Gout: Lioté F

Zhang W, Doherty M, Pascual E, Bardin T, Barskova V, Conaghan P, Gerster J, Jacobs J, Leeb B, Lioté F, McCarthy G, Netter P, Nuki G, Perez-Ruiz F, Pignone A, Pimentão J, Punzi L, Roddy E, Uhlig T, Zimmermann-Gòrska I, Anonymous00035. · Academic Rheumatology, University of Nottingham, Clinical Sciences Building, City Hospital, Nottingham NG5 1PB, UK. · Ann Rheum Dis. · Pubmed #16707533 No free full text.

Abstract: OBJECTIVE: To develop evidence based recommendations for the diagnosis of gout. METHODS: The multidisciplinary guideline development group comprised 19 rheumatologists and one evidence based medicine expert, representing 13 European countries. Ten key propositions regarding diagnosis were generated using a Delphi consensus approach. Research evidence was searched systematically for each proposition. Wherever possible the sensitivity, specificity, likelihood ratio (LR), and incremental cost-effectiveness ratio were calculated for diagnostic tests. Relative risk and odds ratios were estimated for risk factors and co-morbidities associated with gout. The quality of evidence was categorised according to the evidence hierarchy. The strength of recommendation (SOR) was assessed using the EULAR visual analogue and ordinal scales. RESULTS: 10 key propositions were generated though three Delphi rounds including diagnostic topics in clinical manifestations, urate crystal identification, biochemical tests, radiographs, and risk factors/co-morbidities. Urate crystal identification varies according to symptoms and observer skill but is very likely to be positive in symptomatic gout (LR = 567 (95% confidence interval (CI), 35.5 to 9053)). Classic podagra and presence of tophi have the highest clinical diagnostic value for gout (LR = 30.64 (95% CI, 20.51 to 45.77), and LR = 39.95 (21.06 to 75.79), respectively). Hyperuricaemia is a major risk factor for gout and may be a useful diagnostic marker when defined by the normal range of the local population (LR = 9.74 (7.45 to 12.72)), although some gouty patients may have normal serum uric acid concentrations at the time of investigation. Radiographs have little role in diagnosis, though in late or severe gout radiographic changes of asymmetrical swelling (LR = 4.13 (2.97 to 5.74)) and subcortical cysts without erosion (LR = 6.39 (3.00 to 13.57)) may be useful to differentiate chronic gout from other joint conditions. In addition, risk factors (sex, diuretics, purine-rich foods, alcohol, lead) and co-morbidities (cardiovascular diseases, hypertension, diabetes, obesity, and chronic renal failure) are associated with gout. SOR for each proposition varied according to both the research evidence and expert opinion. CONCLUSIONS: 10 key recommendations for diagnosis of gout were developed using a combination of research based evidence and expert consensus. The evidence for diagnostic tests, risk factors, and co-morbidities was evaluated and the strength of recommendation was provided.

Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, Gerster J, Jacobs J, Leeb B, Lioté F, McCarthy G, Netter P, Nuki G, Perez-Ruiz F, Pignone A, Pimentão J, Punzi L, Roddy E, Uhlig T, Zimmermann-Gòrska I, Anonymous00034. · Academic Rheumatology, University of Nottingham, Clinical Sciences Building, City Hospital, Nottingham NG5 1PB, UK. · Ann Rheum Dis. · Pubmed #16707532 No free full text.

