Publications by authors named "George Nuki"

31 Publications

Cardiovascular safety of febuxostat - Authors' reply.

Lancet 2021 09;398(10304):955-956

MEMO Research, Division of Molecular and Clinical Medicine, University of Dundee, Dundee DD1 9SY, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(21)01383-0DOI Listing
September 2021

Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial.

Lancet 2020 11 9;396(10264):1745-1757. Epub 2020 Nov 9.

MEMO Research, Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK. Electronic address:

Background: Febuxostat and allopurinol are urate-lowering therapies used to treat patients with gout. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency recommended a post-licensing study assessing the cardiovascular safety of febuxostat compared with allopurinol.

Methods: We did a prospective, randomised, open-label, blinded-endpoint, non-inferiority trial of febuxostat versus allopurinol in patients with gout in the UK, Denmark, and Sweden. Eligible patients were 60 years or older, already receiving allopurinol, and had at least one additional cardiovascular risk factor. Those who had myocardial infarction or stroke in the previous 6 months or who had severe congestive heart failure or severe renal impairment were excluded. After a lead-in phase in which allopurinol dose was optimised towards achieving a serum urate concentration of less than 0·357 mmol/L (<6 mg/dL), patients were randomly assigned (1:1, with stratification according to previous cardiovascular events) to continue allopurinol (at the optimised dose) or start febuxostat at 80 mg/day, increasing to 120 mg/day if necessary to achieve the target serum urate concentration. The primary outcome was a composite of hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death. The hazard ratio (HR) for febuxostat versus allopurinol in a Cox proportional hazards model (adjusted for the stratification variable and country) was assessed for non-inferiority (HR limit 1·3) in an on-treatment analysis. This study is registered with the EU Clinical Trials Register (EudraCT 2011-001883-23) and ISRCTN (ISRCTN72443728) and is now closed.

Findings: From Dec 20, 2011, to Jan 26, 2018, 6128 patients (mean age 71·0 years [SD 6·4], 5225 [85·3%] men, 903 [14·7%] women, 2046 [33·4%] with previous cardiovascular disease) were enrolled and randomly allocated to receive allopurinol (n=3065) or febuxostat (n=3063). By the study end date (Dec 31, 2019), 189 (6·2%) patients in the febuxostat group and 169 (5·5%) in the allopurinol group withdrew from all follow-up. Median follow-up time was 1467 days (IQR 1029-2052) and median on-treatment follow-up was 1324 days (IQR 870-1919). For incidence of the primary endpoint, on-treatment, febuxostat (172 patients [1·72 events per 100 patient-years]) was non-inferior to allopurinol (241 patients [2·05 events per 100 patient-years]; adjusted HR 0·85 [95% CI 0·70-1·03], p<0·0001). In the febuxostat group, 222 (7·2%) of 3063 patients died and 1720 (57·3%) of 3001 in the safety analysis set had at least one serious adverse event (with 23 events in 19 [0·6%] patients related to treatment). In the allopurinol group, 263 (8·6%) of 3065 patients died and 1812 (59·4%) of 3050 had one or more serious adverse events (with five events in five [0·2%] patients related to treatment). Randomised therapy was discontinued in 973 (32·4%) patients in the febuxostat group and 503 (16·5%) patients in the allopurinol group.

Interpretation: Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol.

Funding: Menarini, Ipsen, and Teijin Pharma Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(20)32234-0DOI Listing
November 2020

Changing paradigms in the management of gout.

J R Coll Physicians Edinb 2020 Jun;50(2):124-132

Western General Hospital, Edinburgh, EH4 2XU, UK.

The incidence and prevalence of gout have increased, as have comorbid obesity, diabetes mellitus, hypertension, chronic kidney and cardiovascular disease. Gout is now the commonest type of inflammatory arthritis despite availability of safe, effective and potentially 'curative' urate-lowering drugs. Modern imaging studies show that gout is a chronic inflammatory crystal deposition disorder even at the first acute attack and they illuminate the need to eliminate urate crystals by continuing reduction of the serum urate below its solubility threshold. Clinical outcomes, adherence to therapy and quality of gout care in primary care and hospital practice can be greatly improved by better use of allopurinol and flare prophylaxis, greater patient engagement, education and follow-up, and by nurse-led models of care that employ a 'treat-to-target' principle (SUA< 360 or 300µmol/l). Advances in understanding the physiology and genetic control of urate transport in the kidney and gut have led to novel, more selective uricosuric drugs, and basic research on mediators of urate crystal-induced inflammation has pointed to alternative therapeutic targets for treating and preventing gout flares. Current guidelines for the management of gout and indications for the use of some more recently introduced drugs; febuxostat, lesinurad, pegloticase and interleukin-1 antagonists are also briefly reviewed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4997/JRCPE.2020.209DOI Listing
June 2020

Prevalence and sociodemographic determinants of dyspepsia in the general population of Rwanda.

BMJ Open Gastroenterol 2020 05;7(1)

Calvary Mater Newcastle, Waratah, New South Wales, Australia

Introduction: Dyspepsia accounts for a significant burden of worldwide disease, but there is a relative paucity of data from the sub-Saharan African setting. We undertook to describe the burden, risk factors and severity of dyspepsia across Rwanda.

