Altered N-methyl D-aspartate receptor subunit expression causes changes to the circadian clock and cell phenotype in osteoarthritic chondrocytes.

The chondrocyte circadian clock is altered in osteoarthritis. This change is implicated in the disease-associated changes in chondrocyte phenotype and cartilage loss. Why the clock is changed is unknown. N-methyl-D-aspartate receptors (NMDAR) are critical for regulating the hypothalamic clock. Chondrocytes also express NMDAR and the type of NMDAR subunits expressed changes in osteoarthritis. OBJECTIVE: To determine if NMDAR regulate the chondrocyte clock and phenotype. DESIGN: Chondrocytes isolated from macroscopically-normal (MN) and osteoarthritic human cartilage were treated with NMDAR antagonists or transfected with GRIN2A or GRIN2B-targetting siRNA. H5 chondrocytes were transfected with GluN2B-expression plasmids. Clock genes and chondrocyte phenotypic markers were measured by RT-qPCR. RESULTS: PER2 amplitude was higher and BMAL1 amplitude lower in osteoarthritic compared to MN chondrocytes. In osteoarthritic chondrocytes, NMDAR inhibition restored PER2 and BMAL1 expression to levels similar to MN chondrocytes, and resulted in reduced MMP13 and COL10A1. Paradoxically, NMDAR inhibition in MN chondrocytes resulted in increased PER2, decreased BMAL1 and increased MMP13 and COL10A1. Osteoarthritic, but not MN chondrocytes expressed GluN2B NMDAR subunits. GluN2B knockdown in osteoarthritic chondrocytes restored expression of circadian clock components and phenotypic markers to levels similar to MN chondrocytes. Ectopic expression of GluN2B resulted in reduced BMAL1, increased PER2 and altered SOX9, RUNX2 and MMP13 expression. Knockdown of PER2 mitigated the effects of GluN2B on SOX9 and MMP13. CONCLUSIONS: NMDAR regulate the chondrocyte clock and phenotype suggesting NMDAR may also regulate clocks in other peripheral tissues. GluN2B expression in osteoarthritis may contribute to pathology by altering the chondrocyte clock.

ABCG2 loss-of-function polymorphism predicts poor response to allopurinol in patients with gout.

Many patients fail to achieve the recommended serum urate (SU) target (<6 mgdl-1) with allopurinol. The aim of our study was to examine the association of ABCG2 with SU target in response to standard doses of allopurinol using a cohort with confirmed adherence. Good response was defined as SU<6 mgdl-1 on allopurinol ⩽300 mgd-1 and poor response as SU⩾6 mgdl-1 despite allopurinol >300 mgd-1. Adherence was confirmed by oxypurinol concentrations. ABCG2 genotyping was performed using pre-designed single nucleotide polymorphism (SNP) TaqMan assays. Of 264 patients, 120 were good responders, 68 were poor responders and 76 were either non-adherent or could not be classified. The minor allele of ABCG2 SNP rs2231142 conferred a significantly increased risk of poor response to allopurinol (odds ratio=2.71 (1.70-4.48), P=6.0 × 10-5). This association remained significant after adjustment for age, sex, body mass index, ethnicity, estimated glomerular filtration rate, diuretic use and SU off urate-lowering therapy. ABCG2 rs2231142 predicts poor response to allopurinol, as defined by SU⩾6 mgdl-1 despite allopurinol >300 mgd-1.

Patients with gout have short telomeres compared with healthy participants: association of telomere length with flare frequency and cardiovascular disease in gout.

AIM AND BACKGROUND: Chronic inflammation associates with increased senescence, which is a strong predictor for cardiovascular disease. We hypothesised that inflammation accelerates senescence and thereby enhances the risk of cardiovascular disease in gout. METHODS: We assessed replicative senescence by quantifying telomere length (TL) in a discovery cohort of 145 Dutch patients with gout and 273 healthy individuals and validated our results in 474 patients with gout and 293 healthy participants from New Zealand. Subsequently, we investigated the effect of cardiovascular disease on TL of all participants. Also, we measured TL of CD4+ and CD8+ T lymphocytes, B lymphocytes, monocytes, natural killer cells and plasmacytoid dendritic cells. Additionally, we assessed the potential temporal difference in TL and telomerase activity. RESULTS: TL in PBMCs of healthy donors decreased over time, reflecting normal ageing. Patients with gout demonstrated shorter telomeres (p=0.001, R2=0.01873). In fact, the extent of telomere erosion in patients with gout was higher at any age compared with healthy counterparts at any age (p<0.0001, R2=0.02847). Patients with gout with cardiovascular disease had the shortest telomeres and TL was an independent risk factor for cardiovascular disease in patients with gout (p=0.001). TL was inversely associated with the number of gouty flares (p=0.005). CONCLUSIONS: Patients with gout have shorter telomeres than healthy participants, reflecting increased cellular senescence. Telomere shortening was associated with the number of flares and with cardiovascular disease in people with gout.

