety and tolerability of these treatments. METHODS: In this 1-week, multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group study, patients with a clinical diagnosis of gout, an acute attack of gout in four or more joints within the 48 h prior to evaluation, and at least moderate pain intensity in the target joint were randomized to treatment with lumiracoxib 400 mg o.d. (n = 118) or indomethacin 50 mg t.i.d. (n = 117). The primary efficacy endpoint was the mean change in pain intensity from baseline over days 2-5, assessed on a 5-point Likert scale, where non-inferiority could be claimed if the lower limit of the confidence interval (CI) was greater than -0.5. The patient's and physician's global assessment of response to treatment, and physician's assessment of tenderness, swelling and erythema of the study joint were also assessed. RESULTS: The estimated difference between treatments for the change from baseline in pain intensity over days 2-5 was -0.004 (95% CI -0.207 to 0.199, P > 0.05), indicating that lumiracoxib 400 mg o.d. had comparable efficacy to indomethacin 50 mg t.i.d. for the primary efficacy variable. There was no significant difference between treatments in any of the secondary efficacy variables. Adverse events were reported by 10.2% of patients treated with lumiracoxib and 22.2% of those receiving indomethacin. CONCLUSIONS: Lumiracoxib is as effective as indomethacin for treatment of acute gout and may have a better safety and tolerability profile.

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Z Rheumatol. 2007 Jul;66(4):317-325.
[Crystal-induced arthritis - old but important.]
[Article in German]
Winzer M, Gräßler J, Aringer M.
Medizinische Klinik und Poliklinik III, Universitätsklinikum Carl-Gustav-Carus,Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Deutschland, martin.aringer@uniklinikum-dresden.de.

Gout is the most common inflammatory arthropathy for men. Asymptomatic hyperuricemia, which should lead to diet, but not to medication, is much more common still. Increased uric acid levels mostly result from diminished renal excretion, which is more commonly familiar than secondary (renal failure, diuretics). With the first episode of often typical (red, hot, exquisitely painful first MTP joint) acute arthritis or with urate nephrolithiasis, increased uric acid turns pathological. Attacks are treated with NSAIDs or corticosteroids. More common attacks, chronic gout, or urate nephropathy are definite indications for long-term (at least 5 years) therapy with allopurinol or febuxostat. Additional anti-inflammatory medication will be necessary during the first months. Calcium pyrophosphate deposition arthropathy, the second common crystal-induced arthritis, is diagnosed by synovial fluid analysis or for chondrocalcinosis. Treatment for attacks resembles therapy of acute gout; causal therapy is possible in case of secondary forms (e.g. hypothyroidism. hyperparathyroidism, hemochromatosis).

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Ann Rheum Dis. 2007 May 15; [Epub ahead of print]
Concordance of the management of chronic gout in a UK primary care population with the EULAR gout recommendations.
Roddy E, Zhang W, Doherty M.
Academic Rheumatology, University of Nottingham, United Kingdom.

OBJECTIVES: /B> - To assess concordance of the management of chronic gout in UK primary care with the EULAR gout recommendations. METHODS: /B> - A postal questionnaire was sent to all adults aged over 30 years registered with two general practices. Possible cases of gout attended for clinical assessment where the diagnosis was verified clinically. Aspects of chronic gout management including provision of life-style modification advice, use of urate-lowering therapies (ULT) including dose titration to serum urate (SUA) level, prophylaxis against acute attacks and diuretic cessation were assessed in accordance with the EULAR recommendations. RESULTS: /B> - Of 4249 completed questionnaires returned (32%), 488 reported gout or acute attacks and were invited for clinical assessment. From 359 attendees, 164 clinically confirmed cases of gout were identified. Advice regarding alcohol consumption was recalled by 59 (41%), weight loss by 36 (25%) and diet by 42 (29%). Allopurinol was
the only ULT used and was taken by 44 (30%); 31 (70%) were taking 300mg daily. Mean SUA was lower in allopurinol-users than non-users (318 vs 434 micromol/l) and was less frequently > 360 micromol/l in allopurinol-users (23% vs 75%). Eight subjects had recently commenced allopurinol - 2 were taking prophylactic colchicine/NSAID. Sixteen (64%) of 25 subjects with diuretic-induced gout were still taking a diuretic. CONCLUSION: /B> - Treatment of chronic gout is often suboptimal and poorly concordant with EULAR recommendations. Life-style advice is infrequently offered. Allopurinol is restricted to a minority. Persistent hyperuricaemia was often seen in allopurinol non-users but also in allopurinol-users suggesting that higher doses than 300mg of allopurinol are often necessary.

