Anne-Kathrin Tausche

2016 updated EULAR evidence-based recommendations for the management of gout

Background New drugs and new evidence concerning the use of established treatments have become available since the publication of the first European League Against Rheumatism (EULAR) recommendations for the management of gout, in 2006. This situation has prompted a systematic review and update of the 2006 recommendations. Methods The EULAR task force consisted of 15 rheumatologists, 1 radiologist, 2 general practitioners, 1 research fellow, 2 patients and 3 experts in epidemiology/methodology from 12 European countries. A systematic review of the literature concerning all aspects of gout treatments was performed. Subsequently, recommendations were formulated by use of a Delphi consensus approach. Results Three overarching principles and 11 key recommendations were generated. For the treatment of flare, colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), oral or intra-articular steroids or a combination are recommended. In patients with frequent flare and contraindications to colchicine, NSAIDs and corticosteroids, an interleukin-1 blocker should be considered. In addition to education and a non-pharmacological management approach, urate-lowering therapy (ULT) should be considered from the first presentation of the disease, and serum uric acid (SUA) levels should be maintained at<6 mg/dL (360 µmol/L) and <5 mg/dL (300 µmol/L) in those with severe gout. Allopurinol is recommended as first-line ULT and its dosage should be adjusted according to renal function. If the SUA target cannot be achieved with allopurinol, then febuxostat, a uricosuric or combining a xanthine oxidase inhibitor with a uricosuric should be considered. For patients with refractory gout, pegloticase is recommended. Conclusions These recommendations aim to inform physicians and patients about the non-pharmacological and pharmacological treatments for gout and to provide the best strategies to achieve the predefined urate target to cure the disease.

An autologous epidermal equivalent tissue-engineered from follicular outer root sheath keratinocytes is as effective as split-thickness skin autograft in recalcitrant vascular leg ulcers

The outer root sheath of hair follicles plays an important role in epidermal regeneration in vivo. Keratinocytes isolated by explantation of outer root sheath tissue have extensive proliferative capacity irrespective of donor age, which probably depends on pluripotent epithelial stem cells residing in the outer root sheath. These keratinocytes can be organotypically grown to epidermal equivalents in vitro. We report here that in a multicenter, randomized phase II study, EpiDex™, a tissue‐engineered, fully differentiated autologous epidermal equivalent derived from keratinocytes of the outer root sheath of plucked anagen hair follicles, is as effective as split‐thickness skin autografting in the promotion of healing and complete closure of recalcitrant vascular leg ulcers. (WOUND REP REG 2003;11:248–252)

2015 Gout Classification Criteria: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative

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.

Gout—Current Diagnosis and Treatment

BACKGROUND Because of the changing dietary habits of an aging population, hyperuricemia is frequently found in combination with other metabolic disorders. Longstanding elevation of the serum uric acid level can lead to the deposition of monosodium urate crystals, causing gout (arthritis, urate nephropathy, tophi). In Germany, the prevalence of gouty arthritis is estimated at 1.4%, higher than that of rheumatoid arthritis. There are no German guidelines to date for the treatment of gout. Its current treatment is based largely on expert opinion. METHODS Selective literature review on the diagnosis and treatment of gout. RESULTS AND CONCLUSIONS Asymptomatic hyperuricemia is generally not an indication for pharmacological intervention to lower the uric acid level. When gout is clinically manifest, however, acute treatment of gouty arthritis should be followed by determination of the cause of hyperuricemia, and long-term treatment to lower the uric acid level is usually necessary. The goal of treatment is to diminish the bodys stores of uric acid crystal deposits (the intrinsic uric acid pool) and thereby to prevent the inflammatory processes that they cause, which lead to structural alterations. In the long term, serum uric acid levels should be kept below 360 micromol/L (6 mg/dL). The available medications for this purpose are allopurinol and various uricosuric agents, e.g., benzbromarone. There is good evidence to support the treatment of gouty attacks by the timely, short-term use of non-steroidal anti-inflammatory drugs (NSAID), colchicine, and glucocorticosteroids.

The adverse cardiopulmonary phenotype of caveolin-1 deficient mice is mediated by a dysfunctional endothelium