Treat-to-target (T2T) recommendations for gout.

OBJECTIVES: The treat-to-target (T2T) concept has been applied successfully in several inflammatory rheumatic diseases. Gout is a chronic disease with a high burden of pain and inflammation. Because the pathogenesis of gout is strongly related to serum urate levels, gout may be an ideal disease in which to apply a T2T approach. Our aim was to develop international T2T recommendations for patients with gout. METHODS: A committee of experts with experience in gout agreed upon potential targets and outcomes, which was the basis for the systematic literature search. Eleven rheumatologists, one cardiologist, one nephrologist, one general practitioner and one patient met in October 2015 to develop T2T recommendations based on the available scientific evidence. Levels of evidence, strength of recommendations and levels of agreement were derived. RESULTS: Although no randomised trial was identified in which a comparison with standard treatment or an evaluation of a T2T approach had been performed in patients with gout, indirect evidence was provided to focus on targets such as normalisation of serum urate levels. The expert group developed four overarching principles and nine T2T recommendations. They considered dissolution of crystals and prevention of flares to be fundamental; patient education, ensuring adherence to medications and monitoring of serum urate levels were also considered to be of major importance. CONCLUSIONS: This is the first application of the T2T approach developed for gout. Since no publication reports a trial comparing treatment strategies for gout, highly credible overarching principles and level D expert recommendations were created and agreed upon.

Twenty-eight loci that influence serum urate levels: analysis of association with gout.

OBJECTIVES: Twenty-eight genetic loci are associated with serum urate levels in Europeans. Evidence for association with gout at most loci is absent, equivocal or not replicated. Our aim was to test the loci for association with gout meeting the American College of Rheumatology gout classification criteria in New Zealand European and Polynesian case-control sample sets. METHODS: 648 European cases and 1550 controls, and 888 Polynesian (Ma¯ori and Pacific) cases and 1095 controls were genotyped. Association with gout was tested by logistic regression adjusting for age and sex. Power was adequate (>0.7) to detect effects of OR>1.3. RESULTS: We focused on 24 loci without previous consistent evidence for association with gout. In Europeans, we detected association at seven loci, one of which was the first report of association with gout (IGF1R). In Polynesian, association was detected at three loci. Meta-analysis revealed association at eight loci-two had not previously been associated with gout (PDZK1 and MAF). In participants with higher Polynesian ancestry, there was association in an opposing direction to Europeans at PRKAG2 and HLF (HLF is the first report of association with gout). There was obvious inconsistency of gout association at four loci (GCKR, INHBC, SLC22A11, SLC16A9) that display very similar effects on urate levels. CONCLUSIONS: We provide the first evidence for association with gout at four loci (IGF1R, PDZK1, MAF, HLF). Understanding why there is lack of correlation between urate and gout effect sizes will be important in understanding the aetiology of gout.

The safety and efficacy of benzbromarone in gout in Aotearoa New Zealand.