Methods: We performed a population-based clustered cross-sectional survey between November 2015 and January 2016, nationwide in Rwanda, using the Short Form Leeds Dyspepsia Questionnaire to describe the presence and severity of dyspepsia, and the Short Form Nepean Dyspepsia Index to describe the concomitant quality of life effects. Univariate and multivariate logistic regression models were constructed to correlate measured sociodemographic factors with dyspepsia.

Results: The prevalence of clinically significant dyspepsia in the general Rwandan population was 14.2% (283/2000). The univariate factors that significantly predicted severity were gender, profession, socioeconomic status, and non-steroidal anti-inflammatory drug, aspirin and alcohol use, with gender, current smoking, aspirin use both in the past and currently, and alcohol use in the past remaining significant on multivariate modelling. Dyspeptics had a significantly lower gastrointestinal-related quality of life, though the sociodemographic factors measured did not modify the observed quality of life.

Conclusion: Dyspepsia is prevalent in the Rwandan setting and is associated with a significant burden on quality of life. More work is required to determine the pathological entities involved, and the optimal approach to mitigating this burden.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjgast-2020-000387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222881PMC
May 2020

Gout, Hyperuricaemia and Crystal-Associated Disease Network (G-CAN) consensus statement regarding labels and definitions of disease states of gout.

Ann Rheum Dis 2019 11 9;78(11):1592-1600. Epub 2019 Sep 9.

Department of Rheumatology, Hôpital Lariboisière, Paris, France.

Objective: There is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease states of gout.

Methods: A content analysis of gout-related articles from rheumatology and general internal medicine journals published over a 5-year period identified potential disease states and the labels commonly assigned to them. Based on these findings, experts in gout were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach agreement on disease state labels and definitions.

Results: The content analysis identified 13 unique disease states and a total of 63 unique labels. The Delphi exercise (n=76 respondents) and face-to-face meeting (n=35 attendees) established consensus agreement for eight disease state labels and definitions. The agreed labels were as follows: 'asymptomatic hyperuricaemia', 'asymptomatic monosodium urate crystal deposition', 'asymptomatic hyperuricaemia with monosodium urate crystal deposition', 'gout', 'tophaceous gout', 'erosive gout', 'first gout flare' and 'recurrent gout flares'. There was consensus agreement that the label 'gout' should be restricted to current or prior clinically evident disease caused by monosodium urate crystal deposition (gout flare, chronic gouty arthritis or subcutaneous tophus).

Conclusion: Consensus agreement has been established for the labels and definitions of eight gout disease states, including 'gout' itself. The Gout, Hyperuricaemia and Crystal-Associated Disease Network recommends the use of these labels when describing disease states of gout in research and clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2019-215933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288724PMC
November 2019

2018 updated European League Against Rheumatism evidence-based recommendations for the diagnosis of gout.

Ann Rheum Dis 2020 01 5;79(1):31-38. Epub 2019 Jun 5.

Rheumatology, Assistance Publique - Hopitaux de Paris, Paris, France.

Although gout is the most common inflammatory arthritis, it is still frequently misdiagnosed. New data on imaging and clinical diagnosis have become available since the first EULAR recommendations for the diagnosis of gout in 2006. This prompted a systematic review and update of the 2006 recommendations. A systematic review of the literature concerning all aspects of gout diagnosis was performed. Recommendations were formulated using a Delphi consensus approach. Eight key recommendations were generated. A search for crystals in synovial fluid or tophus aspirates is recommended in every person with suspected gout, because demonstration of monosodium urate (MSU) crystals allows a definite diagnosis of gout. There was consensus that a number of suggestive clinical features support a clinical diagnosis of gout. These are monoarticular involvement of a foot or ankle joint (especially the first metatarsophalangeal joint); previous episodes of similar acute arthritis; rapid onset of severe pain and swelling; erythema; male gender and associated cardiovascular diseases and hyperuricaemia. When crystal identification is not possible, it is recommended that any atypical presentation should be investigated by imaging, in particular with ultrasound to seek features suggestive of MSU crystal deposition (double contour sign and tophi). There was consensus that a diagnosis of gout should not be based on the presence of hyperuricaemia alone. There was also a strong recommendation that all people with gout should be systematically assessed for presence of associated comorbidities and risk factors for cardiovascular disease, as well as for risk factors for chronic hyperuricaemia. Eight updated, evidence-based, expert consensus recommendations for the diagnosis of gout are proposed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2019-215315DOI Listing
January 2020

Spontaneous dog osteoarthritis - a One Medicine vision.

Nat Rev Rheumatol 2019 05;15(5):273-287

Skeletal Biology Group, Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, UK.

Osteoarthritis (OA) is a global disease that, despite extensive research, has limited treatment options. Pet dogs share both an environment and lifestyle attributes with their owners, and a growing awareness is developing in the public and among researchers that One Medicine, the mutual co-study of animals and humans, could be beneficial for both humans and dogs. To that end, this Review highlights research opportunities afforded by studying dogs with spontaneous OA, with a view to sharing this active area of veterinary research with new audiences. Similarities and differences between dog and human OA are examined, and the proposition is made that suitably aligned studies of spontaneous OA in dogs and humans, in particular hip and knee OA, could highlight new avenues of discovery. Developing cross-species collaborations will provide a wealth of research material and knowledge that is relevant to human OA and that cannot currently be obtained from rodent models or experimentally induced dog models of OA. Ultimately, this Review aims to raise awareness of spontaneous dog OA and to stimulate discussion regarding its exploration under the One Medicine initiative to improve the health and well-being of both species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41584-019-0202-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7097182PMC
May 2019

Gout, Hyperuricemia, and Crystal-Associated Disease Network Consensus Statement Regarding Labels and Definitions for Disease Elements in Gout.