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Intern Med J. 2007 Apr;37(4):258-66.
Emerging therapies in the long-term management of hyperuricaemia and gout.
Stamp LK, O'Donnell JL, Chapman PT.
Department of Medicine, Christchurch School of Medicine and Health Sciences, University of Otago, Christchurch, New Zealand. lisa.stamp@cdhb.govt.nz

Gout is a common chronic arthritis that can lead to significant disability. Gout is one of the few rheumatological conditions that can be diagnosed with certainty, has a known cause and can be cured with appropriate therapy. Hypouricaemic agents reduce uric acid concentrations through inhibiting uric acid production (allopurinol) or enhancing uric acid excretion (probenecid, benzbromarone). Allopurinol is the most commonly used hypouricaemic agent but at recommended doses often fails to reduce adequately uric acid concentrations and prevent acute attacks of gout. The use of probenecid is limited by lack of efficacy in renal impairment. In the last few years, new agents in the management of hyperuricaemia and gout have become available. Febuxostat, a new xanthine oxidase inhibitor, is an effective hypouricaemic agent although further data are required for patients with renal impairment and other significant medical conditions. Rasburicase, a recombinant uricase (which catalyses the conversion of uric acid to the more readily excreted allantoin) is available for prevention of tumour lysis syndrome. However, its repeated use, as would be required in chronic gout, is limited by antigenicity. A less antigenic PEGylated uricase can rapidly reduce serum uric acid concentrations and promote resorption of tophi. However, further information with regard to the long-term risks and benefits of these agents is required. These agents may ultimately be used in the short term to rapidly deplete urate stores (induction therapy) followed by long-term therapy with an alternative hypouricaemic agent to prevent subsequent accumulation of uric acid (maintenance therapy).

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Am J Med. 2007 Mar;120(3):221-4.
Updates in the management of gout.
Keith MP, Gilliland WR.
Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA. mpkeith@bethesda.med.navy.mil

The majority of patients with gout are cared for by primary care physicians. Although both the physician and patient may easily recognize the acute arthritis of gout, errors in selecting the most appropriate medication and proper dose are common. The clinical stages of gout include asymptomatic hyperuricemia, intermittent gouty arthritis, and chronic tophaceous gout. Treatment of gout is usually considered after the first attack of arthritis, typically podagra. The aims of treatment are to alleviate the pain and inflammation associated with acute attacks, prevent future attacks, and decrease uric acid levels. Confusion frequently arises because certain medications such as colchicine may have dual purposes: to treat an acute attack and to suppress future attacks. The purpose of this management update is to provide practical advice about prescribing the proper medication considering both treatment goals and patient comorbidities.

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Arthritis Rheum. 2007 Mar;56(3):1021-8.
Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout.
Sundy JS, Ganson NJ, Kelly SJ, Scarlett EL, Rehrig CD, Huang W, Hershfield MS.
Duke University Medical Center, Durham, North Carolina 27710, USA.