BACKGROUND: Benzbromarone is a potent uricosuric but is not widely available due to concerns about hepatotoxicity. In Aotearoa New Zealand, benzbromarone has been available since April 2013, subject to funding restrictions, for patients with inadequate urate-lowering response or intolerance to allopurinol and probenecid. AIM: To assess the safety and efficacy of benzbromarone in a real-life setting. METHODS: All patients who received funding for benzbromarone from 1 April 2013 to 30 September 2014 were identified. Prescribers were sent a questionnaire for each individual. Information on demographics, efficacy of previous urate-lowering drugs and reasons for discontinuation were collected. Specific information about the dose, effect on serum urate, adverse effects and liver function tests after commencing benzbromarone was recorded. RESULTS: Completed questionnaires were returned for 123 of 164 (75%) patients. Mean (SD) serum urate prior to benzbromarone was 0.57 (0.12) mmol/L, and estimated glomerular filtration rate was 50.3 (22.8) mL/min/1.73 m(2) . The median dose of benzbromarone was 100 mg/day (25-200 mg/day). Six months after commencing benzbromarone, mean (SD) serum urate was 0.35 (0.12) mmol/L. Benzbromarone-related adverse events included rash (n = 4), diarrhoea (n = 9), nausea (n = 6) and urate stones (n = 3). Liver function test abnormalities were uncommon and tended to be mild. There were 14 patient deaths; none was considered related to benzbromarone. Allopurinol had been prescribed prior to benzbromarone in 117 of 123 patients; median maximum allopurinol dose was 200 mg/day (range 25-600 mg/day), and 19% patients received allopurinol >300 mg/day. CONCLUSION: Benzbromarone provides useful urate-lowering efficacy and does not appear unsafe in patients with gout. Urate-lowering therapy prescribing requires further optimisation.

Exploring cartilage damage in gout using 3-T MRI: distribution and associations with joint inflammation and tophus deposition.

OBJECTIVE: Few imaging studies have investigated cartilage in gout. Magnetic resonance imaging (MRI) can image cartilage damage and also reveals other features of gouty arthropathy. The objective was to develop and validate a system for quantifying cartilage damage in gout. METHODS: 3-T MRI scans of the wrist were obtained in 40 gout patients. MRI cartilage damage was quantified using an adaptation of the radiographic Sharp van der Heijde score. Two readers scored cartilage loss at 7 wrist joints: 0 (normal), 1 (partial narrowing), 2 (complete narrowing) and concomitant osteoarthritis was recorded. Bone erosion, bone oedema and synovitis were scored (RAMRIS) and tophi were assessed. Correlations between radiographic and MRI cartilage scores were investigated, as was the reliability of the MRI cartilage score and its associations. RESULTS: The GOut MRI Cartilage Score (GOMRICS) was highly correlated with the total Sharp van der Heijde (SvdH) score and the joint space narrowing component (R = 0.8 and 0.71 respectively, p < 0.001). Reliability was high (intraobserver, interobserver ICCs = 0.87 [0.57-0.97], 0.64 [0.41-0.79] respectively), and improved on unenhanced scans; interobserver ICC = 0.82 [0.49-0.95]. Cartilage damage was predominantly focal (82% of lesions) and identified in 40 out of 280 (14%) of joints. Cartilage scores correlated with bone erosion (R = 0.57), tophus size (R = 0.52), and synovitis (R = 0.55), but not bone oedema scores. CONCLUSIONS: Magnetic resonance imaging can be used to investigate cartilage in gout. Cartilage damage was relatively uncommon, focal, and associated with bone erosions, tophi and synovitis, but not bone oedema. This emphasises the unique pathophysiology of gout.

IL-1ß induces changes in expression of core circadian clock components PER2 and BMAL1 in primary human chondrocytes through the NMDA receptor/CREB and NF-κB signalling pathways.

The circadian clock is a specialised cell signalling circuit present in almost all cells. It controls the timing of key cell activities such as proliferation and differentiation. In osteoarthritis, expression of two components of the circadian clock, BMAL1 and PER2 is altered in chondrocytes and this change has been causally linked with the increase in proliferation and altered chondrocyte differentiation in disease. IL-1ß, an inflammatory cytokine abundant in OA joints, has previously been shown to induce changes in BMAL1 and PER2 expression in chondrocytes. The purpose of this study is to identify the mechanism involved. We found IL-1ß treatment of primary human chondrocytes led to activation of NMDA receptors as evidenced by an increase in phosphorylation of GluN1 and an increase in intracellular calcium which was blocked by the NMDAR antagonist MK801. Levels of phosphorylated CREB were also elevated in IL-1ß treated cells and this effect was blocked by co-treatment of cells with IL-1ß and the NMDAR antagonist MK-801. Knockdown of CREB or inhibition of CREB activity prevented the IL-1ß induced increase in PER2 expression in chondrocytes but had no effect on BMAL1. Phosphorylated p65 levels were elevated in IL-1ß treated chondrocytes indicating increased NF-κB activation. Inhibition of NF-κB activity prevented the IL-1ß induced reduction in BMAL1 expression and partially mitigated the IL-1ß induced increase in PER2 expression in chondrocytes. These data indicate that the NMDAR/CREB and NF-κB signalling pathways regulate the core circadian clock components PER2 and BMAL1 in chondrocytes. Given that changes in expression of these clock components have been observed in a wide range of diseases, these findings may be broadly relevant for understanding the mechanism leading to circadian clock changes in pathology.

