Monday, November 14, 2011

Hyperuricemia and Gout

Gout follows hyperuricemia, which follows overindulging in food and drinks. On twitter you would block and report such fellows! The incidence of gout has risen during the last decades (Arromdee et al. have shown the incidence to double from the 70ies to the 90ies; Zhu et al. have shown an increase of up to 114% in certain subgroups in the US).
Marc Pillinger, MD, who is Associate Professor of Medicine and Pharmacology at the NYU Langone Medical Center, gave an interesting talk on gout at the 2011 ACR Scientific Meeting in Chicago. He asked about the factors, why gou and hyperuricemia are increasing in the population. People live longer, there are more people with kidney disease, diuretics are used more often, diet patterns have changed, and obesityhas become epidemic. Gout is expensive and gout patients habour lots of co-morbidities as hypertension, hyperlipidemia, chronic kidney disease, diabetes, coronary artery disease. Studies indicate, that lowering uric acid in these patients might reverse these co-morbidities (hypertension, hyperlipidemia, chronic kidney disease, diabetes, coronary artery disease) – lots of research work still to be done though! Some studies found an increased prevalence and severity of osteoarthritis.
Old treatment options are reducing inflammation by NSAIDs, colchicine, corticosteroids, and lowering uric acid by allopurinol, benzbromarone, probenecid. New treatment options are reducing inflammation by anakinra (Il-1 receptor antagonist), rilonacept (Il-1 trap), canakimumab (Anti-Il-1 Ig), and lowering uric acid by febuxostat, pegloticase (pegylated uricase), lesinurad. Pegloticase is highly effective to reduce urid acid, and reduces tophi.

Some foods promote gout as purines in meat and seafood, but also alcoholic beverages, fructose, and more.
Beer is the worst alcoholic beverage to promote hyperuricemia and gout. A really large study (more than 47,000 men) conducted at the Massachusetts General Hospital by Dr. Hyon Choi and her colleagues showed, that consumers of two to four beers a week had a risk increase of 25%, consuming at least 2 beers a day results in a risk increase of 200% of developing gout. Though alcohol itself increases the risk, it is the amount of purines found in beer, that make it worse than the other alcoholic beverages. High-fructose corn syrup (HFCS) results in high uric acid formation, and should therefore be avoided (there are other serious health concerns such as cardiovascular disease, diabetes, and fatty liver disease).

Let’s have a look at some excerpts from abstracts from the 2011 ACR Scientific Meeting in Chicago:

[223] Gout Vs Hyperuricemia As Risk Factors for Coronary Artery Disease – A Pilot Study.
Victoria Furer, Rennie N. G. Howard, Jonathan Samuels and Michael H. Pillinger.
NYU Hospital for Joint Diseases, New York, NY
Conclusion: This well-characterized, prospectively-enrolled cohort study suggests that the presence of gout conveys an additional level of CAD risk beyond that of hyperuricemia. Although larger studies are needed, our pilot study demonstrates the feasibility of using a prospective enrollment strategy to distinguish between hyperuricemia and gout comorbidity.

[1013] Rilonacept for Gout Flare Prevention in Patients on Uric Acid-Lowering Therapy: Results of a Double-Blind, Placebo-Controlled, Phase 3, International Safety Study.

John S. Sundy1, H. Ralph Schumacher2, Judith Kirstein3, Essack Mitha4, Steven P. Weinstein5, Jian Wang5, Shirletta King-Davis5 and Robert R. Evans5.
1Duke University Medical Center, Durham, NC, 2VA Medical Center and University of Pennsylvania, Philadelphia, PA, 3Advanced Clinical Research, West Jordan, UT, 4Newtown Clinical Research, Johannesburg, Gauteng, South Africa, 5Regeneron Pharmaceuticals, Inc., Tarrytown, NY
Conclusion: Rilonacept demonstrated an acceptable safety and tolerability profile in gout patients with typical comorbid conditions. The rate of serious infections was low. Rilonacept resulted in a substantial reduction in gout flares in patients at high risk of flaring.

[1014] Rilonacept Efficacy for Gout Flare Prevention in Patients with Tophi and/or Polyarticular Disease Who Initiate Uric Acid-Lowering Therapy.

Robert Terkeltaub1, H. Ralph Schumacher2, A. Kivitz3, Steven P. Weinstein4, Richard Wu4, Rebecca Gall4 and Robert R. Evans4.
1VA Medical Ctr, San Diego, CA, 2VA Medical Center and University of Pennsylvania, Philadelphia, PA, 3Altoona Center for Clinical Research, Duncansville, PA, 4Regeneron Pharmaceuticals, Inc., Tarrytown, NY
Conclusion: The presence of tophi and/or polyarticular disease represents a risk factor for gout flares in patients initiating uric acid-lowering therapy. Among patients with these risk factors, rilonacept demonstrated efficacy for gout flare prevention that was generally similar to that observed for the overall population.