Arthritis Care Res (Hoboken) 2019 03;71(3):427-434

University of Queensland School of Medicine and Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.

Objective: The language currently used to describe gout lacks standardization. The aim of this project was to develop a consensus statement on the labels and definitions used to describe the basic disease elements of gout.

Methods: Experts in gout (n = 130) were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach consensus on the labeling and definitions for the basic disease elements of gout. Disease elements and labels in current use were derived from a content analysis of the contemporary medical literature, and the results of this analysis were used for item selection in the Delphi exercise and face-to-face consensus meeting.

Results: There were 51 respondents to the Delphi exercise and 30 attendees at the face-to-face meeting. Consensus agreement (≥80%) was achieved for the labels of 8 disease elements through the Delphi exercise; the remaining 3 labels reached consensus agreement through the face-to-face consensus meeting. The agreed labels were monosodium urate crystals, urate, hyperuric(a)emia, tophus, subcutaneous tophus, gout flare, intercritical gout, chronic gouty arthritis, imaging evidence of monosodium urate crystal deposition, gouty bone erosion, and podagra. Participants at the face-to-face meeting achieved consensus agreement for the definitions of all 11 elements and a recommendation that the label "chronic gout" should not be used.

Conclusion: Consensus agreement was achieved for the labels and definitions of 11 elements representing the fundamental components of gout etiology, pathophysiology, and clinical presentation. The Gout, Hyperuricemia, and Crystal-Associated Disease Network recommends the use of these labels when describing the basic disease elements of gout.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/acr.23607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252290PMC
March 2019

Improving management of gout in primary care: a new UK management guideline.

Br J Gen Pract 2017 06;67(659):284-285

Research Institute for Primary Care and Health Sciences, Keele University, Keele, and Haywood Academic Rheumatology Centre, Staffordshire and Stoke-on-Trent Partnership Trust, Stoke-on-Trent.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3399/bjgp17X691313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442952PMC
June 2017

Current management of gout: practical messages from 2016 EULAR guidelines.

Pol Arch Intern Med 2017 04 21;127(4):267-277. Epub 2017 Apr 21.

The European League Against Rheumatism published updated recommendations for the management of gout in 2016, comprising 3 overarching principles and 11 key recommendations for clinical practice. Patient education about the pathophysiology of gout and its comorbidities, as well as the existence of effective treatments are important, and understanding the principles of managing acute attacks and eliminating urate crystals by lifelong lowering of the serum urate (SU) below a target level are essential. Advice about lifestyle, diet, weight, and other risk factors, as well as the need to screen for, and manage, comorbidities is emphasized. For the treatment of flares, colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), and oral or intraarticular steroids, or a combination thereof, are recommended. In patients with frequent flares and contraindications to colchicine, NSAIDs, and corticosteroids, an interleukin-1 blocker should be considered. Urate-lowering therapy (ULT) should be discussed from the first presentation of the disease, and SU levels should be maintained at less than 6 mg/dl (360 µmol/l), or less than 5 mg/dl (300 µmol/l) in patients with severe gout. Allopurinol is recommended as first-line ULT with dose adjustment according to renal function. If the SU target cannot be achieved with allopurinol, then febuxostat, a uricosuric, or combining a xanthine oxidase inhibitor with a uricosuric should be considered. All ULTs should be started at low dose and titrated upwards until the SU target is achieved. Unless contraindicated, flare prophylaxis with low-dose colchicine or with NSAIDs at low dosage is recommended during the first 6 months of ULT. In patients with refractory gout, pegloticase can be considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.20452/pamw.4001DOI Listing
April 2017

2015 Gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.

Ann Rheum Dis 2015 Oct;74(10):1789-98

University of Otago, Wellington, New Zealand.

Objective: Existing criteria for the classification of gout have suboptimal sensitivity and/or specificity, and were developed at a time when advanced imaging was not available. The current effort was undertaken to develop new classification criteria for gout.

Methods: An international group of investigators, supported by the American College of Rheumatology and the European League Against Rheumatism, conducted a systematic review of the literature on advanced imaging of gout, a diagnostic study in which the presence of monosodium urate monohydrate (MSU) crystals in synovial fluid or tophus was the gold standard, a ranking exercise of paper patient cases, and a multi-criterion decision analysis exercise. These data formed the basis for developing the classification criteria, which were tested in an independent data set.

Results: The entry criterion for the new classification criteria requires the occurrence of at least one episode of peripheral joint or bursal swelling, pain, or tenderness. The presence of MSU crystals in a symptomatic joint/bursa (ie, synovial fluid) or in a tophus is a sufficient criterion for classification of the subject as having gout, and does not require further scoring. The domains of the new classification criteria include clinical (pattern of joint/bursa involvement, characteristics and time course of symptomatic episodes), laboratory (serum urate, MSU-negative synovial fluid aspirate), and imaging (double-contour sign on ultrasound or urate on dual-energy CT, radiographic gout-related erosion). The sensitivity and specificity of the criteria are high (92% and 89%, respectively).