Abstract: OBJECTIVE: To develop evidence based recommendations for the management of gout. METHODS: The multidisciplinary guideline development group comprised 19 rheumatologists and one evidence based medicine expert representing 13 European countries. Key propositions on management were generated using a Delphi consensus approach. Research evidence was searched systematically for each proposition. Where possible, effect size (ES), number needed to treat, relative risk, odds ratio, and incremental cost-effectiveness ratio were calculated. The quality of evidence was categorised according to the level of evidence. The strength of recommendation (SOR) was assessed using the EULAR visual analogue and ordinal scales. RESULTS: 12 key propositions were generated after three Delphi rounds. Propositions included both non-pharmacological and pharmacological treatments and addressed symptomatic control of acute gout, urate lowering therapy (ULT), and prophylaxis of acute attacks. The importance of patient education, modification of adverse lifestyle (weight loss if obese; reduced alcohol consumption; low animal purine diet) and treatment of associated comorbidity and risk factors were emphasised. Recommended drugs for acute attacks were oral non-steroidal anti-inflammatory drugs (NSAIDs), oral colchicine (ES = 0.87 (95% confidence interval, 0.25 to 1.50)), or joint aspiration and injection of corticosteroid. ULT is indicated in patients with recurrent acute attacks, arthropathy, tophi, or radiographic changes of gout. Allopurinol was confirmed as effective long term ULT (ES = 1.39 (0.78 to 2.01)). If allopurinol toxicity occurs, options include other xanthine oxidase inhibitors, allopurinol desensitisation, or a uricosuric. The uricosuric benzbromarone is more effective than allopurinol (ES = 1.50 (0.76 to 2.24)) and can be used in patients with mild to moderate renal insufficiency but may be hepatotoxic. When gout is associated with the use of diuretics, the diuretic should be stopped if possible. For prophylaxis against acute attacks, either colchicine 0.5-1 mg daily or an NSAID (with gastroprotection if indicated) are recommended. CONCLUSIONS: 12 key recommendations for management of gout were developed, using a combination of research based evidence and expert consensus. The evidence was evaluated and the SOR provided for each proposition.

Perez-Ruiz F, Lioté F. · Hospital de Cruces, Baracaldo, Pais Vasco, Spain. · Arthritis Rheum. · Pubmed #17907217 links to  free full text

This publication has no abstract.

Lioté F, Ea HK. · Fédération de Rhumatologie (pôle appareil locomoteur), INSERM U606, Paris 7 Medical University, centre Viggo Petersen (Assistance Publique- Hôpitaux de Paris), hôpital Lariboisière, 2, rue Ambroise Paré, 75010 PARIS, France. · Curr Rheumatol Rep. · Pubmed #17531179 No free full text.

Abstract: Crystal-induced inflammation pathogenesis is undergoing a transition with respect to monosodium urate, calcium pyrophosphate dihydrate, and even basic calcium phosphate crystals. It is now recognized that innate immunity could be involved in the earlier pathogenic events and that the inflammasome, along with other signaling pathways, is activated and results in interleukin-1 processing and secretion, ultimately activating cells as a paracrine or autocrine cytokine. Management of acute and chronic monosodium urate crystal-induced inflammation, namely gout, has been critically reviewed by a dedicated European working group, and on the behalf of the European League against Rheumatism, 12 evidence-based recommendations have been reported. Calcium pyrophosphate dihydrate chronic inflammation could benefit from colchicine and from methotrexate as an anti-inflammatory agent.

Lioté F, Ea HK. · Fédération de Rhumatologie, Pôle Appareil Locomoteur (Centre Viggo Petersen), Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. · Rheum Dis Clin North Am. · Pubmed #16716881 No free full text.

Abstract: Pathogenesis of gout inflammation remains unknown, but recent advances have been made with respect to initiation, amplification, and self-limitation. Direct crystal-cell membrane contact leads to cell activation, involving membrane-associated molecules. Resolution of acute gout inflammation is a mechanism that is controlled by monocyte-macrophage switch, which results in the loss of cytokine production capability and, conversely, the ability to produce anti-inflammatory molecules. MRI and ultrasound findings provide preliminary data that are not yet used in clinical trials. Diagnosis and management recommendations are missing, but this gap will be filled soon with the upcoming European League Against Rheumatism Task Force's recommendations on gout.

Lioté F. · Centre Viggo Petersen, INSERUM U349 Hôpital Lariboisière, 2 Rue Ambroise Paré, F75475 Paris, France. · Curr Rheumatol Rep. · Pubmed #12744816 No free full text.

Abstract: Gout is not a new disease for clinicians; nevertheless, there are still many secrets awaiting discovery for improving knowledge with respect to uric acid metabolism and monosodium urate crystal-induced inflammation. This review of the literature will focus on new insights on the pathogenesis of idiopathic hyperuricemia, and on secondary hyperuricemia and gout. There are also important advances on the pathophysiology of acute gout, especially as a self-limited process (switch from monocyte to macrophage, peroxisome proliferator activated receptor-gamma, and nitric oxide), but also of chronic gouty arthropathy. Armaments for treating hyperuricemia and gout may be already improved by losartan or fenofibrate and, in the future, by urate oxydase-polyethylene glycol 20 and renal handling regulatory molecules. Finally, control of hyperuricemia may also be considered in the prevention and treatment of cardiovascular disease.