[1016] Long-Term Efficacy and Safety of Canakinumab Versus Triamcinolone Acetonide in Acute Gouty Arthritis Patients.

J.P. Brown1, A. So2, A. Dikranian3, R. Alten4, T. Bardin5, H. R. Schumacher6, A. Gimona7, G. Krammer7, A. Karpov7 and N. Schlesinger8.
1CHUQ-CHUL Research Centre, Laval University, Quebec City, QC, 2CHUV, Lausanne, Switzerland, 3San Diego Arthritis Medical Clinic, San Diego, CA, 4Charite´ Teaching Hospital–Schlosspark-Klinik, Berlin, Germany, 5Hoˆpital Lariboisie`re, Paris, France, 6University of Pennsylvania and VA Medical Center, Philadelphia, PA, 7Novartis Pharma AG, Basel, Switzerland, 8UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ
Conclusion: In frequently flaring patients with limited treatment options, canakinumab demonstrated superior 24 week efficacy against TA with comparable safety and tolerability to 12-week data.

[1021] Efficacy and Safety of Lesinurad (RDEA594), A Novel Uricosuric Agent, Given In Combination with Allopurinol in Allopurinol-Refractory Gout Patients: Preliminary Results from the Randomized, Double-Blind, Placebo-Controlled, Phase 2B Extension Study.

John Sundy1, Fernando Perez-Ruiz2, Eswar Krishnan3, Vijay Hingorani4, Jody Welp4, Matt Suster4, Kimberly Manhard4, Matt Cravets4, David Hagerty4 and Barry Quart4.
1Duke University Medical Center, Durham, NC, 2Hospital De Cruces, Baracaldo, Spain, 3Stanford University, Stanford, CA, 4Ardea Biosciences, Inc., San Diego, CA
Conclusion: Addition of lesinurad produced consistent, sustained reductions in sUA levels in patients not adequately responding to standard doses of ALLO. Most subjects achieved target sUA levels of _6 mg/dL on either the 200 or 400mg lesinurad dose. Lesinurad was well-tolerated and no dose-related side effects were observed with combination treatment. Lesinurad is a promising investigational drug for the treatment of hyperuricemia in gout

[1022] Febuxostat (vs. Allopurinol) In Treating the Hyperuricemia of Gout In Diabetic Patients.

Michael A. Becker1, Patricia A. MacDonald2, Barbara Hunt2 and Robert L. Jackson2.
1University of Chicago Medical Center, Chicago, IL, 2Takeda Global Research & Development Center, Inc., Deerfield, IL
Conclusion: Despite very high rates of CV, renal, and additional metabolic co-morbidities, diabetic gouty subjects tolerated UL therapy with either FEB or ALLO, but FEB 80mg treatment achieved sUA _6.0 mg/dL more often than ALLO treatment at commonly prescribed doses.

[1023] Rilonacept for Gout Flare Prevention: Subgroup Analysis of Patients Initiating or Continuing Uric Acid-Lowering Therapy in a Randomized, Placebo-Controlled Trial.

John S. Sundy1, H. Ralph Schumacher2, Roy M. Fleischmann3, Johannes M. Engelbrecht4, Steven P. Weinstein5, Jian Wang5, Shirletta King-Davis5 and Robert R. Evans5.
1Duke University Medical Center, Durham, NC, 2VA Medical Center and University of Pennsylvania, Philadelphia, PA, 3MCRC, University of Texas, Dallas, TX, 4Vergelegan Medi-Clinic, West Cape, South Africa, 5Regeneron Pharmaceuticals, Inc., Tarrytown, NY
Conclusion: Weekly treatment with rilonacept 160mg resulted in similar efficacy in patients initiating or continuing uric acid-lowering therapy who were at risk of gout flares. Pre-filled syringes demonstrated efficacy similar to lyophilized drug in vials. Efficacy was also consistent in patients meeting the additional inclusion criteria from previous phase 3 studies. No new safety signals were observed.

[1025] Pharmacological Treatment of Acute Gout: A Systematic Review.

Puja Khanna1, Manjit K. Singh2, John D. FitzGerald3, Sangmee Bae2, Shraddha Prakash3, Marian Kaldas3, Maneesh Gogia3, Paul Maranian4, Robert Terkeltaub5 and Dinesh Khanna6.
1University of Michigan, Ann Harbor, MI, 2David Geffen School of Medicine at UCLA, Los Angeles, CA, 3UCLA, Los Angeles, CA, 4UCLA Medical School, Los Angeles, CA, 5VA Medical Ctr, San Diego, CA, 6University of Michigan, Ann Arbor, MI
Conclusion: NSAIDs and colchicine are effective in treating acute gout attack. Corticosteroid, ACTH, and canakinumamb can be used in patients who have contraindications to NSAIDs and colchicine.