Conclusions: The new classification criteria, developed using a data-driven and decision-analytic approach, have excellent performance characteristics and incorporate current state-of-the-art evidence regarding gout.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2015-208237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602275PMC
October 2015

2015 Gout Classification Criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.

Arthritis Rheumatol 2015 Oct;67(10):2557-68

University of Otago, Wellington, New Zealand.

Objective: Existing criteria for the classification of gout have suboptimal sensitivity and/or specificity, and were developed at a time when advanced imaging was not available. The current effort was undertaken to develop new classification criteria for gout.

Methods: An international group of investigators, supported by the American College of Rheumatology and the European League Against Rheumatism, conducted a systematic review of the literature on advanced imaging of gout, a diagnostic study in which the presence of monosodium urate monohydrate (MSU) crystals in synovial fluid or tophus was the gold standard, a ranking exercise of paper patient cases, and a multicriterion decision analysis exercise. These data formed the basis for developing the classification criteria, which were tested in an independent data set.

Results: The entry criterion for the new classification criteria requires the occurrence of at least 1 episode of peripheral joint or bursal swelling, pain, or tenderness. The presence of MSU crystals in a symptomatic joint/bursa (i.e., synovial fluid) or in a tophus is a sufficient criterion for classification of the subject as having gout, and does not require further scoring. The domains of the new classification criteria include clinical (pattern of joint/bursa involvement, characteristics and time course of symptomatic episodes), laboratory (serum urate, MSU-negative synovial fluid aspirate), and imaging (double-contour sign on ultrasound or urate on dual-energy computed tomography, radiographic gout-related erosion). The sensitivity and specificity of the criteria are high (92% and 89%, respectively).

Conclusion: The new classification criteria, developed using a data-driven and decision analytic approach, have excellent performance characteristics and incorporate current state-of-the-art evidence regarding gout.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.39254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566153PMC
October 2015

Improving cardiovascular and renal outcomes in gout: what should we target?

Nat Rev Rheumatol 2014 Nov 19;10(11):654-61. Epub 2014 Aug 19.

Hôpital Lariboisière, Fédération de Rhumatologie, Centre Viggo Petersen 2, rue Ambroise Parè 75475 Cedex 10, Paris, France.

Epidemiological and experimental studies have shown that hyperuricaemia and gout are intricately linked with hypertension, metabolic syndrome, chronic kidney disease and cardiovascular disease. A number of studies suggest that hyperuricaemia and gout are independent risk factors for the development of these conditions and that these conditions account, in part, for the increased mortality rate of patients with gout. In this Review, we first discuss the links between hyperuricaemia, gout and these comorbidities, and present the mechanisms by which uric acid production and gout might favour the development of cardiovascular and renal diseases. We then emphasize the potential benefit of urate-lowering therapies on cardiovascular and renal outcomes in patients with hyperuricaemia. The mechanisms that link elevated serum uric acid levels and gout with these comorbidities seem to be multifactorial, implicating low-grade systemic inflammation and xanthine oxidase (XO) activity, as well as the deleterious effects of hyperuricaemia itself. Patients with asymptomatic hyperuricaemia should be treated by nonpharmacological means to lower their SUA levels. In patients with gout, long-term pharmacological inhibition of XO is a treatment strategy that might also reduce cardiovascular and renal comorbidities, because of its dual effect of lowering SUA levels as well as reducing free-radical production during uric acid formation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nrrheum.2014.124DOI Listing
November 2014

Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia.

BMJ Open 2014 Jul 10;4(7):e005354. Epub 2014 Jul 10.

Medicines Monitoring Unit (MEMO), Ninewells Hospital, University of Dundee, Dundee, UK.

Introduction: Gout affects 2.5% of the UK's adult population and is now the most common type of inflammatory arthritis. The long-term management of gout requires reduction of serum urate levels and this is most often achieved with use of xanthine oxidase inhibitors, such as allopurinol. Febuxostat is the first new xanthine oxidase inhibitor since allopurinol and was licensed for use in 2008. The European Medicines Agency requested a postlicensing cardiovascular safety study of febuxostat versus allopurinol, which has been named the Febuxostat versus Allopurinol Streamlined trial (FAST).

Methods And Analysis: FAST is a cardiovascular safety study using the prospective, randomised, open, blinded endpoint design. FAST is recruiting in the UK and Denmark. Recruited patients are aged over 60 years, prescribed allopurinol for symptomatic hyperuricaemia and have at least one additional cardiovascular risk factor. After an allopurinol lead-in phase where the dose of allopurinol is optimised to achieve European League against Rheumatism (EULAR) urate targets (serum urate <357 µmol/L), patients are randomised to either continue optimal dose allopurinol or to use febuxostat. Patients are followed-up for an average of 3 years. The primary endpoint is first occurrence of the Anti-Platelet Trialists' Collaboration (APTC) cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary endpoints are all cause mortality and hospitalisations for heart failure, unstable, new or worsening angina, coronary or cerebral revascularisation, transient ischaemic attack, non-fatal cardiac arrest, venous and peripheral arterial vascular thrombotic event and arrhythmia with no evidence of ischaemia. The primary analysis is a non-inferiority analysis with a non-inferiority upper limit for the HR for the primary outcome of 1.3.

