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MC Cleophas,1,2 LA Joosten,1–3 LK Stamp,4 N Dalbeth,5 OM Woodward,6 Tony R Merriman7 1Department of Internal Medicine, 2Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands; 3Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 4Department of Medicine, University of Otago Christchurch, Christchurch, 5Department of Medicine, University of Auckland, Auckland, New Zealand; 6Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA; 7Department of Biochemistry, University of Otago, Dunedin, New Zealand Abstract: As a result of the association of a common polymorphism (rs2231142, Q141K) in the ATP-binding cassette G2 (ABCG2) transporter with serum urate concentration in a genome-wide association study, it was revealed that ABCG2 is an important uric acid transporter. This review discusses the relevance of ABCG2 polymorphisms in gout, possible etiological mechanisms, and treatment approaches. The 141K ABCG2 urate-increasing variant causes instability in the nucleotide-binding domain, leading to decreased surface expression and function. Trafficking of the protein to the cell membrane is altered, and instead, there is an increased ubiquitin-mediated proteasomal degradation of the variant protein as well as sequestration into aggresomes. In humans, this leads to decreased uric acid excretion through both the kidney and the gut with the potential for a subsequent compensatory increase in renal urinary excretion. Not only does the 141K polymorphism in ABCG2 lead to hyperuricemia through renal overload and renal underexcretion, but emerging evidence indicates that it also increases the risk of acute gout in the presence of hyperuricemia, early onset of gout, tophi formation, and a poor response to allopurinol. In addition, there is some evidence that ABCG2 dysfunction may promote renal dysfunction in chronic kidney disease patients, increase systemic inflammatory responses, and decrease cellular autophagic responses to stress. These results suggest multiple benefits in restoring ABCG2 function. It has been shown that decreased ABCG2 141K surface expression and function can be restored with colchicine and other small molecule correctors. However, caution should be exercised in any application of these approaches given the role of surface ABCG2 in drug resistance. Keywords: ABCG2, BCRP, gout, urate, uric acid, polymorphism, allopurinol

Objective: There is increasing evidence that variation in gene copy number (CN) influences clinical phenotype. The low-affinity Fcgamma receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment to sites of inflammation and activation of polymorphonuclear neutrophils (PMNs). Given recent evidence that low FCGR3B CN is a risk factor for systemic but not organ-specific autoimmune disease and the potential importance of PMN in the pathophysiology of rheumatoid arthritis (RA), the authors hypothesised that FCGR3B gene dosage influences susceptibility to RA.Methods: FCGR3B CN was measured in 643 cases of RA and 461 controls from New Zealand (NZ), with follow-up analysis in 768 cases and 702 controls from the Netherlands and 250 cases and 211 controls from the UK. All subjects were of Caucasian ancestry.Results: Significant evidence for an association between CN <2 and RA was observed in the Dutch cohort (OR 2.01 (95% CI 1.37 to 2.94), p=3 x 10-4) but not in the two smaller cohorts (OR 1.45 (95% CI 0.92 to 2.26), p=0.11 and OR 1.33 (95% CI 0.58 to 3.02), p=0.50 for the NZ and UK populations, respectively). The association was evident in a meta-analysis which included a previously published Caucasian sample set (OR 1.67 (95% CI 1.28 to 2.17), p=1.2 x 10-4).Conclusions: One possible mechanism to explain the association between reduced FCGR3B CN and RA is the reduced clearance of immune complex during inflammation. However, it is not known whether the association between RA and FCGR3B CN is aetiological or acts as a proxy marker for another biologically relevant variant. More detailed examination of genetic variation within the FCGR gene cluster is required. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To examine the role of genetic variation in the renal urate transporter SLC2A9 in gout in New Zealand sample sets of Maori, Pacific Island, and Caucasian ancestry and to determine if the Maori and Pacific Island samples could be useful for fine-mapping. METHODS: Patients (n= 56 Maori, 69 Pacific Island, and 131 Caucasian) were recruited from rheumatology outpatient clinics and satisfied the American College of Rheumatology criteria for gout. The control samples comprised 125 Maori subjects, 41 Pacific Island subjects, and 568 Caucasian subjects without arthritis. SLC2A9 single-nucleotide polymorphisms rs16890979 (V253I), rs5028843, rs11942223, and rs12510549 were genotyped (possible etiologic variants in Caucasians). RESULTS: Association of the major allele of rs16890979, rs11942223, and rs5028843 with gout was observed in all sample sets (P = 3.7 x 10(-7), 1.6 x 10(-6), and 7.6 x 10(-5) for rs11942223 in the Maori, Pacific Island, and Caucasian samples, respectively). One 4-marker haplotype (1/1/2/1; more prevalent in the Maori and Pacific Island control samples) was not observed in a single gout case. CONCLUSION: Our data confirm a role of SLC2A9 in gout susceptibility in a New Zealand Caucasian sample set, with the effect on risk (odds ratio >2.0) greater than previous estimates. We also demonstrate association of SLC2A9 with gout in samples of Maori and Pacific Island ancestry and a consistent pattern of haplotype association. The presence of both alleles of rs16890979 on susceptibility and protective haplotypes in the Maori and Pacific Island sample is evidence against a role for this nonsynonymous variant as the sole etiologic agent. More extensive linkage disequilibrium in Maori and Pacific Island samples suggests that Caucasian samples may be more useful for fine-mapping. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine gene expression of the interleukin-17 (IL-17) family members (IL-17A-F) in rheumatoid subcutaneous nodules, and to assess the cytokines involved in regulating IL-17A expression. METHODS: Total RNA was isolated from 19 nodules obtained from 16 different patients with rheumatoid arthritis (RA). Reverse transcription-polymerase chain reaction (PCR) was used to screen for gene expression of the IL-17 subtypes (IL-17A-F) in all nodules. Quantitative real-time PCR was used to measure the expression of interferon-gamma (IFNgamma), IL-6, IL-23, IL-12, and transforming growth factor beta (TGFbeta), relative to GAPDH as control, in a subset of 10 nodules. RESULTS: IL-17A gene expression was present in only 1 of 19 nodules, IL-17B in 17 of 19 nodules, IL-17C in 18 of 19 nodules, IL-17D in 16 of 19 nodules, and IL-17E in 3 of 19 nodules. IL-17F was absent in all samples. Cytokines that stimulate IL-17A production (IL-6, IL-23) as well as those that inhibit IL-17A production (IL-12, IFNgamma, TGFbeta) were present in the majority of nodules. Quantitative real-time PCR showed a similar pattern of gene expression for the individual cytokines between the different nodules. The mean +/- SD expression of IL-6 relative to GAPDH was 2.28 +/- 2.2 ng, and that of TGFbeta was 2.96 +/- 1.14 ng. There was a lower relative expression of IL-23 (0.05 +/- 0.05 ng), while the expression of IFNgamma was 0.67 +/- 0.68 ng and that of IL-12 was 0.48 +/- 0.23 ng. CONCLUSION: IL-17 family members are varyingly expressed in rheumatoid nodules. The paucity of IL-17A in nodules suggests an important difference from that observed in the synovium. The expression of IL-23 below a critical threshold level seems the most likely explanation for the virtual absence of IL-17A. The presence of tissue destruction within the nodule despite the absence of IL-17A suggests that IL-17A may be an important amplifier rather than an absolute requirement for inflammation in RA. [ABSTRACT FROM AUTHOR]

Gout is a chronic disease that is caused by an innate immune response to deposited monosodium urate crystals in the setting of hyperuricemia. Here, we provide insights into the molecular mechanism of the poorly understood inflammatory component of gout from a genome-wide association study (GWAS) of 2.6 million people, including 120,295 people with prevalent gout. We detected 377 loci and 410 genetically independent signals (149 previously unreported loci in urate and gout). An additional 65 loci with signals in urate (from a GWAS of 630,117 individuals) but not gout were identified. A prioritization scheme identified candidate genes in the inflammatory process of gout, including genes involved in epigenetic remodeling, cell osmolarity and regulation of NOD-like receptor protein 3 (NLRP3) inflammasome activity. Mendelian randomization analysis provided evidence for a causal role of clonal hematopoiesis of indeterminate potential in gout. Our study identifies candidate genes and molecular processes in the inflammatory pathogenesis of gout suitable for follow-up studies., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: The study objective was to determine predictors of gout flare when commencing allopurinol using the "start-low go-slow" dose escalation strategy., Methods: A post hoc analysis of a 