Urate-induced epigenetic modifications in myeloid cells.

OBJECTIVES: Hyperuricemia is a metabolic condition central to gout pathogenesis. Urate exposure primes human monocytes towards a higher capacity to produce and release IL-1ß. In this study, we assessed the epigenetic processes associated to urate-mediated hyper-responsiveness. METHODS: Freshly isolated human peripheral blood mononuclear cells or enriched monocytes were pre-treated with solubilized urate and stimulated with LPS with or without monosodium urate (MSU) crystals. Cytokine production was determined by ELISA. Histone epigenetic marks were assessed by sequencing immunoprecipitated chromatin. Mice were injected intraarticularly with MSU crystals and palmitate after inhibition of uricase and urate administration in the presence or absence of methylthioadenosine. DNA methylation was assessed by methylation array in whole blood of 76 participants with normouricemia or hyperuricemia. RESULTS: High concentrations of urate enhanced the inflammatory response in vitro in human cells and in vivo in mice, and broad-spectrum methylation inhibitors reversed this effect. Assessment of histone 3 lysine 4 trimethylation (H3K4me3) and histone 3 lysine 27 acetylation (H3K27ac) revealed differences in urate-primed monocytes compared to controls. Differentially methylated regions (e.g. HLA-G, IFITM3, PRKAB2) were found in people with hyperuricemia compared to normouricemia in genes relevant for inflammatory cytokine signaling. CONCLUSION: Urate alters the epigenetic landscape in selected human monocytes or whole blood of people with hyperuricemia compared to normouricemia. Both histone modifications and DNA methylation show differences depending on urate exposure. Subject to replication and validation, epigenetic changes in myeloid cells may be a therapeutic target in gout.

What is associated with being active in arthritis? Analysis from the Obstacles to Action study.

BACKGROUND: Many adults with arthritis do not achieve physical activity levels recommended for good health. This study aimed to identify factors associated with physical activity participation in people with arthritis. METHODS: 1106 out of 8163 adults with self-reported arthritis were identified from the 2003 Obstacles to Action study. Participants were classified as active if they reported 30 min of moderate activity > or = 5 days a week or 20 min of vigorous activity > or = 3 days a week (n = 613), or insufficiently active if they did not (n = 438). Sociodemographic factors, attitudes, self-efficacy, motivators and barriers to being active were analysed. RESULTS: Active people with arthritis had a lower burden of chronic disease than insufficiently active people (18% with three or more chronic medical conditions vs 33%, P < 0.0001). Active participants believed more strongly in the benefits of physical activity, reported higher levels of encouragement from others and had greater overall levels of self-efficacy when compared with the less active participants (P for all <0.0001). Arthritis, fatigue and discomfort were ranked by both groups as the top three barriers. However, the active participants reported lower impact scores for these barriers than the inactive group (P for all <0.0001). These findings persisted after adjusting for occupational status, body mass index and comorbidities. CONCLUSION: Active adults with arthritis have lower levels of chronic disease, greater self-efficacy and fewer psychosocial barriers. Recognition of such barriers and motivators may be useful when designing intervention programmes to help people with arthritis initiate or intensify physical activity participation.

Mechanisms of bone erosion in gout: a quantitative analysis using plain radiography and computed tomography.