Ethics And Dissemination: FAST (ISRCTN72443728) has ethical approval in the UK and Denmark, and results will be published in a peer reviewed journal.

Trial Registration Number: FAST is registered in the EU Clinical Trials Register (EUDRACT No: 2011-001883-23) and International Standard Randomised Controlled Trial Number Register (ISRCTN No: ISRCTN72443728).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2014-005354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4120410PMC
July 2014

Up-titration of allopurinol in patients with gout.

Semin Arthritis Rheum 2014 Aug 23;44(1):25-30. Epub 2014 Jan 23.

Medicines Monitoring Unit (MEMO), University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK.

Objectives: European League against Rheumatism (EULAR) gout management guidelines recommend achieving a target urate level <6.0 mg/dL (<357 µmol/L). Allopurinol is the most widely used urate-lowering therapy; however, many gout patients who are prescribed allopurinol do not have urate levels optimally controlled. The objective of this analysis was to review the efficacy and tolerability of allopurinol up-titration in achieving the EULAR target levels.

Method: The Febuxostat versus Allopurinol Streamlined Trial (FAST) is an ongoing multi-centre study comparing the cardiovascular safety of febuxostat and allopurinol (target recruitment: 5706 patients). Recruited patients were already taking allopurinol and the protocol required up-titration of daily allopurinol dose, in 100 mg increments, to achieve the EULAR urate target level prior to randomisation. We reviewed pre-randomisation data from the first 400 recruited and subsequently randomised FAST patients.

Results: Of 400 patients, 144 (36%) had urate levels ≥357 µmol/L at screening and required allopurinol up-titration. Higher urate levels were significantly associated with lower allopurinol dose, male sex, increased BMI, increased alcohol intake and diuretic use. Mean fall in urate levels after a single 100-mg dose increase was 71 µmol/L. The number of up-titrations required ranged from one to five (median = 1) with 65% of patients controlled after one 100-mg up-titration. Overall, 97% of up-titrated patients achieved target urate levels with median final allopurinol dose of 300 mg daily. Side effects and complications of up-titration were minimal.

Conclusion: Overall, 36% of FAST patients were not at target urate levels and required up-titration. Allopurinol up-titration was effective in achieving urate target levels and was generally well tolerated by patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.semarthrit.2014.01.004DOI Listing
August 2014

An appraisal of the 2012 American College of Rheumatology Guidelines for the Management of Gout.

Authors:
George Nuki

Curr Opin Rheumatol 2014 Mar;26(2):152-61

Institute of Genetics and Molecular Medicine, University of Edinburgh.

Purpose Of Review: Appraisal of the 2012 American College of Rheumatology (ACR) Guidelines for the Management of Gout.

Recent Findings: The ACRs first clinical practice guidelines for the management of gout focus on recommendations for nonpharmacologic and pharmacologic approaches to hyperuricaemia and the treatment and prophylaxis of acute gouty arthritis. The RAND/UCLA appropriateness methodology employed assessed risks and benefits of alternative treatments for efficacy, safety and quality but not for cost-effectiveness. Novel recommendations include the use of either allopurinol or febuxostat for first-line urate-lowering drug therapy (ULT), screening for HLA-B*5801 prior to initiation of allopurinol in Asians at relatively high risk for allopurinol hypersensitivity, and the use of pegloticase for patients with severe, symptomatic, tophaceous gout refractory to, or intolerant of, appropriately dosed ULTs. Appraisal and comparison with other guidelines using Guidelines International Network and Appraisal of Guidelines, Research and Evaluation (AGREE II) criteria showed good scores for scope and purpose, stakeholder involvement, rigour of development, clarity of presentation, editorial independence and, overall quality, but not for applicability.

Summary: The ACR guidelines provide comprehensive, up-to-date, good-quality, evidence-based, expert consensus recommendations for the management of gout in clinical practice but score poorly for applicability. To improve the management of gout in the community a summary of key recommendations, criteria for audit and standards of care are now required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/BOR.0000000000000034DOI Listing
March 2014

Cost-effectiveness of febuxostat in chronic gout.

Eur J Health Econ 2014 Jun 30;15(5):453-63. Epub 2013 May 30.

RTI Health Solutions, Sheffield, UK.

Our objective was to evaluate data on the cost-effectiveness of febuxostat compared with standard clinical practice with allopurinol in patients with gout that was presented to the Scottish Medicines Consortium (SMC) in 2010. A Markov health-state model estimated the direct health-related costs and clinical benefits expressed as quality-adjusted life-years (QALYs). Adults with chronic gout and established hyperuricaemia received treatment sequences of daily doses of allopurinol 300 mg alone or allopurinol 300 mg followed by febuxostat 80 mg/120 mg. The proportion of patients achieving the target serum uric acid (sUA) level of less than 6 mg/dl (0.36 mmol/l) was linked to the utility per sUA level to generate an incremental cost-effectiveness ratio (ICER). Second-line therapy with febuxostat 80 mg/120 mg versus with allopurinol alone resulted in an ICER of £3,578 per QALY over a 5-year time horizon. Additional univariate analyses showed that ICER values were robust and ranged from £2,550 to £7,165 per QALY when different parameters (e.g., low- and high-dose allopurinol titrations and variations in treatment-induced flare rates) were varied. Febuxostat reduces sUA below the European League Against Rheumatism target of 0.36 mmol/l (6 mg/dl) in significantly more patients with gout than allopurinol in its most frequently prescribed dose of 300 mg per day. The SMC accepted febuxostat as cost-effective as a suitable second-line option for urate-lowering therapy for the treatment of patients with chronic hyperuricaemia in conditions where urate deposition has already occurred (including a history or presence of tophus and/or gouty arthritis) when treatment with allopurinol was inadequate, not tolerated, or contraindicated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10198-013-0486-zDOI Listing
June 2014