Recently generated caveolin-1 deficient mice (cav-1(-/-)) display several physiological alterations such as severe heart failure and lung fibrosis. The molecular mechanisms how the loss of caveolin-1 (cav-1) mediates these alterations are currently under debate. A plethora of studies support a role of cav-1 as a negative regulator of endothelial nitric oxide synthase (eNOS). Accordingly, constitutive eNOS hyperactivation was observed in cav-1(-/-). Given the hyperactivated eNOS enzyme we hypothesized that disturbed eNOS function is involved in the development of the cardiopulmonary pathologies in cav-1(-/-). The present study argues that loss of cav-1 results in enhanced eNOS activity but not in increased vascular tetrahydrobiopterin (BH(4)) levels (which acts as an essential eNOS cofactor) thereby causing a stoichiometric discordance between eNOS activity and BH(4) sufficient to cause dysfunctional eNOS signaling. The resultant oxidative stress is largely responsible for major cardiac and pulmonary defects observed in cav-1(-/-). BH(4) donation to cav-1(-/-) led to a normalized BH(4)/BH(2) ratio, to reduced oxidant stress, to substantial improvements of both systolic and diastolic heart function and to marked amelioration of the impaired lung phenotype. Notably, the antioxidant tetrahydroneopterin which is not essential for eNOS function showed no relevant effect. Taken together these novel findings indicate that dysfunctional eNOS is of central importance in the genesis of the cardiopulmonary phenotype of cav-1(-/-). Additionally, these findings are generally of paramount importance since they underline the deleterious role of an uncoupled eNOS in cardiovascular pathology and they additionally suggest BH(4) as an effective cure.

International position paper on febuxostat

This position paper aims to clarify the presumed place of febuxostat in the management of gout patients. Since this novel xanthine oxidase inhibitor is now available, an international group of gout experts decided to formulate an international consensus statement. This statement presents the place for this new xanthine oxidase inhibitor in the treatment of gout which may contribute to optimize treatment of gout patients in Europe and worldwide.

Performance of classification criteria for gout in early and established disease

Objectives To compare the sensitivity and specificity of different classification criteria for gout in early and established disease. Methods This was a cross-sectional study of consecutive rheumatology clinic patients with joint swelling in which gout was defined by presence or absence of monosodium urate crystals as observed by a certified examiner at presentation. Early disease was defined as patient-reported onset of symptoms of 2 years or less. Results Data from 983 patients were collected and gout was present in 509 (52%). Early disease was present in 144 gout cases and 228 non-cases. Sensitivity across criteria was better in established disease (95.3% vs 84.1%, p<0.001) and specificity was better in early disease (79.9% vs 52.5%, p<0.001). The overall best performing clinical criteria were the Rome criteria with sensitivity/specificity in early and established disease of 60.3%/84.4% and 86.4%/63.6%. Criteria not requiring synovial fluid analysis had sensitivity and specificity of less than 80% in early and established disease. Conclusions Existing classification criteria for gout have sensitivity of over 80% in early and established disease but currently available criteria that do not require synovial fluid analysis have inadequate specificity especially later in the disease. Classification criteria for gout with better specificity are required, although the findings should be cautiously applied to non-rheumatology clinic populations.

Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout.

IntroductionThe acute gout flare results from a localised self-limiting innate immune response to monosodium urate (MSU) crystals deposited in joints in hyperuricaemic individuals. Activation of the caspase recruitment domain-containing protein 8 (CARD8) NOD-like receptor pyrin-containing 3 (NLRP3) inflammasome by MSU crystals and production of mature interleukin-1β (IL-1β) is central to acute gouty arthritis. However very little is known about genetic control of the innate immune response involved in acute gouty arthritis. Therefore our aim was to test functional single nucleotide polymorphism (SNP) variants in the toll-like receptor (TLR)-inflammasome-IL-1β axis for association with gout.Methods1,494 gout cases of European and 863 gout cases of New Zealand (NZ) Polynesian (Māori and Pacific Island) ancestry were included. Gout was diagnosed by the 1977 ARA gout classification criteria. There were 1,030 Polynesian controls and 10,942 European controls including from the publicly-available Atherosclerosis Risk in Communities (ARIC) and Framingham Heart (FHS) studies. The ten SNPs were either genotyped by Sequenom MassArray or by Affymetrix SNP array or imputed in the ARIC and FHS datasets. Allelic association was done by logistic regression adjusting by age and sex with European and Polynesian data combined by meta-analysis. Sample sets were pooled for multiplicative interaction analysis, which was also adjusted by sample set.ResultsEleven SNPs were tested in the TLR2, CD14, IL1B, CARD8, NLRP3, MYD88, P2RX7, DAPK1 and TNXIP genes. Nominally significant (P < 0.05) associations with gout were detected at CARD8 rs2043211 (OR = 1.12, P = 0.007), IL1B rs1143623 (OR = 1.10, P = 0.020) and CD14 rs2569190 (OR = 1.08; P = 0.036). There was significant multiplicative interaction between CARD8 and IL1B (P = 0.005), with the IL1B risk genotype amplifying the risk effect of CARD8.ConclusionThere is evidence for association of gout with functional variants in CARD8, IL1B and CD14. The gout-associated allele of IL1B increases expression of IL-1β – the multiplicative interaction with CARD8 would be consistent with a synergy of greater inflammasome activity (resulting from reduced CARD8) combined with higher levels of pre-IL-1β expression leading to increased production of mature IL-1β in gout.

