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Objectives To determine factors that predict inadequate serum urate (SU) lowering response in a randomized controlled trial of allopurinol dose escalation (DE) in gout. Methods Participants undergoing allopurinol DE were classified as: complete response (CR)—reached target SU at month 9 and 12 of the DE phase or if still dose escalating at month 9 reached target SU by month 12; partial response (PR)—reached target at some stage but not fulfilling criteria for CR; or inadequate response (IR)—did not reach target SU at any time. Results IR was uncommon, occurring in 13/150 (8.7%), compared with 82 (54.7%) CR, and 55 (36.6%) PR. Mean (s. e. m.) SU was higher at the end of the 12-month DE in IR compared with both CR and PR groups; 7.6 (0.31) vs 5.01 (0.06) and 5.97 (0.17) mg/dl respectively (P < 0.001). In univariate analysis, compete responders tended to be older, be receiving less allopurinol, have longer gout duration and were more likely to be New Zealand (NZ) European ethnicity, compared with IR+PR. Using multi-variate logistic regression analysis, only longer duration of gout and NZ European ethnicity remained significant independent predictors of CR. Baseline SU ⩾ 8 mg/dl had a sensitivity of 69.2% and specificity of 85.1% in predicting IR. The odds ratio for an IR if baseline SU was ⩾8 mg/dl was 11.7 (95% CI 3.3, 41.2). Conclusion A minority of people with gout never reach target SU when allopurinol dose is increased in a treat-to-target manner. Approximately one-third of those with SU ⩾ 8mg/dl despite allopurinol ⩾300mg/d have an IR to DE. Trial registration Australian New Zealand Clinical Trails Registry, https://www.anzctr.org.au, ACTRN12611000845932. [ABSTRACT FROM AUTHOR]

Objectives. The aims of this study were to establish whether, in patients with gout, MPO is released from neutrophils and urate is oxidized to allantoin and if these effects are attenuated by allopurinol.Methods. MPO, urate, allantoin and oxypurinol were measured in plasma from 54 patients with gout and 27 healthy controls. Twenty-three patients had acute gout, 13 of whom were receiving allopurinol, and 31 had intercritical gout, 20 of whom were receiving allopurinol. Ten additional gout patients had samples collected before and after 4 weeks of allopurinol.Results. Plasma MPO and its specific activity were higher (P < 0.05) in patients with acute gout not receiving allopurinol compared with controls. MPO protein in patients’ plasma was related to urate concentration (r = 0.5, P < 0.001). Plasma allantoin was higher (P < 0.001) in all patient groups compared with controls. In controls and patients not receiving allopurinol, allantoin was associated with plasma urate (r = 0.62, P < 0.001) and MPO activity (r = 0.45, P < 0.002). When 10 patients were treated with allopurinol, it lowered their plasma urate and allantoin (P = 0.002). In all patients receiving allopurinol, plasma allantoin was related to oxypurinol (r = 0.65, P < 0.0001). Oxypurinol was a substrate for purified MPO that enhanced the oxidation of urate.Conclusion. Increased concentrations of urate in gout lead to the release of MPO from neutrophils and the oxidation of urate. Products of MPO and reactive metabolites of urate may contribute to the pathology of gout and hyperuricaemia. At low concentrations, oxypurinol should reduce inflammation, but high concentrations may contribute to oxidative stress. [ABSTRACT FROM PUBLISHER]

Objective. Gout is strongly associated with obesity. The aim of this study was to determine if obesity altered the inflammatory phenotype of non-adipose tissue-resident macrophages in response to the gout-causing agent monosodium urate (MSU) crystals.Methods. C57BL/6J mice were fed a high-fat diet for 12 weeks. Resident peritoneal macrophages were stimulated ex vivo with MSU crystals (200 µg/ml for 18 h) and the supernatants were collected. Mice were challenged with MSU crystals in vivo (3 mg, intraperitonal) and the peritoneal lavage fluid was collected (8 and 16 h). Cytokine and chemokine levels were analysed by multiplex bead array and peritoneal cell populations were analysed by flow cytometry.Results. Peritoneal macrophages from obese mice produced elevated background levels of IL-6, monocyte chemoattractant protein 1 (MCP-1) and keratinocyte-derived cytokine (KC) that decreased following MSU crystal stimulation ex vivo. MSU-induced IL-1β production was higher for macrophages from obese mice compared with controls. High background levels of IL-6, MCP-1, KC and GM-CSF, but not IL-1β, were measured in the peritoneal fluid of unchallenged obese mice. MSU crystal challenge in vivo raised IL-1β levels equally in both control and obese mice, whereas elevated background levels of IL-6, MCP-1, KC and GM-CSF levels dropped in obese mice. There was a consistent trend towards lower numbers of naive peritoneal resident macrophages and MSU-recruited monocytes and neutrophils in obese mice.Conclusion. Obesity induces a background pro-inflammatory environment orchestrated by non-adipose tissue-resident macrophages. However, this may not automatically translate into exacerbation of MSU crystal-induced inflammation in gout. [ABSTRACT FROM PUBLISHER]