Tophi and frequent gout flares are associated with impairments to quality of life, productivity, and increased healthcare resource use: Results from a cross-sectional survey.

Health Qual Life Outcomes 2012 Sep 22;10:117. Epub 2012 Sep 22.

University of Michigan, MI, USA.

Background: The prevalence of gout is increasing, and most research on the associated burden has focused on serum urate (sUA) levels. The present study quantifies the impact of the presence of tophi and frequency of acute gout attacks on health-related quality of life (HRQOL), productivity, and healthcare resource utilization.

Methods: Patients with self-reported gout (n=620; 338 in US and 282 across France, Germany, and UK) were contacted based on inclusion in the 2010 US and EU National Health and Wellness Surveys (Kantar Health) and the Lightspeed Research ailment panel. Respondents were categorized into mutually-exclusive groups based on number of gout flares experienced in the past 12 months (0/don't recall, 1-2, 3, 4-5, 6+), current presence of tophi (none, 1+, or not sure), and sUA level awareness (yes, no). HRQOL (SF-12v2), healthcare provider visits in the last 6 months, and work productivity and activity impairment (WPAI) were compared across groups.

Results: Most patients were males, mean age of 61 years, who reported experiencing at least one acute gout flare in the past 12 months, and 12.3% (n=76) reported presence of tophi. Among the 27.7% (n=172) of patients who were aware of their sUA levels, higher sUA was associated with more flares and tophi. Decreased HRQOL was associated with more frequent flares and presence of tophi. In multivariable models predicting outcomes based on presence of tophi and number of flares, both flares (≥4) and tophi (≥1) were associated with HRQOL decrements on physical and mental component summary scores and health utilities (all p<0.05), after adjustment for age, gender, and time since diagnosis. Flares were also associated with greater activity impairment.

Conclusions: Impairments associated with gout flares and presence of tophi, across patients in the US and EU, underscore the importance of effective management of this potentially curable condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1477-7525-10-117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499162PMC
September 2012

Gout: why is this curable disease so seldom cured?

Ann Rheum Dis 2012 Nov 3;71(11):1765-70. Epub 2012 Aug 3.

Department of Rheumatology, City Hospital, Nottingham, UK.

Gout is the most common inflammatory arthritis and one in which pathogenesis and risk factors are best understood. One of the treatment objectives in current guidelines is 'cure'. However, audits show that only a minority of patients with gout receive adequate advice and treatment. Suboptimal care and outcomes reflect inappropriately negative perceptions of the disease, both in patients and providers. Historically, gout has been portrayed as a benign and even comical condition that is self-inflicted through overeating and alcohol excess. Doctors often focus on managing acute attacks rather than viewing gout as a chronic progressive crystal deposition disease. Urate-lowering treatment is underprescribed and often underdosed. Appropriate education of patients and doctors, catalysed by recent introduction of new urate-lowering treatments after many years with no drug development in the field, may help to overcome these barriers and improve management of this easily diagnosed and curable form of potentially severe arthritis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2012-201687DOI Listing
November 2012

Colchicine: its mechanism of action and efficacy in crystal-induced inflammation.

Authors:
George Nuki

Curr Rheumatol Rep 2008 Jul;10(3):218-27

University of Edinburgh, Osteoarticular Research Group, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom.

New light has been shed on the mechanisms of action of colchicine in crystal-associated arthropathies. Colchicine, long used to treat gout, arrests microtubule assembly and inhibits many cellular functions. At micromolar concentrations, it suppresses monosodium urate crystal-induced NACHT-LRR-PYD-containing protein-3 (NALP3) inflammasome-driven caspase-1 activation, IL-1beta processing and release, and L-selectin expression on neutrophils. At nanomolar concentrations, colchicine blocks the release of a crystal-derived chemotactic factor from neutrophil lysosomes, blocks neutrophil adhesion to endothelium by modulating the distribution of adhesion molecules on the endothelial cells, and inhibits monosodium urate crystal-induced production of superoxide anions from neutrophils. Cyto-chrome P450 3A4, the multidrug transporter P-glycoprotein, and the drugs that bind these proteins influence its pharmacokinetics and pharmacodynamics. Trial evidence supports its efficacy in acute gout and in preventing gout flares, but it has narrow therapeutic index, and overdosage is associated with gastrointestinal, hepatic, renal, neuromuscular, and cerebral toxicity; bone marrow damage; and high mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11926-008-0036-3DOI Listing
July 2008

British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout.

Rheumatology (Oxford) 2007 Aug 23;46(8):1372-4. Epub 2007 May 23.