Ea HK, Bardin T, Jinnah HA, Aral B, Lioté F, Ceballos-Picot I. · Hôpital Lariboisière, INSERM UMR-S 606, and Paris Diderot University, Paris, France. · Arthritis Rheum. · Pubmed #19565499 No free full text.

Abstract: A deficiency in hypoxanthine guanine phosphoribosyltransferase (HPRT) activity leads to overproduction of uric acid. According to the degree of enzymatic deficiency, a large spectrum of neurologic features can also be observed, ranging from mild or no neurologic involvement to complete Lesch-Nyhan disease. Herein, we describe a patient with hyperuricemia, juvenile-onset gouty arthritis, nephrolithiasis, and mild neurologic symptoms, attributed to a newly identified variant of the hprt gene, c.596T>G, resulting in the amino acid change p.F199C. Residual HPRT activity (8%) protected against severe neurologic involvement in this patient. Modeling of the mutated protein was used to predict the mechanisms that led to partial enzymatic activity. Careful neurologic examination is warranted in juvenile and middle-aged patients with gout, in order to detect mild symptoms that may lead to a diagnosis of HPRT deficiency.

Terkeltaub R, Zelman D, Scavulli J, Perez-Ruiz F, Lioté F. · Veterans Affairs Medical Center, University of California San Diego, 111K, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. · Joint Bone Spine. · Pubmed #19559637 No free full text.

This publication has no abstract.

Shoor S, Lioté F. · The Permanente Medical Group, Santa Clara, California, USA. · Joint Bone Spine. · Pubmed #19541524 No free full text.

Abstract: Evidence is often insufficient to answer questions in clinical practice. In an effort to fill these "gaps" between clinical investigation and daily conundrums, practicing rheumatologists use experience, logic, pathophysiology, individual patients and collegial consultation. In order to capture this science of clinical practice, a group of European and American clinicians and clinician investigators worked in investigative teams or Study Sections, each devoted to utilizing the science of clinical practice to address and critical clinical questions in Rheumatoid Arthritis, Imaging, Vasculitis and Gout that are inadequately answered by published evidence. Conclusions were summarized by a method of debate and discussion. It is anticipated that by defining uncertainty and using such an analytical and experiential method, rheumatologists can assist themselves in solving problems in their daily practice.

Feydy A, Lioté F, Carlier R, Chevrot A, Drapé JL. · Service de Radiologie B, Hôpital Cochin, 27, rue du faubourg Saint Jacques, 75679, Paris Cedex 14, France. · Eur Radiol. · Pubmed #15856241 No free full text.

Abstract: The cervical spine may be specifically involved in crystal-associated arthropathies. In this article, we focus on the three common crystals and diseases: hydroxyapatite crystal deposition disease, calcium pyrophosphate dihydrate (CPPD) deposition disease, and monosodium urate crystals (gout). The cervical involvement in crystal-associated diseases may provoke a misleading clinical presentation with acute neck pain, fever, or neurological symptoms. Imaging allows an accurate diagnosis in typical cases with calcific deposits and destructive lesions of the discs and joints. Most of the cases are related to CPPD or hydroxyapatite crystal deposition; gout is much less common.

Liu R, Lioté F, Rose DM, Merz D, Terkeltaub R. · VA Medical Center and University of California, San Diego, CA 92161, USA. · Arthritis Rheum. · Pubmed #14730623 links to  free full text

Abstract: OBJECTIVE: Articular deposition of monosodium urate monohydrate (MSU) crystals may promote cartilage and bone erosion. Therefore, the aim of this study was to determine how MSU crystals stimulate chondrocytes. METHODS: Nitric oxide (NO) release, and expression of inducible nitric oxide synthase (iNOS) and matrix metalloproteinase 3 (MMP-3) were assessed in cultured chondrocytes treated with MSU. MSU-induced functional signaling by specific protein kinases (p38, Src, and the focal adhesion kinase [FAK] family members proline-rich tyrosine kinase 2 [Pyk-2] and FAK) was also examined using selective pharmacologic inhibitors and transfection of kinase mutants. RESULTS: MSU induced MMP-3 and iNOS expression and NO release in chondrocytes in a p38-dependent manner that did not require interleukin-1 (IL-1), as demonstrated by using IL-1 receptor antagonist. MSU induced rapid tyrosine phosphorylation of Pyk-2 and FAK, their adaptor protein paxillin, and interacting kinase c-Src. Pyk-2 and c-Src signaling both mediated p38 MAPK activation in response to MSU. Pyk-2 and c-Src signaling played a major role in transducing MSU-induced NO production and MMP-3 expression. But, despite the observed FAK phosphorylation, a selective pharmacologic FAK inhibitor and a FAK dominant-negative mutant both failed to block MSU-induced NO release or MMP-3 expression in parallel experiments. CONCLUSION: In chondrocytes, MSU crystals activate a signaling kinase cascade typically employed by adhesion receptors that involves upstream Src and FAK family activation and downstream p38 activation. In this cascade, Pyk-2, Src, and p38 kinases transduce MSU-induced NO production and MMP-3 expression. Our results identify Pyk-2 and c-Src as novel sites for potential therapeutic intervention in cartilage degradation in chronic gout.