Objectives. Bone erosion has been linked with tophus deposition in gout but the roles of osteitis (MRI bone oedema) and synovitis remain uncertain. Our aims in this prospective 3 T MRI study were to investigate the frequency of these features in gout and determine their relation to one another.Methods. 3 T MRI scans of the wrist were obtained in 40 gout patients. Scans were scored independently by two radiologists for bone oedema, erosions, tophi and synovitis. Dual-energy CT (DECT) scans were scored for tophi in a subgroup of 10 patients.Results. Interreader reliability was high for erosions and tophi [intraclass correlation coefficients (ICCs) 0.77 (95% CI 0.71, 0.87) and 0.71 (95% CI 0.52, 0.83)] and moderate for bone oedema [ICC = 0.60 (95% CI 0.36, 0.77)]. Compared with DECT, MRI had a specificity of 0.98 (95% CI 0.93, 0.99) and sensitivity of 0.63 (95% CI 0.48, 0.76) for tophi. Erosions were detected in 63% of patients and were strongly associated with tophi [odds ratio (OR) = 13.0 (95% CI 1.5, 113)]. In contrast, no association was found between erosions and bone oedema. Using concordant data, bone oedema was scored at 6/548 (1%) sites in 5/40 patients (12.5%) and was very mild (median carpal score = 1, maximum = 45). In logistic regression analysis across all joints nested within individuals, tophus, but not synovitis, was independently associated with erosion [OR = 156.5 (21.2, >999.9), P < 0.0001].Conclusion. Erosions were strongly associated with tophi but not bone oedema or synovitis. MRI bone oedema was relatively uncommon and low grade. These findings highlight the unique nature of the osteopathology of gout. [ABSTRACT FROM PUBLISHER]

Objective. To investigate the effect of hyperuricaemia on serum chemokine (C-C motif) ligand 2 (CCL2) levels and blood monocytes in people with gout. Methods. Whole blood was collected from subjects with a history of acute or chronic gout but not currently experiencing an attack of gout, subjects with asymptomatic hyperuricaemia and healthy individuals with normouricaemia. Serum concentrations of CCL2 were measured by bead array and levels of CD14+/CD11b+ blood monocytes determined by flow cytometry.Results. Subjects with gout and asymptomatic hyperuricaemia had higher serum levels of CCL2 and showed an increase in the percentage of circulating CD14+ monocytes compared with subjects with normouricaemia. Conclusion. Hyperuricaemia causes elevated serum CCL2 levels and increased monocyte recruitment that may be driven by soluble uric acid-induced CCL2 production. Hyperuricaemia may initiate subclinical priming of circulating blood monocytes for adhesion and trafficking during a gout attack. [ABSTRACT FROM AUTHOR]

Objective. To determine the effects of furosemide on serum urate (SU), plasma oxypurinol and urinary urate.Methods. Twenty-three cases with gout receiving furosemide and allopurinol were recruited. Twenty-three controls with gout receiving allopurinol but no diuretics were matched on age, gender, estimated glomerular filtration rate and allopurinol dose. SU, plasma oxypurinol and urinary urate were assessed on a single occasion. The effects of a single dose of furosemide 40 mg were examined in a separate group of 10 patients receiving allopurinol but not diuretic.Results. Cases had significantly higher SU and plasma oxypurinol compared with controls despite receiving similar doses of allopurinol. There was no difference in urinary urate excretion. There was a significant increase in area under the curve (AUC)0–24 for oxypurinol after administration of furosemide 40 mg.Conclusion. The interaction between allopurinol and furosemide results in increased SU and plasma oxypurinol. The exact mechanisms remain unclear but complex interactions that result in attenuation of the hypouricaemic effects of oxypurinol are likely.Trial registration: Australian New Zealand Clinical Trials Registry, www.anzctr.org.au, 12609000529246. [ABSTRACT FROM PUBLISHER]

Objectives. To validate the Dudley Inflammatory Bowel Disease Questionnaire (DISQ) for determining the presence and severity of bowel symptoms in axial SpA.Methods. Seventy-seven SpA patients were assessed for disease activity using the BASDAI. All participants, including 32 healthy controls and 29 patients with Crohn's Disease (CD), completed the DISQ and an assessment of stool form and frequency. Validation of the DISQ was undertaken in accordance with OMERACT criteria.Results. Validity of the DISQ for measuring bowel symptoms in SpA was confirmed (Cronbach's α 0.79). Mean DISQ scores (s.d.) were: controls 2.6 (2.6), SpA 8.7 (6.1) and CD 17.1 (10.2). Differences were significant between controls and SpA, and SpA and CD, and correlated with disease activity (ρ 0.27, P = 0.02). In SpA, DISQ scores of those taking NSAIDs (n = 59) did not differ from those not taking NSAIDs (n = 18) (P = 0.31). Stool form and frequency differed significantly between SpA patients and healthy controls (P < 0.001). Using the DISQ the prevalence of clinically relevant bowel symptoms in SpA is 31%, and 7.8% experience bowel symptoms equivalent to active CD.Conclusion. The DISQ is a valid measure of bowel symptoms in SpA. Bowel symptoms are prevalent in SpA and correlate with disease activity. Symptoms do not relate to treatment with NSAIDs. We conclude that bowel symptoms should be included as a domain in the clinical assessment of patients with SpA and that the DISQ has potential as an outcome measure in clinical trials. [ABSTRACT FROM PUBLISHER]

A letter to the editor is presented in response to the article "Digital tomosynthesis for bone erosion scoring in gout: comparison with plain radiography and computed tomography" on the June 27, 2014 issue.