Rheumatology Department, Princess Royal Hospital, Brighton and Sussex University Hospitals Trust, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/kem056aDOI Listing
August 2007

A concise history of gout and hyperuricemia and their treatment.

Arthritis Res Ther 2006 12;8 Suppl 1:S1. Epub 2006 Apr 12.

University of Edinburgh Rheumatic Diseases Unit, Scotland, UK.

First identified by the Egyptians in 2640 BC, podagra (acute gout occurring in the first metatarsophalangeal joint) was later recognized by Hippocrates in the fifth century BC, who referred to it as 'the unwalkable disease'. The term is derived from the Latin word gutta (or 'drop'), and referred to the prevailing medieval belief that an excess of one of the four 'humors'--which in equilibrium were thought to maintain health--would, under certain circumstances, 'drop' or flow into a joint, causing pain and inflammation. Throughout history, gout has been associated with rich foods and excessive alcohol consumption. Because it is clearly associated with a lifestyle that, at least in the past, could only be afforded by the affluent, gout has been referred to as the 'disease of kings'. Although there is evidence that colchicine, an alkaloid derived from the autumn crocus (Colchicum autumnale), was used as a powerful purgative in ancient Greece more than 2000 years ago, its first use as a selective and specific treatment for gout is attributed to the Byzantine Christian physician Alexander of Tralles in the sixth century AD. Uricosuric agents were first used at the end of the 19th century. In the modern era, nonsteroidal anti-inflammatory drugs are usually the drugs of choice for treating acute gout. Perhaps the most important historical advance in the treatment of hyperuricemia was the development of xanthine oxidase inhibitors, which are effective in reducing plasma and urinary urate levels and have been shown to reverse the development of tophaceous deposits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/ar1906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226106PMC
July 2006

Treatment of crystal arthropathy--history and advances.

Authors:
George Nuki

Rheum Dis Clin North Am 2006 May;32(2):333-57, vi

Queen's Medical Research Institute, University of Edinburgh, Scotland, UK.

The history of gout and the many distinguished historical figures who have suffered the agonies of this crystal deposition disorder have claimed the attention of medical historians like no other disease. Its treatment with uric acid lowering drugs became a twentieth century paradigm for the successful management and prevention of a chronic rheumatic disease, but the colorful history of the treatment of gout and crystal deposition disorders stretches back over 4,000 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rdc.2006.03.003DOI Listing
May 2006

Association of low general health status, measured prospectively by Euroqol EQ5D, with osteoporosis, independent of a history of prior fracture.

Osteoporos Int 2005 May 28;16(5):483-9. Epub 2004 Jul 28.

Rheumatic Diseases Unit, University Department of Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Scotland, UK.

Objectives: There have been no studies of generic health-related quality of life (HR-QOL) measured prospectively, in patients referred for bone mass measurement. The aim of this study was to examine the relationship between HR-QOL, measured before DXA scanning was undertaken, and bone mineral density (BMD). Comparison of HR-QOL with the age- and sex-matched general population was also made.

Design: HR-QOL questionnaires were completed by patients who were being entered into a randomized, prospective, parallel group trial to assess the impact of direct access DXA scanning (DADS) versus referral to a hospital consultant, upon clinical decision making by general practitioners (GPs) (Dhillon et al., Osteoporos Int 14:326-333, 2003). HR-QOL questionnaires were completed prior to both randomization and DXA scanning.

Participants: 325 patients from 18 representative general practices of a total of 77 in the city of Edinburgh. Patients had been referred by their GPs who had access to national guidelines on the identification of patients at high risk of osteoporosis.

Outcome Measures: Generic HR-QOL was measured using Euroqol (EQ5D). This provides a profile of self-reported problems in five dimensions (EQ5D(profile)), health utility (EQ5D(utility)), and a visual analogue global self-rated health assessment (EQ5D(vas)).

Results: Odds ratios (ORs) for any self-reported problems on EQ5D(profile) were higher in patients with osteoporosis than those without, and compared with the general population. Age-adjusted mean (SD) EQ5D(utility )was significantly lower in patients with osteoporosis than in those without (0.65 [0.28] vs 0.76 [0.27]; p< 0.01), but the difference lessened with advancing age. Age-adjusted mean (SD) EQ5D(vas) was significantly reduced in patients with compared with no osteoporosis (68 [20] vs 76 [16]; p<0.01). There were no such differences in patients with a history of prior fracture compared with those without a history of prior fracture.

Conclusions: Female patients with osteoporosis have reduced generic HR-QOL compared with the age-matched female general population, irrespective of a history of prior fracture. The causal relationship between osteoporosis and HR-QOL, if any, is unclear. Further studies are needed to define this relationship and to determine whether treatment of osteoporosis has a beneficial effect on HR-QOL independent of fracture risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00198-004-1705-3DOI Listing
May 2005

Recommendations for the use of new methods to assess the efficacy of disease-modifying drugs in the treatment of osteoarthritis.

Osteoarthritis Cartilage 2004 Apr;12(4):263-8

Department of Registration and Clinical Studies, French Agency For the Safety of Health Products (AFSSAPS), France.