OBJECTIVE: To evaluate the efficacy, immunogenicity, and tolerability of intravenous (IV) PEGylated recombinant mammalian urate oxidase (PEG-uricase) for the treatment of severe gout. METHODS: Single infusions of PEG-uricase (at doses ranging from 0.5 mg to 12 mg) were administered to 24 patients (6 cohorts of 4 patients each) in a phase I clinical trial. Plasma uricase activity (pUox), the plasma urate concentration (pUAc), and the uric acid-to-creatinine ratio (UAc:Cr) in urine were monitored for 21 days after dosing. Adverse events and the IgG antibody response to PEG-uricase were followed up for 35 days. RESULTS: All patients completed the trial. Maximum pUox was linearly related to the IV dose of PEG-uricase, the area under the curve (AUC) value increased linearly (up to a dose of 8 mg), and the pUox half-life was 6.4-13.8 days. After doses of 4-12 mg, the pUAc fell within 24-72 hours, from a mean +/- SD value of 11.1 +/- 0.6 mg/dl to 1.0 +/- 0.5 mg/dl; the AUC value for the pUAc was equivalent to maintaining the pUAc at 1.2-4.7 mg/dl for 21 days postinfusion. The UAc:Cr ratio in urine fell in parallel with the pUAc. IgG antibodies to PEG-uricase, mostly IgG2 and specific for PEG, developed in 9 patients, who had more rapid enzyme clearance but no allergic reactions. All adverse events were mild to moderate, with gout flares being most common. CONCLUSION: The bioavailability, efficacy, and tolerability of IV PEG-uricase were greater than the bioavailability, efficacy, and tolerability observed in a previous phase I trial of subcutaneous PEG-uricase. Infusing 4-12 mg of PEG-uricase every 2-4 weeks should maintain the pUAc well below the therapeutic target of 6 mg/dl and greatly reduce renal uric acid excretion. This treatment could be effective in depleting expanded tissue urate stores in patients with chronic or tophaceous gout.

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Curr Opin Rheumatol. 2007 Mar;19(2):122-7.
Therapeutic advances in gout.
Pascual E, Sivera F.
Rheumatology Section, Hospital General Universitario de Alicante, Alicante, Spain. pascual_eli@gva.es

PURPOSE OF REVIEW: The purpose of this review is to highlight the recent developments in the management of gout. RECENT FINDINGS: Guidelines for the diagnosis and management of gout from EULAR, quality of care indicators, and outcome measures for clinical trials have been published. The standards of gout diagnosis and management are very low. Allopurinol remains the mainstay for serum uric acid lowering therapy. In an important percentage of patients receiving allopurinol, serum uric acid levels are insufficient to promote crystal dissolution. Febuxostat, a new serum uric acid lowering drug, has shown good results. Information on uricase continues to appear. For treatment of gouty inflammation, etoricoxib (a new cyclooxygenase 2 inhibitor) has been shown to be as effective as indomethacin. Finally, the association of gout with the metabolic syndrome and its comorbidities, and the newly described association of gout with myocardial infarction, bring lifestyle and dietary modifications to the front in the management of gout. SUMMARY: Proper gout management requires changes to the physician's attitude towards the disease; essentially: (1) an unequivocal diagnosis based in urate crystal identification, (2) a clearly settled aim of the treatment: crystal elimination from the joints and elsewhere, and (3) proper use of the available therapeutic alternatives. Promoting a proper lifestyle appears to be especially important.

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Ned Tijdschr Geneeskd. 2007 Feb 24;151(8):458-60. Comment on: Ned Tijdschr Geneeskd. 2007 Feb 24;151(8):472-7.
[Gout and diuretics; still an issue]
[Article in Dutch]
Jacobs JW, Bijlsma JW.
Universitair Medisch Centrum Utrecht, afd. Reumatologie en Klinische Immunologie, F02.127, Postbus 85.500, 3508 GA Utrecht. j.w.g.jacobs@umcutrecht.nl

A recent case-control study on the effect of diuretics on the incidence ofgout included 70 cases, i.e. patients who had experienced their first attack of gout during a period of 8 years and 210 matched controls without gout. Of the 70 new gout cases, 14 had been using diuretics during the 8-year period for at least 3 consecutive months preceding the gouty attack. Regression analyses suggested that diuretics did not independently increase the risk of gout, and that the association between diuretics and gout was completely confounded by cardiovascular indications for diuretic therapy. It may be argued, however, that, taking into account the earlier reported relatively small increases in the incidence of gout at increasing levels of uric acid, the reviewed study lacks the statistical power needed to prove that diuretic therapy is not an independent risk factor for gout. Therefore, the generally accepted guideline still stands that if gout develops during diuretic therapy, this medication should be stopped if possible.