OBJECTIVE: The underlying basis of bone erosion in gout remains speculative. The aim of this study was to understand the mechanisms of bone erosion in gout using non-invasive imaging techniques. METHODS: Paired plain radiographs and computed tomography (CT) scans of 798 individual hand and wrist joints from 20 patients with gout were analysed. Radiographs were scored for erosion (0-5) using the Sharp/van der Heijde method. CT scans were scored for the presence and diameter of bone erosions and tophi. The presence of intraosseous tophus (tophus visualised within bone) was recorded. The relationships between radiographic erosion, CT erosion and tophus scores were analysed. RESULTS: With increasing radiographic erosion scores, the percentage of joints with intraosseous tophus increased (p<0.001). For those joints with a radiographic erosion score of 4 or 5, 96/98 (98%) had CT evidence of intraosseous tophus. There was a significant relationship between the radiographic erosion scores and intraosseous tophus size (p<0.001). For those joints with CT erosion, 194/237 (81.8%) had visible intraosseous tophus. Of the joints with CT erosions greater than 5 mm, 106/112 (94.6%) had visible intraosseous tophus and all (56/56) erosions greater than 7.5 mm had intraosseous tophus. There was a strong correlation between CT erosion diameter and intraosseous tophus diameter (r = 0.93, p<0.001). Intraosseous tophi were larger than non-intraosseous tophi, but had similar density and calcification. CONCLUSION: There is a strong relationship between bone erosion and the presence of intraosseous tophus. These results strongly implicate tophus infiltration into bone as the dominant mechanism for the development of bone erosion and joint damage in gout.

Cellular characterisation of magnetic resonance imaging bone oedema in rheumatoid arthritis; implications for pathogenesis of erosive disease.

OBJECTIVES: Magnetic resonance imaging (MRI) bone oedema is an important predictor of bone erosion in rheumatoid arthritis (RA). This study aimed to determine the cellular components of MRI bone oedema, and clarify the relationship between bone erosion and MRI bone oedema. METHODS: Twenty-eight bones from 11 patients with RA undergoing orthopaedic surgery were analysed by quantitative and semi-quantitative immunohistochemistry. Pre-operative contrast-enhanced MRI scans were analysed for bone oedema. RESULTS: The density of osteoclasts was higher in those samples with MRI bone oedema than those without MRI bone oedema (p = 0.01). Other cells identified within bone marrow included macrophages and plasma cells, and these were more numerous in samples with MRI bone oedema (p = 0.02 and 0.05 respectively). B cells were present in lower numbers, but B cell aggregates were identified in some samples with MRI bone oedema. There was a trend to increased RANKL expression in samples with MRI bone oedema (p = 0.09). Expression of RANKL correlated with the number of osteoclasts (r = 0.592, p = 0.004). CONCLUSIONS: The increased number of osteoclasts and RANKL expression in samples with MRI bone oedema supports the hypothesis that bone erosion in RA occurs through activation of local bone resorption mechanisms within subchondral bone as well as through synovial invasion into bone.

Evidence for association of an interleukin 23 receptor variant independent of the R381Q variant with rheumatoid arthritis.

OBJECTIVE: The rare allele of a non-synonymous interleukin 23 receptor (IL23R) single nucleotide polymorphism (SNP) rs11209026 (p.Arg381Gln) confers strong protection against Crohn disease (CD) and psoriasis. Other IL23R variants also exhibit association with CD, genetically independent of rs11209026. In rheumatoid arthritis (RA), IL23 is an important determinant of the production of IL17A, a cytokine of consequence in inflammation and bone destruction. While there is no previous support for strong association of IL23R with RA, the possibility of a weaker role for IL23R variants in the aetiology of RA cannot be eliminated. METHODS: A New Zealand RA cohort was tested for association with six IL23R SNPs and the resulting data combined with a reanalysis of the Wellcome Trust Case Control Consortium data and a previously published Spanish data set. The combined data set totals over 3000 Caucasian cases and 3800 controls, which has sufficient power to detect a risk of as low as odds ratio (OR) = 1.2. RESULTS: Our data emphasise the lack of association of rs11209026 with RA (OR 1.01, 95% confidence interval (CI) 0.88 to 1.16, p = 0.86). However there was some evidence for association of rs1343151 with RA (OR 1.14, 95% CI 1.06 to 1.22, p = <0.001). CONCLUSIONS: While requiring further replication, these data further support a role for the IL17A/IL23 pathway in RA. Understanding how different variants of IL23R associate, at varying levels of strength, with contrasting groups of immune-mediated diseases (CD, psoriasis, ankylosing spondylitis, RA) will enhance knowledge on the aetiology of these diseases.

Crystal ball gazing: new therapeutic targets for hyperuricaemia and gout.