Lioté F, Champy R, Moenner M, Boval-Boizard B, Badet J. · Centre Viggo Petersen, Hôpital Lariboisière, Paris, France. · Clin Exp Immunol. · Pubmed #12653852 links to  free full text

Abstract: Angiogenesis is a key process in the pathogenesis of inflammatory arthritis. Angiogenin is one of the most potent inducers of neovascularization in experimental models in vivo. To look for evidence that angiogenin is involved in inflammatory joint disease, we examined plasma and synovial fluid (SF) samples from rheumatology patients and synovial fibroblast cell culture supernatants. Angiogenin levels were determined by radioimmunoassay and ELISA. Plasma angiogenin concentrations ranged from 96 to 478 ng/ml, with no significant difference between patients and normal controls. In SF, angiogenin concentrations were significantly higher in patients with acute or chronic synovitis (rheumatoid arthritis (RA): median, 104 ng/ml; range 13-748, n = 14; crystal-induced arthritis (CIA): median, 149 ng/ml; range, 37-616, n = 14, and other chronic inflammatory arthritis: median, 42 ng/ml; range, 15-205; n = 9) than in the 18 patients with osteoarthritis (OA) (median, 20 ng/ml; range 8-116) (P < 0.0001, anova). Angiogenin levels in SF from RA patients in remission with secondary OA were similar to those achieved in primary OA, and decreased in parallel with the resolution of acute gout. Angiogenin protein was released by cultured synovial fibroblasts from OA and RA patients, and reached 1.18 ng/106 cells/day. These data suggest that angiogenin may mediate local inflammation in arthritis via effects on angiogenesis and leucocyte regulation.

Schiltz C, Lioté F, Prudhommeaux F, Meunier A, Champy R, Callebert J, Bardin T. · Laboratoire de Radiologie Expérimentale et de Physiopathologie Articulaire (JE2149), Centre Viggo Petersen, Hôpital Lariboisière, 2 rue Ambroise Paré, 75475 Paris Cedex 10, France. · Arthritis Rheum. · Pubmed #12115197 links to  free full text

Abstract: OBJECTIVE: To quantify the inflammatory cell response in rat air pouch pseudosynovial membrane during monosodium urate monohydrate (MSU) crystal-induced inflammation. METHODS: In the rat air-pouch model, we used a computer-assisted histomorphometric method to quantify cell distributions, based on cell linear densities, in histologic sections of membranes from pouches injected with MSU or saline. The volume, white blood cell (WBC) count, and histamine content of the pouch exudates were determined at several time points. RESULTS: Injection of 10 mg of MSU crystals into the pouch produced an acute exudate. After peaking at 24 hours, the exudate volume and WBC count decreased spontaneously over the next 3 days, simulating the self-limited course of acute gout. Membrane thickness followed a parallel course. Membrane polymorphonuclear cell (PMN) linear densities were closely correlated with exudate WBC counts, suggesting PMN recruitment from the subintimal synovial membrane. Both monocyte/macrophage and mast cell linear densities increased in the subintimal layer 2 hours after crystal injection (P = 0.038 and P = 0.03, respectively, versus controls), whereas PMN linear densities showed 2 peaks, one at 4 hours and the other 24 hours. The exudate histamine content peaked 6 hours after crystal injection, when mast cell linear densities were minimal in the membranes, suggesting mast cell degranulation. CONCLUSION: An increase in monocyte/macrophage and mast cell densities in the membrane preceded the PMN influx in the pouch membrane and exudate, suggesting that mast cells may be involved in the early phase of MSU crystal-induced inflammation, at least in this rat model.