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Clin Rheumatol. 2007 Feb 17; [Epub ahead of print]
Biochemical effectiveness of allopurinol and allopurinol-probenecid in previously benzbromarone-treated gout patients.
Reinders MK, van Roon EN, Houtman PM, Brouwers JR, Jansen TL.
Department of Clinical Pharmacy and Pharmacology, Medical Centre Leeuwarden, Henri Dunantweg 2, 8934 AD, Leeuwarden, The Netherlands.

In 2003, the uricosuric drug benzbromarone was withdrawn from the market. The first alternative drug of choice was the xanthine oxidase inhibitor allopurinol. The purpose was to (1) investigate the efficacy of allopurinol (standard dosage) compared with previous treatment with benzbromarone; and (2) investigate the combination therapy allopurinol-probenecid as an effective alternative treatment compared with previous benzbromarone treatment. A prospective, open study was carried out in a cohort of 51 gout patients who discontinued benzbromarone therapy because of market withdrawal. Patients were given 200-300 mg allopurinol (stage 1). When allopurinol failed to attain the target serum urate (sUr) levels </=0.30 mmol/l, probenecid 1,000 mg/day was added (stage 2). Treatment with benzbromarone monotherapy (range: 100-200 mg/day; mean 138 mg/day) resulted in 92% of patients reaching target levels sUr </= 0.30 mmol/l with a decrease of 61[11]% compared to baseline. In stage 1, 32 patients completed treatment with allopurinol monotherapy (range 200-300 mg/day; mean 256 mg/day), which resulted in 25% of patients attaining sUr target levels. Decrease in sUr levels was 36[11]%, which was significantly less compared to treatment with benzbromarone (p < 0.001). In stage 2, 14 patients received allopurinol-probenecid combination therapy, which resulted in 86% of patients attaining target sUr levels (after failure on allopurinol monotherapy), which was comparable to previous treatment with benzbromarone (p = 0.81). Decrease in sUr levels was 53[9]% (CI 95%: 48-58%), which was a non-significant difference compared to previous treatment with benzbromarone (p = 0.23). Benzbromarone is a very effective antihyperuricemic drug with 91% success in attainment of target sUr levels </=0.30 mmol/l. Allopurinol 200-300 mg/day was shown to be a less potent alternative for most selected patients to attain target sUr levels (13% success). In patients failing on allopurinol monotherapy, the addition of probenecid proves to be an effective treatment strategy for attaining sUr target levels (86% success).

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Drugs Aging. 2007;24(1):21-36.
Management of gout in older adults : barriers to optimal control.
Hoskison KT, Wortmann RL.
Department of Internal Medicine, The University of Oklahoma College of Medicine, Tulsa, Oklahoma, USA.

Gout, a common inflammatory arthritis, can be diagnosed with absolute certainty. Gout results from the body's reaction to urate crystals deposited in tissues, and this pathophysiology is well understood. If used appropriately, available therapies can be entirely effective in not only treating the symptoms of gout, but also in eliminating the excess urate from the body, thereby eradicating the disease. Because of these facts, management of patients with gout should be successful. However, management of gout is particularly challenging in the elderly, even though the principles of management are the same for all age groups. The purpose of this article is to review these principles and discuss them as they pertain to the elderly.The classic gout attack is acute in onset, extremely painful and associated with marked swelling, warmth, erythema and tenderness of a single joint. However, the diagnosis of gout may be challenging in the elderly because atypical presentations are more common in this group.Treatment of acute gout involves the use of NSAIDs, colchicine, corticosteroids or corticotropin (adrenocorticotropic hormone). Unfortunately, co-morbid conditions such as chronic kidney disease, peptic ulcer disease and congestive heart failure may make the use of these agents dangerous or contraindicated. Thus, it is important to try to treat an acute flare of gout at the earliest sign, because the sooner treatment is initiated, the faster the inflammation will resolve.Urate-lowering agents include allopurinol and uricosuric agents. These also must be used judiciously in the elderly. However, if used at the lowest dose that maintains the serum urate level below 5.0-6.0 mg/dL, the excess urate in the body will be eliminated, acute flares will no longer occur and tophi will resolve.Gout is often seen in association with hypertension, excessive alcohol consumption, obesity and hypertriglyceridaemia. These conditions and the medications used to treat them may contribute to the hyperuricaemia. Treating these conditions and using medications that do not promote hyperuricaemia will aid in the management of gout.Despite the challenges that often complicate the management of gout in the elderly, an understanding of the pathophysiology of the disease and both the indications and limitations of the medications used should allow successful treatment.