12-month double-blind placebo-controlled noninferiority trial with participants randomized 1:1 to colchicine 0.5 mg daily or placebo for the first six months was undertaken. Multivariate logistic regression models were used to identify independent predictors of gout flares in the first and last six months of the trial., Results: Multivariable analysis revealed a significant association between risk of a gout flare in the first six months and flare in the month before starting allopurinol (odds ratio [OR] 2.65, 95% confidence interval [CI] 1.36-5.17) and allopurinol 100 mg starting dose (OR 3.21, 95% CI 1.41-7.27). The predictors of any gout flares in the last six months of the trial, after stopping colchicine or placebo, were having received colchicine (OR 2.95, 95% CI 1.48-5.86), at least one flare in the month before stopping study drug (OR 5.39, 95% CI 2.21-13.15), and serum urate ≥0.36 mmol/L at month 6 (OR 2.85, 95% CI 1.14-7.12)., Conclusion: Anti-inflammatory prophylaxis when starting allopurinol using the "start-low go-slow" dose escalation strategy may be best targeted at those who have had a gout flare in the month before starting allopurinol and are commencing allopurinol 100 mg daily. For those with ongoing gout flares during the first six months of starting allopurinol who have not yet achieved serum urate target, a longer period of prophylaxis may be required., (© 2024 The Author(s). Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Little is known about the preferences of people with rheumatoid arthritis (RA) regarding tapering of biologic disease-modifying antirheumatic drugs (bDMARDs). The aim of this study was to assess the preferences of people with RA in relation to potential treatment-related benefits and risks of bDMARD tapering and the health care service-related attributes that affect tapering., Methods: Participants with RA who had experience taking a bDMARD completed an online discrete choice experiment. Participants were asked their preferences when given three hypothetical treatment scenarios in which varying the frequency of treatment might alter their chance of adverse effects, of regaining disease control, and of other health care service-related effects. Preference weights were estimated using a multinomial logit model., Results: There were 142 complete responses. Reduced dosing frequency of bDMARD treatment had the largest impact on preference (mean 1.0, 95% confidence interval [CI] 0.8-1.2), followed by chance of disease flare (mean 0.7, 95% CI 0.6-0.9). Participants were willing to accept an increased risk of flare between 10.6% (95% CI 3.2-17.9) and 60.6% (95% CI 48.1-72.9) in exchange for benefits associated with tapering bDMARDs. Participants with better quality of life were more likely to choose to remain on current treatment. The predicted uptake of bDMARD tapering was high among people with RA, suggesting bDMARD tapering was a favored option., Conclusion: For individuals with RA, making decisions about tapering bDMARDs involves considering several factors, with the most important determinants identified as dosing frequency and the risk of disease flare. Understanding patient perspectives of bDMARD tapering may enable physicians to make patient-focused shared health care decisions., (© 2024 The Author(s). Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: To compare the performance of the 2016 preliminary gout remission definition and a simplified gout remission definition in a clinical trial of nurse-led gout care., Methods: Data from a 2-year parallel arm, non-blinded, randomised controlled trial of 517 community-derived people with gout were analyzed. Participants were assigned 1:1 to receive nurse-led care or general practitioner usual care. Remission was defined using the 2016 preliminary gout remission definition and a simplified gout remission definition without patient reported outcomes. Binary logistic regression was used to compare intervention groups. General linear models were used to compare Gout Impact Scale (GIS) scores between those in remission and those not in remission using either definition., Results: Participants in the nurse-led care group were more likely to achieve remission using either definition; at Year 2 the odds ratio was 7.92 [95 % CI 4.86-12.92] using the 2016 preliminary definition and 11.88 [95 % CI 7.49-18.84] using the simplified definition. For all participants, the 2016 preliminary definition was fulfilled by 9.9 % at Year 1 and 28.4 % at Year 2, p < 0.001 and the simplified definition was fulfilled by 17.6 % at Year 1 and 42.7 % at Year 2, p < 0.001. People in remission using either definition