SAT0532 Updated Eular Evidence-Based Recommendations for the Diagnosis of Gout

Background Gout has become the most common inflammatory arthritis but is still frequently misdiagnosed. New data on imaging and clinical diagnosis have become available since publication of the first EULAR recommendations for the diagnosis of gout in 2006. This has prompted a systematic review and update of the 2006 recommendations. Objectives To develop updated evidence-based recommendations for the diagnosis of gout Methods The 2014 EULAR task force comprised 15 rheumatologists, 1 radiologist, 2 GPs, 2 patients and 2 experts in methodology from 12 European countries. The expert group first voted to determine whether each of the 2006 recommendations for diagnosis should be retained, modified or deleted. MEDLINE, EMBASE and Cochrane Library reports were searched systematically to obtain research evidence from 2005 to 2013 on all aspects of the diagnosis of gout. Internal and external validity of the articles was assessed. The quality of evidence was categorised according to GRADE. The task force was presented with a synopsis of this literature review and generated a first draft of key recommendations after a two-day meeting. Final recommendations were agreed using a Delphi consensus approach. The level of agreement to each recommendation was assessed using EULAR numeral rating scales. Results A search for crystals in synovial fluid (SF) or tophus aspirates was recommended in every person with suspected gout, because demonstration of monosodium urate (MSU) crystals allows a definitive diagnosis of gout. SF should also be examined for crystals in any arthritis of unknown aetiology. There was consensus that a number of suggestive clinical features supported a clinical diagnosis of gout. These are: mono articular involvement of a foot or ankle joint (especially the first MTP); previous episodes of similar acute arthritis; rapid onset of severe pain and swelling (at its worst in <24 h); erythema; male gender; and associated cardiovascular diseases and hyperuricaemia. When crystal identification is not possible, it was recommended that any atypical presentation should be investigated by imaging, in particular with ultrasound to seek features suggestive of urate deposits (double contour sign and tophi). There was consensus a that a diagnosis of gout should not be based on the presence of hyperuricaemia alone. There was also a strong recommendation that all persons with gout should be systematically assessed for the presence of associated co-morbidities and risk factors for cardiovascular disease, as well as for risk factors for chronic hyperuricaemia. Conclusions Eight updated, evidence-based, expert consensus recommendations for the diagnosis of gout are proposed. Disclosure of Interest P. Richette Speakers bureau: Ménarini, Ipsen, Savient, Novartis, Astra-ZenecaM, E. Pascual Speakers bureau: Menarini, Savient, Novartis, Astra Zaneca, M. Doherty Speakers bureau: Menarini, Ardea and Novartis, V. Barskova: None declared, F. Becce: None declared, M. Coyfish: None declared, H. Janssens: None declared, T. Jansen Speakers bureau: Ménarini, F. Lioté Speakers bureau: Novartis, Ipsen, Menarini, SOBI, Mayolly-Spindler, Astra-Zeneca, Ardea, Savient, C. Mallen: None declared, G. Nuki Speakers bureau: Ipsen, Menarini, Novartis and Savient., F. Perez-Ruiz Speakers bureau: Astra-Zeneca, Menarini, Metabolex, Novartis, Pfizer, SOBI, J. Pimentão Speakers bureau: Ménarini, T. Piwell: None declared, L. Punzi Speakers bureau: Ménarini, A. So Speakers bureau: Novartis, SOBI, Astra-Zeneca and Menarini, A.-K. Tausche Speakers bureau: Menarini, Savient, Novartis, Sobi, Ardea Bioscience, T. Uhlig: None declared, J. Zavada Speakers bureau: Ménarini, Novartis, W. Zhang Speakers bureau: Savient, F. Tubach: None declared, T. Bardin Speakers bureau: Ménarini, Ipsen, Savient, Novartis, Astra-Zeneca, SOBI DOI 10.1136/annrheumdis-2014-eular.5546

Diagnostic Arthrocentesis for Suspicion of Gout Is Safe and Well Tolerated

Objective. To determine the frequency of adverse events of diagnostic arthrocentesis in patients with possible gout. Methods. Consecutive patients underwent arthrocentesis and were evaluated at 6 weeks to determine adverse events. The 95% CI were obtained by bootstrapping. Results. Arthrocentesis was performed in 910 patients, and 887 (97.5%) were evaluated for adverse events. Any adverse event was observed in 12 participants (1.4%, 95% CI 0.6–2.1). There was 1 case (0.1%, 95% CI 0–0.34) of septic arthritis. Conclusions. Diagnostic arthrocentesis is associated with a low frequency of adverse events. Septic arthritis rarely occurs.