Recent studies in diverse disciplines have led to significant advances in the understanding of the basic biology of hyperuricaemia and gout, with important implications for future treatment. These findings include genetic variation within SLC2A9 as a key regulator of urate homeostasis, and identification of urate-anion exchanger urate transporter 1 (URAT1) and other renal uric acid transporters. Recognition of urate as an endogenous danger signal and activator of the adaptive immune response suggests an important role for urate crystals in non-microbial immune surveillance. The central role of NALP3 inflammasome activation and IL-1beta signalling in the initiation of the acute gout attack raises the possibility of new therapeutic targets. Disordered osteoclastogenesis in patients with chronic gout highlights potential therapies for prevention of joint damage. This review summarizes these findings and the potential relevance for future management of gout.

A modified Delphi exercise to determine the extent of consensus with OMERACT outcome domains for studies of acute and chronic gout.

OBJECTIVES: To reach consensus with recommendations made by an OMERACT Special Interest Group (SIG). METHODS: Rheumatologists and industry representatives interested in gout rated and clarified, in three iterations, the importance of domains proposed by the OMERACT SIG for use in acute and chronic gout intervention studies. Consensus was defined as a value of less than 1 of the UCLA/RAND disagreement index. RESULTS: There were 33 respondents (61% response rate); all agreed the initial items were necessary, except "total body urate pool". Additional domains were suggested and clarification sought for defining "joint inflammation" and "musculoskeletal function". Items that demonstrated no clear decision were re-rated in the final iteration. There were six highly rated items (rating 1-2) with four slightly lower rating items (rating 3) for acute gout; and 11 highly rated items with eight slightly lower ratings for chronic gout. CONCLUSIONS: Consensus is that the following domains be considered mandatory for acute gout studies: pain, joint swelling, joint tenderness, patient global, physician global, functional disability; and for chronic gout studies: serum urate, gout flares, tophus regression, health-related quality of life, functional disability, pain, patient global, physician global, work disability and joint inflammation. Several additional domains were considered discretionary.

Functional MRI in NPSLE patients reveals increased parietal and frontal brain activation during a working memory task compared with controls.

OBJECTIVES: Anatomical MRI brain scans may not reflect neurological dysfunction in patients with NPSLE. We used blood-oxygen-level-dependent functional MRI (BOLD-fMRI) to investigate working memory function in NPSLE patients. METHODS: Twenty-seven females took part: nine NPSLE patients (mean age 40 yrs; SLEDAI 10.9); nine RA patients and nine healthy controls. Subjects were tested using the n-back paradigm for working memory, where patients indicate when a stimulus matches one presented n trials previously. Functional scans used 3 mm slices x 30, repetition time 2570 ms, echo time 50 ms. Echo planar images were superimposed onto T1w anatomical images (Siemens 1.5 T). Data analysis used Brain Voyager QX Version 1.7. RESULTS: During the memory task, there was activation in areas serving working memory, executive function and attention in all groups. Nine regions of interest were selected for activation during working memory (N-back task vs fixation, P < or = 0.005). In six out of nine regions, there was greater activation in the NPSLE group. This reached significance in three regions: the posterior inferior parietal lobules of both hemispheres [Brodmann area (BA) 7] separately and combined (P = 0.014, 0.016 and 0.004, respectively), and the supplementary motor area (mid-line frontal lobe) (BA32/6; P = 0.032). CONCLUSIONS: NPSLE patients showed greater frontoparietal activation than the other groups during the memory task, suggesting a greater need to recruit extra cortical pathways, possibly to supplement impaired function of standard pathways.

The Health Assessment Questionnaire Disability Index is a valid measure of physical function in gout.

OBJECTIVE: There are no disability instruments that have specifically been validated for gout. The aim of this study was to determine the construct validity of the Health Assessment Questionnaire Disability Index (HAQ-DI) in gout and the internal validity using Rasch analysis. METHODS: An observational cohort study of two groups of clinic patients with gout (n=20, n=53), in which clinical and functional measures were correlated with HAQ-DI scores. Rasch analysis was used to determine the internal validity of summated scores as a measure of physical disability. RESULTS: The HAQ-DI items fitted a Rasch measurement model, confirming internal validity of the scale, although there was evidence of disordered thresholds and rescoring items as a 3-option response rather than a 4-option response improved model fit and resolved the disordered thresholds. HAQ-DI scores showed a bimodal distribution and evidence of floor effects. Clinical indices correlated highly with HAQ-DI scores in gout patients, particularly other measures of physical function. A strong relationship between days of sick leave and HAQ-DI was observed in gout patients (r2=0.44, p<0.001). CONCLUSIONS: It is concluded that HAQ-DI has good construct and internal validity in gout but a modified scoring approach better fits a Rasch model.