had better gout outcomes assessed using the GIS, including greater control over their gout., Conclusion: Both definitions discriminated between the intervention groups and showed high construct validity. The simplified definition identified more people as being in gout remission at Year 1 and Year 2. The simplified definition is a feasible and valid option for defining gout remission., Competing Interests: Declaration of competing interest Nicola Dalbeth has received consulting or speaker fees from AstraZeneca, Dyve Biosciences, Horizon, Selecta, Arthrosi, JW Pharmaceutical Corporation, PK Med, LG Chem, JPI, PTC Therapeutics, Protalix, outside the submitted work. Lisa Stamp has received royalties from Up-to-Date and consulting fees from Pharmac NZ. Aliya Sarmanova was affiliated with the Nottingham University at the time of the study conduct and is currently affiliated with Roche Diagnostics International, Clinical Development and Medical Affairs. The other authors have no conflicting interests to report., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To investigate (1) the effect of colchicine prophylaxis on gout remission when commencing urate-lowering therapy (ULT), and (2) illness perceptions of people in remission using 2 definitions of gout remission., Methods: Data from a 12-month double-blind placebo-controlled trial of 200 people with gout commencing allopurinol were analyzed. Participants were randomly assigned to prophylaxis with 0.5 mg daily colchicine or placebo for 6 months, followed by 6 months of additional follow-up. Gout remission was assessed using the 2016 preliminary definition or simplified definition without patient-reported outcomes. Illness perceptions were assessed using a gout-specific version of the Brief Illness Perception Questionnaire., Results: In the first 6 months, few participants were in remission according to either the 2016 preliminary definition (3% for colchicine and 4% for placebo) or the simplified definition (7% for colchicine and 12% for placebo). In the second 6 months, after study drug (colchicine or placebo) discontinuation, fewer participants in the colchicine group than in the placebo group were in remission according to the 2016 preliminary definition (4% vs 14%, P = 0.03), and the simplified definition (14% vs 28%, P = 0.02). Participants fulfilling remission using either definition had more favorable perceptions about their gout symptoms and illness concerns, as well as consequences, when using the simplified definition., Conclusion: Using either definition, 6 months of colchicine prophylaxis when initiating ULT does not provide an advantage in the fulfillment of gout remission. People fulfilling either definition report fewer symptoms, less concern about their gout, and, when using the simplified definition, are less affected by gout.

Objectives: The minor allele of the common rs2231142 ABCG2 variant predicts inadequate response to allopurinol urate lowering therapy. We hypothesize that additional variants in genes encoding urate transporters and allopurinol-to-oxypurinol metabolic enzymes also predict allopurinol response., Methods: This study included a subset of participants with gout from the Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients, whose whole genome was sequenced (n = 563). Good responders had a 4:1 or 5:1 ratio of good (serum urate (SU) <0.36 mmol/l on allopurinol ≤300 mg/day) to poor (SU ≥ 0.36 mmol/l despite allopurinol >300 mg/day) responses over 5-6 timepoints, while inadequate responders had a 1:4 or 1:5 ratio of good to poor responses. Adherence to allopurinol was determined by pill counts, and for a subgroup (n = 303), by plasma oxypurinol >20μmol/l. Using the sequence kernel association test (SKAT) we estimated the combined effect of rare and common variants in urate secretory (ABCC4, ABCC5, ABCG2, SLC17A1, SLC17A3, SLC22A6, SLC22A8) and reuptake genes (SLC2A9, SLC22A11) and in allopurinol-to-oxypurinol metabolic genes (AOX1, MOCOS, XDH) on allopurinol response., Results: There was an association of rare and common variants in the allopurinol-to-oxypurinol gene group (PSKAT-C = 0.019), and in MOCOS, encoding molybdenum cofactor sulphurase, with allopurinol response (PSKAT-C = 0.011). Evidence for genetic association with allopurinol response in the allopurinol-to-oxypurinol gene group (PSKAT-C = 0.002) and MOCOS (PSKAT-C < 0.001) was stronger when adherence to allopurinol therapy was confirmed by plasma oxypurinol., Conclusion: We provide evidence for common and rare genetic variation in MOCOS associating with allopurinol response., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: This study aimed to identify variables that predict gout remission in people with erosive gout receiving urate-lowering therapy., Methods: We analyzed data from a two-year, double-masked randomized-controlled trial of people with erosive gout, randomized to a serum urate target of <0.20 mmol/L or <0.30 mmol/L using oral urate-lowering therapies. All participants had dual-energy computed tomography (DECT) scans of the feet and ankles at baseline. The proportion of participants achieving gout remission according to the 2016 preliminary gout remission criteria and simplified gout remission criteria (without the patient reported outcomes) was analyzed. Logistic regression models were used to evaluate predictors of gout remission in year 2., Results: The preliminary gout remission criteria were fulfilled in 11 of 97 participants (11%) at year 1 and 21 of 92 participants (23%) at year 2. The simplified criteria were fulfilled in 26 of 97 participants (27%) in year 1 and 40 of 92 participants (44%) in year 2. In multivariable regression models, baseline DECT monosodium urate crystal volume was the only significant independent predictor of gout remission at year 2, using either criteria. Each 1-cm 3 increase in the baseline DECT monosodium urate crystal volume decreased the odds of fulfilling the 2016 preliminary gout remission criteria (odds ratio [OR] 0.65, 95% confidence interval [CI] 0.46-0.93; P = 0.02) and the simplified gout remission criteria (OR 0.57, 95% CI 0.41-0.78; P < 0.001)., Conclusion: In people with erosive gout on urate-lowering therapy, higher baseline DECT monosodium urate crystal volume is associated with lower odds of gout remission after two years of treatment, defined by either the preliminary gout remission criteria or simplified gout remission criteria., (© 2024 The Author(s). Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: The study objective was to examine the disease, demographic, and imaging features associated with different inflammatory phenotypes of calcium pyrophosphate deposition (CPPD) disease, ie, recurrent acute calcium pyrophosphate (CPP) crystal arthritis, chronic CPP crystal inflammatory arthritis, and crowned dens syndrome (CDS)., Methods: Data from an international cohort (assembled from 25 sites in 7 countries for the development and validation of the 2023 CPPD classification criteria from the American College of Rheumatology/EULAR) that met the criteria were included. Three cross-sectional studies were conducted to determine the phenotypic characteristics of recurrent acute CPP crystal arthritis, chronic CPP crystal inflammatory arthritis, and CDS. Multivariable logistic regression analysis was used to calculate adjusted odds ratio (aOR) and 95% confidence interval (CI) to examine the association between potential risk factors and the inflammatory phenotype., Results: Among the 618 people included (56% female; mean age [standard deviation] 74.0 [11.9] years), 602 (97.4%) had experienced acute CPP crystal arthritis, 332 (53.7%) had recurrent acute arthritis, 158 (25.6%) had persistent inflammatory arthritis, and 45 (7.3%) had had CDS. Recurrent acute CPP crystal arthritis associated with longer disease duration (aOR 2.88 [95% CI 2.00-4.14]). Chronic CPP crystal inflammatory arthritis was associated with acute wrist arthritis (aOR 2.92 [95% CI 1.81-4.73]), metacarpophalangeal joint osteoarthritis (aOR 1.87 [95% CI 1.17-2.97]), and scapho-trapezo-trapezoid (STT) joint osteoarthritis (aOR 1.83 [95% CI 1.15-2.91]), and it was negatively associated with either metabolic or familial risk for CPPD (aOR 0.60 [95% CI 0.37-0.96]). CDS was associated with male sex (aOR 2.35 [95% CI 1.21-4.59]), STT joint osteoarthritis (aOR 2.71 [95% CI 1.22-6.05]), and more joints affected with chondrocalcinosis (aOR 1.46 [95% CI 1.15-1.85])., Conclusion: CPPD disease encompasses acute and chronic inflammatory phenotypes, each with specific clinical and imaging features that need to be considered in the diagnostic workup., (© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Allopurinol is the most widely used urate-lowering medication worldwide. However, allopurinol failure is frequently observed in clinical practice. In this review, we provide a framework for assessing allopurinol failure, which includes failure of allopurinol to control serum urate concentrations, failure of allopurinol to control clinical symptoms, and failure of allopurinol due to an adverse drug reaction. Understanding the causes of allopurinol failure underpins the approach required to turn failure into success in gout management., (Copyright © 2024 by the Journal of Rheumatology.)