Background: Recent innovations in the pharmaceutical drug discovery environment have generated new chemical entities with the potential to become disease modifying drugs for osteoarthritis (DMOAD's). Regulatory agencies acknowledge that such compounds may be granted a DMOAD indication, providing they demonstrate that they can slow down disease progression; progression would be calibrated by a surrogate for structural change, by measuring joint space narrowing (JSN) on plain X-rays with the caveat that this delayed JSN translate into a clinical benefit for the patient. Recently, new technology has been developed to detect a structural change of the OA joint earlier than conventional X-rays.

Objective: The Group for the Respect of Ethics and Excellence in Science (GREES) organized a working party to assess whether these new technologies may be used as surrogates to plain x-rays for assessment of DMOADs.

Methods: GREES includes academic scientists, members of regulatory authorities and representatives from the pharmaceutical industry. After an extensive search of the international literature, from 1980 to 2002, two experts meetings were organized to prepare a resource document for regulatory authorities. This document includes recommendations for a possible update of guidelines for the registration of new chemical entities in osteoarthritis.

Results: Magnetic resonance imaging (MRI) is now used to measure parameters of cartilage morphology and integrity in OA patients. While some data are encouraging, correlation between short-term changes in cartilage structure observed with MRI and long-term radiographic or clinical changes are needed. Hence, the GREES suggests that MRI maybe used as an outcome in phase II studies, but that further data is needed before accepting MRI as a primary end-point in phase III clinical trials. Biochemical markers of bone and cartilage remodelling are being tested to predict OA and measure disease progression. Recently published data are promising but validation as surrogate end-points for OA disease progression requires additional study. The GREES suggests that biochemical markers remain limited to 'proof of concept' studies or as secondary end-points in phase II and III clinical trials. However, the GREES emphasizes the importance of acquiring additional information on biochemical markers in order to help better understand the mode of action of drugs to be used in OA. Regulatory agencies consider that evidence of improvement in clinical outcomes is critical for approval of DMOAD. Time to total joint replacement surgery is probably the most relevant clinical end-point for the evaluation of efficacy of a DMOAD. However, at this time, time to surgery can not be used in clinical trials because of bias by non disease-related factors like patient willingness for surgery or economic factors. At this stage, it appears that DMOAD should demonstrate a significant difference compared to placebo. Benefit should be measured by 3 co-primary end-points: JSN, pain and function. Secondary end-points should include the percentage of patients who are 'responder' (or 'failure'). The definition of a 'failure' patient would be someone with progression of JSN>0.5mm over a period of 2-3 years or who has a significant worsening in pain and/or function, based on validated cut-off values. The definition of the clinically relevant cut-off points for pain and function must be based on data evaluating the natural history of the disease (epidemiological cohorts or placebo groups from long-term studies). These cut-offs points should reflect a high propensity, for an individual patient, to later require joint replacement.

Conclusion: GREES has outlined a set of guidelines for the development of a DMOAD for OA. Although these guidelines are subject to change as new information becomes available, the information above is based on the present knowledge in the field with the addition of expert opinion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.joca.2004.01.006DOI Listing
April 2004

Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized, double-blind, placebo-controlled trial.

Arthritis Rheum 2002 Nov;46(11):2838-46

University of Edinburgh, Edinburgh, Scotland, UK.

Objective: To demonstrate the long-term efficacy of anakinra, a human recombinant interleukin-1 receptor antagonist, in patients with rheumatoid arthritis (RA), and to assess the long-term safety of anakinra at different daily doses.

Methods: The efficacy and safety of anakinra were previously demonstrated in a double-blind, placebo-controlled, 24-week evaluation in 472 patients with active RA. Of 345 patients who completed the placebo-controlled phase of the study, 309 continued in a 52-week, multicenter, double-blind, parallel-group extension phase of the study. Patients received subcutaneous injections of anakinra (30, 75, or 150 mg) once daily. Efficacy was assessed among the 309 patients for the first 24 weeks of the extension phase (48 weeks total therapy), using the American College of Rheumatology composite score (ACR20), its components, and radiographs of the hands and wrists. Safety was assessed in all 472 patients over the entire 52-week extension phase (76 weeks total exposure).

Results: A total of 218 patients completed the extension phase. Of the 91 patients who withdrew prematurely, 46 did so following adverse events, and 26 withdrew because of lack of efficacy. Among patients receiving anakinra who entered the extension phase, the level of improvement was maintained for 48 weeks. The ACR20 response was 51% at week 24 and 46% at week 48, and this effect was consistent across all dose groups. The durability of the response to anakinra was further demonstrated in an evaluation of the sustained ACR20 response, which was similar during the first and second 24-week periods (36% and 42%, respectively). At week 48, ACR50 and ACR70 responses were demonstrated in 18% and 3% of patients, respectively, who continued taking anakinra (all dose groups) and in 20% and 1% of patients, respectively, who were originally receiving placebo and then were randomized to all doses of anakinra. Anakinra was well tolerated for 76 weeks. The only side effects that appeared to be treatment-related were skin reactions at the injection site. There was no evidence of decreased tolerance, an increased number of withdrawals, or an increased incidence of clinical complications associated with extended anakinra therapy.

Conclusion: The clinical benefits of treatment with daily self-administered subcutaneous injections of anakinra in a cohort of patients with active RA were maintained for up to 48 weeks. Anakinra was well tolerated over 76 weeks. These observations support the long-term use of anakinra for the treatment of patients with RA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.10578DOI Listing
November 2002
-->