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Minerva Med. 2006 Dec;97(6):495-509.
Pathogenesis, clinical findings and management of acute and chronic gout.
Corrado A, D'Onofrio F, Santoro N, Melillo N, Cantatore FP.
Unit of Rheumatology, University of Foggia, Hospital Colonello D'Avanzo, Foggia, Italy.

Gout is a chronic metabolic disease caused by a disorder of the purine metabolism leading to hyperuricaemia. It is determined by the deposition of monosodium urate crystals in joints and other tissues which causes an acute inflammatory response and can induce a permanent tissue damage which defines the urate chronic joint disease which is characterised by the appearance of ulceration of the joint cartilage, marginal osteophytosis, geodic and erosive lesions and chronic inflammation of synovial membrane. Gout and hyperuricaemia usually occur after the age of 30 years and more frequently in men. Hyperuricaemia is the result of an increased production of uric acid or its hypoexcretion by the kidneys, or both. In the pathogenesis of gout and hyperuricaemia are involved genetic and environmental factors; further, different pathologic condition such as glycogenosis, renal insufficiency, use of some drugs, are associated with gout. Treatment of acute gout includes colchicine, nonsteroidal anti-inflammatory drugs and glucocorticoids, whereas in the intercritical periods colchicine is effective for preventive purposes. Urate-lowering therapy with xanthine-oxidase inhibitors or uricosuric agents is indicate only in patients with more than two gout crisis per year, tophaceous deposits, uric acid nephrolithiasis, and interstitial renal disease, as asymptomatic hyperuricaemia does not requires any treatment but can be controlled with preventive dietetic measures and changes in lifestyle.

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Int J Environ Res Public Health. 2006 Dec;3(4):338-42.
Health benefits of geologic materials and geologic processes.
Finkelman RB.
U.S. Geological Survey, Mail Stop 956, Reston, VA 20192 USA and Ulli G. Limpitlaw, Earth Sciences, University of Northern Colorado, Greeley, CO 80639, USA. E-mail: rbf@usgs.gov.

The reemerging field of Medical Geology is concerned with the impacts of geologic materials and geologic processes on animal and human health. Most medical geology research has been focused on health problems caused by excess or deficiency of trace elements, exposure to ambient dust, and on other geologically related health problems or health problems for which geoscience tools, techniques, or databases could be applied. Little, if any, attention has been focused on the beneficial health effects of rocks, minerals, and geologic processes. These beneficial effects may have been recognized as long as two million years ago and include emotional, mental, and physical health benefits. Some of the earliest known medicines were derived from rocks and minerals. For thousands of years various clays have been used as an antidote for poisons. "Terra sigillata," still in use today, may have been the first patented medicine. Many trace elements, rocks, and minerals are used today in a wide variety of pharmaceuticals and health care products. There is also a segment of society that believes in the curative and preventative properties of crystals (talismans and amulets). Metals and trace elements are being used in some of today's most sophisticated medical applications. Other recent examples of beneficial effects of geologic materials and processes include epidemiological studies in Japan that have identified a wide range of health problems (such as muscle and joint pain, hemorrhoids, burns, gout, etc.) that may be treated by one or more of nine chemically distinct types of hot springs, and a study in China indicating that residential coal combustion may be mobilizing sufficient iodine to prevent iodine deficiency disease.