High-grade MRI bone oedema is common within the surgical field in rheumatoid arthritis patients undergoing joint replacement and is associated with osteitis in subchondral bone.

OBJECTIVES: MRI bone oedema has been observed in early and advanced RA and may represent a cellular infiltrate (osteitis) in subchondral bone. We studied MRI scans from RA patients undergoing surgery, seeking to identify regions of bone oedema and examine its histopathological equivalent in resected bone. METHODS: Preoperative contrast-enhanced MRI scans were obtained in 11 RA patients scheduled for orthopaedic surgery to the hands/wrists or feet. In 9, MRI scans were scored by 2 readers for bone oedema (RAMRIS system). Its distribution with respect to surgical site was investigated. In 4 patients, 7 bone samples were examined for a cellular infiltrate, and this was compared with MRI bone oedema, scored for spatial extent and intensity. RESULTS: Inter-reader intraclass correlation coefficients for bone oedema were 0.51 (all sites) and 0.98 (bone samples for histology). Bone oedema was observed at 60% of surgical sites vs 38% of non-surgical sites. High-grade bone oedema (score >/=50% maximum) was strongly associated with the surgical field (OR 9.3 (3.5 to 24.2), p<0.0001). Bone oedema scores correlated with pain (r = 0.67, p = 0.048) and CRP (r = 0.86, p = 0.01). In 4 of the 7 bone samples, there was concordance between bone oedema and subchondral osteitis. In 3, there was no MRI bone oedema, and osteitis was "slight". CONCLUSION: High-grade MRI bone oedema was common within the field of intended surgery and associated with pain. There was concordance between the presence and severity of MRI bone oedema and osteitis on histology, with an MRI threshold effect due to differences in image resolution.

Assessment of outcome in clinical trials of gout--a review of current measures.

There has been renewed interest in the treatment of gout with recent reported intervention studies of new agents such as etoricoxib, febuxostat and pegylated-uricase. However, these studies have highlighted the relative paucity of validated outcome measures with which to judge efficacy. This review outlines the published information regarding which endpoints have been measured in randomized clinical trials, what should be measured, what tools or instruments are available for this and the technical properties of such instruments. It highlights recent work that validates measures of tophi, radiographic damage and patient-reported outcomes. The absence of a valid definition of gout-flare or how flare reduction defines response is problematic; this forms the basis for a current ACR-EULAR sponsored project.

Tophaceous joint disease strongly predicts hand function in patients with gout.

OBJECTIVES: The functional impact of gout is poorly understood. The aim of this study was to determine predictors of hand function in gout. METHODS: Twenty unselected patients with gout were recruited from rheumatology clinics. No patient had an acute gout flare at assessment. Participants were assessed for clinical characteristics of gout, including the site and number of tophi. Hand function was assessed by the Sollerman hand function test. Fingertip to palm (FTP) distance measurement, grip strength and the Disability Assessment of Shoulder and Hand (DASH) questionnaire scores were also recorded. Data were analysed by simple and multiple linear regression models. RESULTS: The median Sollerman score was 75.5 (range 31-80). The median hand FTP distance was 2.91 (0.88-6.69) cm, grip strength was 31 (4-71) kg, and DASH score was 28.77 (0-76.47). Of the clinical characteristics measured, the number of joints of the hand with overlying tophi (hand tophus joint count) was the strongest single predictor of the Sollerman score (r2 = 0.59), and also predicted the other measures of hand mobility and function. A multiple regression model including hand tophus joint count, sex, number of gout flares in the preceding 6 months, gout disease duration and hand tender joint count was a better predictor of the Sollerman score than hand tophus joint count alone (r2 = 0.81, F(4,14) = 3.94, P = 0.024). CONCLUSIONS: Measures of chronic and poorly controlled disease predict hand function in patients with gout. In particular, tophaceous joint disease has a major impact on functional capacity in gout.