[1027] Efficacy of Combined Treatment with Allopurinol and Benzbromarone in Gout Patients with Chronic Renal Impairment.
i Seon Oh1, Seung Won Choi1, Bon San Koo2, Min Wook So2, Yong-Gil Kim2, Chang-Keun Lee2 and Bin Yoo2.
1University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, South Korea, 2University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
Conclusion: This study results suggest that combined treatment with allopurinol and benzbromarone may be an effective strategy for achieving the goal of uric acid levels in gout patients with moderate to severe renal impairment.

[1032] Uncontrolled Serum Uric Acid Is Associated with An Increased Risk of Developing Renal Disease In Veterans with Gout.

Eswar Krishnan1, Hari Sharma2, Bhavik J. Pandya3, Maryna Marynchenko2, Andrew Yu2, Eric Wu2, Jinan Liu4 and Lizheng Shi4.
1Stanford University, Stanford, CA, 2Analysis Group, Inc., Boston, MA, 3Takeda Pharmaceuticals International, Inc., Deerfield, IL, 4Tulane University, New Orleans, LA
Conclusion: Compared to controlled sUA levels, uncontrolled sUA levels are associated with increased risk of a new diagnosis of renal disease among veterans with gout.

[1033] Clinical Characteristics of Difficult-to-Treat Gout Patients: a Principal Components Analysis.

Elizaveta Vaysbrot1, Yoojin Lee1, Sarah McLaughlin1, Neetu Agashivala2, Anthony Yadao3, Timothy E. McAlindon1 and William F. Harvey1.
1Tufts Medical Center, Boston, MA, 2Novartis Pharmaceutical Corporation, East Hanover, NJ, 3Novartis Pharmaceuticals Corporation, East Hanover, NJ
Conclusion: The four out of five factors had components with clinical relationships: cardiovascular diseases, gastrointestinal disorders, metabolic syndrome and features of advanced gout. The components in factor 4 did not have a clear clinical relationship. The study was limited by its retrospective nature, small sample size, and an inexact, exploratory nature of PCA method. Characteristics of this population may vary if using different definitions of difficult-to-treat. Despite the limitations, our results confirm the clinical intuition that the above conditions are linked to difficult-to-treat gout and may help design future research.

[1083] Presence of Gout Is Associated with Increased Osteoarthritis Prevalence and Severity.

Rennie N. G. Howard1, Jonathan Samuels1, Soterios Gyftopoulos1, Svetlana Krasnokutsky2, Joseph Leung3, Christopher Swearingen4 and Michael H. Pillinger1.
1NYU Langone Medical Center/NYU Hospital for Joint Diseases, New York, NY, 2NYU Hospital for Joint Disease, New York, NY, 3New York, NY, 4University of Arkansas for Medical Sciences, Little Rock, AR
Conclusion: Our data suggest that presence of gout puts subjects at significantly higher risk for increased knee OA prevalence and severity. AH may independently convey knee OA risk but our sample size was inadequate
for statistical confirmation. MSU crystal deposition as detected by US was also significantly higher in subjects with knee OA. Presence of gout or AH, as well as MSU crystal deposition on US, could potentially serve as useful biomarkers for knee OA risk, severity and progression. The possibility that gout and/or AH might contribute to OA risk suggests that UA management should be assessed as a potential intervention in OA patients.

[1599] Allopurinol Initiation and the Risk of Death in the General Population.

Yanyan Zhu1, Yuqing Zhang2, John D. Seeger3, Young Hee Rho4, Christine Peloquin1 and Hyon K. Choi1.
1Boston University School of Medicine, Boston, MA, 2Boston University Clinical Edpidemiology Reserach and Training Unit, Boston, MA, 3Brigham and Women’s Hospital/Harvard Medical School, Boston, MA, 4Vanderbilt Medical Center, Nashville, TN
Conclusion: In this general population study, allopurinol initiation was associated with a modestly reduced risk of death. The overall benefits of allopurinol may outweigh its impact of rare, potentially serious adverse effects at a population level

[1602] Uncontrolled Serum Uric Acid In Veteran Gout Patients Is Associated with a Higher Risk of Diabetes.

Bhavik J. Pandya1, Maryna Marynchenko2, Hari Sharma2, Andrew Yu2, Eric Wu2, Lizheng Shi3, Jinan Liu3 and Eswar Krishnan4.
1Takeda Pharmaceuticals International, Inc., Deerfield, IL, 2Analysis Group, Inc., Boston, MA, 3Tulane University, New Orleans, LA, 4Stanford University, Stanford, CA
Conclusion: Among VISN 16 pts with gout, uncontrolled sUA was associated with a higher risk of a new diagnosis of diabetes when compared with controlled sUA.

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