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Ann Pharmacother. 2006 Dec;40(12):2187-94. Epub 2006 Nov 28.
Febuxostat: a selective xanthine oxidase inhibitor for the treatment of hyperuricemia and gout.
Bruce SP.
Albany College of Pharmacy, The Center for Rheumatology, 106 New Scotland Ave. Albany, NY 12203-3492, USA. bruces@acp.edu

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trial data, safety profile, precautions, and place in therapy of febuxostat, a novel nonpurine xanthine oxidase inhibitor in development for the treatment of hyperuricemia and gout. DATA SOURCES: Available studies and abstracts were identified through MEDLINE (1990-November 2006), Science Citation Index, International Pharmaceutical Abstracts, Cochrane Databases, and the American College of Rheumatology and European League Against Rheumatism Web sites. Key search terms were febuxostat, TMX-67, TEI-6720, hyperuricemia, and gout. STUDY SELECTION AND DATA EXTRACTION: All available studies describing the pharmacology of febuxostat were included. Human studies formed the basis for discussion of clinical parameters, including pharmacokinetics, pharmacodynamics, efficacy, and safety of febuxostat. DATA SYNTHESIS: Febuxostat significantly reduces uric acid levels within 2 weeks after initiation of therapy and up to 48% by the end of 104 weeks of therapy. Approximately 60% of patients achieved the primary goal of serum uric acid less than 6 mg/dL during the last 3 months following once-daily administration of febuxostat 80 mg or 120 mg for at least 52 weeks. The most common adverse reactions to febuxostat were abnormal results from liver function tests, diarrhea, headache, arthralgias, and musculoskeletal symptoms. Due to its potency, patients are at an increased risk of experiencing gout flares for at least the first year of therapy. Up to 70% of patients in clinical trials experienced gout flares despite concomitant prophylactic treatment with colchicine or naproxen. Additional clinical trial evidence supports the efficacy and safety of febuxostat in the treatment of hyperuricemia and gout. CONCLUSIONS: Febuxostat is a promising alternative to allopurinol for the treatment of gout and hyperuricemia. The optimal length of prophylactic therapy, clinical significance of abnormal liver function tests results during therapy, and safety in patients with moderate or severe renal insufficiency warrant further investigation.

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Bull Hosp Jt Dis. 2006;64(1-2):82-6.
Gout in 2006—the perfect storm.
Terkeltaub R.

Mechanistic and therapeutic advances in gout have been moving swiftly in the past decade. Clinically, the disease is changing in character. This review discusses several of the pertinent recent developments in understanding gout and in novel therapeutics for the disease. Subjects addressed include the role of URAT1-mediated renal proximal tubule epithelial cell urate anion reabsorption in hyperuricemia. We discuss the therapeutic limitations of allopurinol and uricosurics and the potential applications of novel xanthine oxidase inhibitors and of recombinant uricase preparations. Last, we summarize understanding of the central role of the early induced innate immune response in gouty inflammation, which has suggested the potential value of new strategies for treating gouty inflammation by targeting caspase-1 or IL-1beta.

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Clin Dermatol. 2006 Nov-Dec;24(6):498-508.
Metabolic diseases: gout.
Falasca GF.
Division of Rheumatology, Cooper University Hospital, Robert Wood Johnson Medical School at Camden, University of Medicine and Dentistry of New Jersey, Camden, NJ 08103, USA. falasca-gerald@cooperhealth.edu

Gout is a disease of antiquity but is increasing once again in prevalence despite availability of reasonably effective treatments. This may be related to a combination of factors, including diet, obesity, and diuretic use. Allergic reactions, noncompliance, drug interactions, and sometimes inefficacy all limit the effective use of current hypouricemic agents. There are new treatments for gout on the horizon, including febuxostat, a nonpurine inhibitor of xanthine oxidase with a potentially better combination of efficacy and side effects than allopurinol. Diagnostic progress is being made in that ultrasound may offer a noninvasive means of diagnosing tophaceous deposits in and around joints. The increasing prevalence of gout means that dermatologists will see more cutaneous manifestations of gout, including tophi, draining sinus tracts, panniculitis, and dystrophic calcifications.

