Objective Existing gout classification criteria 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 (ACR) and European League Against Rheumatism (EULAR) conducted the following studies: a systematic literature review of advanced imaging, a diagnostic study in which monosodium urate (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 dataset. Results The entry criterion for the new classification criteria requires at least one 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 gout classification, 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 DECT, 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 have incorporated current state-of-the-art evidence regarding gout.

ObjectiveExisting 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.MethodsAn 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.ResultsThe 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).ConclusionsThe 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.

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.

ObjectiveTo develop recommendations for cardiovascular risk (CVR) management in gout, vasculitis, systemic sclerosis (SSc), myositis, mixed connective tissue disease (MCTD), Sjögren’s syndrome (SS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS).MethodsFollowing European League against Rheumatism (EULAR) standardised procedures, a multidisciplinary task force formulated recommendations for CVR prediction and management based on systematic literature reviews and expert opinion.ResultsFour overarching principles emphasising the need of regular screening and management of modifiable CVR factors and patient education were endorsed. Nineteen recommendations (eleven for gout, vasculitis, SSc, MCTD, myositis, SS; eight for SLE, APS) were developed covering three topics: (1) CVR prediction tools; (2) interventions on traditional CVR factors and (3) interventions on disease-related CVR factors. Several statements relied on expert opinion because high-quality evidence was lacking. Use of generic CVR prediction tools is recommended due to lack of validated rheumatic diseases-specific tools. Diuretics should be avoided in gout and beta-blockers in SSc, and a blood pressure target <130/80 mm Hg should be considered in SLE. Lipid management should follow general population guidelines, and antiplatelet use in SLE, APS and large-vessel vasculitis should follow prior EULAR recommendations. A serum uric acid level <0.36 mmol/L (<6 mg/dL) in gout, and disease activity control and glucocorticoid dose minimisation in SLE and vasculitis, are recommended. Hydroxychloroquine is recommended in SLE because it may also reduce CVR, while no particular immunosuppressive treatment in SLE or urate-lowering therapy in gout has been associated with CVR lowering.ConclusionThese recommendations can guide clinical practice and future research for improving CVR management in rheumatic and musculoskeletal diseases.

ClinicalTrials.gov (http://clinincaltrials.gov), NCT01508702.

Objective. Human urate transporter 1 (hURAT1) is a member of the organic anion transporter family (SLC22A12) that mainly regulates tubular urate reabsorption. Loss-of-function mutations result in idiopathic hypouricemia. The present case-control study was designed to analyze whether hURAT1 might also be a candidate gene for hyperuricemia with primary reduced renal urate excretion.Methods. DNA samples from 389 individuals with reduced fractional excretion of uric acid (FEUA) (<6.5%) and from 263 controls (FEUA >6.5%) were sequenced. Genotype frequencies between groups were compared by Cochran-Armitage trend test.Results. Significantly different genotype distributions could be demonstrated for the ؊788 T>A (promoter; P ‫؍‬ 0.014), the C258T (exon 1; P ‫؍‬ 0.006), and the C426T (exon 2; P ‫؍‬ 0.0002) polymorphisms, but not for the T1309C (exon 8) and the ؉18 C>T (intron 9) polymorphisms. The strongest association with reduced FEUA was observed for the C426T polymorphism, with odds ratios (ORs) of 1.59 and 2.54 (P ‫؍‬ 0.0002) for the CT and TT genotypes, respectively. Adjusted values for FEUA in the C426T genotype, were significantly reduced decreasing to 7.3%, 6.7%, and 6.3% in individuals with the CC, CT, and TT genotypes, respectively (P ‫؍‬ 0.004). Haplotypes were constructed from the ؊788 T>A, C258T, and C426T polymorphisms. Individuals carrying at least 1 ACT haplotype (n ‫؍‬ 349) had a significantly higher risk for reduced FEUA than individuals without any ACT haplotype (n ‫؍‬ 303) (OR 1.39, P ‫؍‬ 0.041).Conclusion. These results indicate that polymorphisms in the N-terminus of the hURAT1 gene were significantly associated with reduced renal uric acid excretion. The main regulating factor seems to be located close to the C426T polymorphism or is in strong linkage disequilibrium.In Germany, as in most Western countries, the prevalence of hyperuricemia is ϳ30% in men and 3% in women (1). Of these individuals, ϳ10% develop gout. The familial nature of hyperuricemia and gout has long been recognized. Among family members of patients with gout, the prevalence of asymptomatic hyperuricemia ranges from 25% to 27% (2,3). In a study of twins, Emmerson et al (4) observed that monozygotic twins had more similar values of urate clearance and fractional excretion of uric acid (FEUA) than did dizygotic twins. The heritability of the renal urate clearance was estimated as ϳ60%, whereas the heritability of the fractional urate excretion was found to be 87% (4). In Ͼ90% of patients with primary gout, reduced renal uric acid clearance causes hyperuricemia.Glomerular filtration and bidirectional urate transport, including both tubular secretion and reabsorption, are the essential physiologic processes in renal handling of uric acid (5). Under normal conditions, uric acid is freely filtered at the kidney glomerulus and almost completely reabsorbed from urine in the proximal tubule. According to the "four-component model" of urate excretion (6), net urate excretion is determined by tubular urate secretion and postsecretory urate ...

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 trade mark, 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.

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0802-3) contains supplementary material, which is available to authorized users.