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Explore (NY). 2006 Nov-Dec;2(6):515-9.
Disease of distinction.
Schwartz SA.
The Rhine Research Center, Virginia Beach, Virginia 23451, USA. saschwartz@eartlink.net

Gout is one of the rare diseases that defines its sufferers by class and culture. It is also one of the first chronic diseases to be clinically described. The Egyptians had identified gout as a distinct disorder by 2640 bce. This paper traces the history of gout from its earliest recorded period down to modern times, with a particular emphasis on the cultural, political, geopolitical, and social aspects. Included is a discussion of its role in the American Revolution. Today, gout is a well-understood clinically managed arthritic disease that excites little comment. This is an entirely modern perspective. For most of human history, gout was a disease of distinction that dominated much of medicine, playing the same role in Rome's third century bce aristocracy it would later play in the aristocracies of 17th and 18th century France and England, when each of these countries dominated the world. Because it was considered a disease of lifestyle until modern times, when genetics began to be understood, gout was associated with rich, high status Caucasian men and their excessive consumption of drink and rich foods. It was virtually unknown in Asia, until Western dietary practices became widespread there. From earliest history, gout has been linked with high IQ and sexual promiscuity, which made it grist for artists and writers, and their social commentary up to the time of Dickens; this is discussed, with examples. Because of its association with the rich, gout also developed a powerful moralistic aspect, particularly during the Christian era when the concept of sin was a cultural fundamental. The loose living and indulgence of the rich and the gout it produced made the disease a parable of Christian ethics. The Italian poet Francesco Petrarch (1304-1374) was one of the first to establish this nuance, and it influenced how gout was seen for centuries. Part of what gave gout its special character was that while it tortured, it rarely killed. Indeed, when death was a frequent visitor to families, it was thought a painful but welcomed prophylactic against diseases that did kill. Even in modern times, gout still favors the rich and powerful. American research conducted in the 1960s found that corporate executives, just like their English gentry, or Roman senatorial predecessors, had higher urate concentrations than their blue-collar employees.

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Cochrane Database Syst Rev. 2006 Oct 18;(4):CD006190.
Colchicine for acute gout.
Schlesinger N, Schumacher R, Catton M, Maxwell L.
UMDNJ/Robert Wood Medical School, Department of Medicine, MEB 474, PO Box 19, New Brunswick, New Jersey 08903-0019, USA. schlesna@UMDNJ.EDU

BACKGROUND: Gout is one of the most common rheumatic diseases worldwide. Colchicine is regarded as beneficial in the treatment of acute gout, but has a high frequency of gastrointestinal adverse events. OBJECTIVES: To evaluate the efficacy and safety of colchicine for relief of the signs and symptoms of acute gouty arthritis, compared to placebo and other treatment interventions. SEARCH STRATEGY: We searched the following electronic databases to March 2006: Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, 2006), MEDLINE (from 1966), EMBASE (from 1980), CINAHL (from 1982), AMED (from 1985), Web of Science (from 1945) and Current Controlled Trials. SELECTION CRITERIA: Published randomised controlled trials (RCTs) and controlled clinical trials evaluating symptom relief and adverse outcomes of colchicine therapy in acute gout were considered for this review. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened search results for inclusion, collected the data in a standardized form and assessed the methodological quality of the trial using validated criteria. Results for continuous outcome measures were expressed as weighted mean differences. Dichotomous outcome measures were pooled using relative risk. The number needed to treat was calculated for significant outcomes. MAIN RESULTS: One RCT (N=43) comparing colchicine to placebo for the treatment of acute gout was included in this review. The results favour the use of colchicine over placebo with an absolute reduction of 34% for pain and a 30% reduction in clinical symptoms such as tenderness on palpation, swelling, redness, and pain. The number needed to treat (NNT) with colchicine versus placebo to reduce pain was 3 and the NNT to reduce clinical symptoms was 2. All participants treated with colchicine experienced gastrointestinal side effects (diarrhea and/or vomiting) and the number needed to harm (NNH) with colchicine versus placebo was 1. No studies comparing colchicine to NSAIDs or other treatments such as corticosteroids or ACTH were identified. AUTHORS' CONCLUSIONS: Colchicine is an effective treatment for the reduction of pain and clinical symptoms in patients experiencing acute attacks of gout, although in the regimen studied its low benefit to toxicity ratio limits its usefulness. It should be used as a second line therapy when NSAIDs or corticosteroids are contraindicated or ineffective. More evidence is needed to compare the efficacy of colchicine to that of NSAIDs or corticosteroids, the current first line therapy for acute gout.
 

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