Objectives: In 2015, the 20-item Tophus Impact Questionnaire (TIQ-20) was developed as a tophus-specific patient-reported outcome measure. The aim of this study was to determine whether TIQ-20 scores change during urate-lowering therapy., Methods: We analysed data from a 2-year clinical trial of allopurinol dose escalation using a treat-to-target serum urate approach. For participants with tophaceous gout, the longest diameter of up to three index tophi was measured, using Vernier calipers, and the TIQ-20 was recorded at study visits. Participants at the one site were invited to participate in a dual-energy CT (DECT) substudy. Participants were included in this analysis if they had tophaceous gout and TIQ-20 scores available at baseline, Year 1 and Year 2 (n = 58, 39 with DECT data). Data were analysed using a mixed-model approach to repeated measures., Results: Improvements were observed in all tophus measures over the 2-year period. The mean (s.d.) TIQ-20 scores reduced over 2 years from 3.59 (1.77) to 2.46 (1.73), P < 0.0001, and the mean (95% CI) TIQ-20 change over the 2 years was -1.13 (-1.54, -0.71). The effect size (Cohen's d) for the change in the sum of the index tophi diameter over 2 years was 0.68, for the DECT urate volume was 0.50, and for the TIQ-20 was 0.71., Conclusion: For people with tophaceous gout treated with allopurinol using a treat-to-target serum urate approach, improvements in TIQ-20 occurred, as did improvements in physical and imaging tophus measures. These findings demonstrate that the TIQ-20 is a responsive patient-reported instrument of tophus impact., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: Dose escalation at the initiation of allopurinol therapy can be protracted and resource intensive. Tools to predict the allopurinol doses required to achieve target serum urate concentrations would facilitate the implementation of more efficient dose-escalation strategies. The aim of this research was to develop and externally evaluate allopurinol dosing tools, one for use when the pre-urate-lowering therapy serum urate is known (Easy-Allo1) and one for when it is not known (Easy-Allo2)., Methods: A revised population pharmacokinetic-pharmacodynamic model was developed using data from 653 people with gout. Maintenance doses to achieve the serum urate target of <0.36 mmol L -1 in >80% of individuals were simulated and evaluated against external data. The predicted and observed allopurinol doses were compared using the mean prediction error (MPE) and root mean square error (RMSE). The proportion of Easy-Allo predicted doses within 100 mg of the observed was quantified., Results: Allopurinol doses were predicted by total body weight, baseline urate, ethnicity and creatinine clearance. Easy-Allo1 produced unbiased and suitably precise dose predictions (MPE 2 mg day -1 95% confidence interval [CI] -13-17, RMSE 91%, 90% within 100 mg of the observed dose). Easy-Allo2 was positively biased by about 70 mg day -1 and slightly less precise (MPE 70 mg day -1 95% CI 52-88, RMSE 131%, 71% within 100 mg of the observed dose)., Conclusions: The Easy-Allo tools provide a guide to the allopurinol maintenance dose requirement to achieve the serum urate target of <0.36 mmol L -1 and will aid in the development of novel dose-escalation strategies for allopurinol therapy., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objective: Despite scarce evidence, guidelines recommend weight loss as a management strategy for patients with gout. We investigated the effect of an intensive dietary intervention on body weight and clinical measures of gout severity in individuals with obesity and gout., Methods: We conducted a 16-week randomized nonmasked parallel-group trial in Denmark, randomly assigning (one-to-one) individuals with obesity and gout to a low-energy diet or a control diet. The primary outcome was change in body weight. Key secondary outcomes were changes in serum urate (SU) level and visual analog scale-assessed pain and fatigue., Results: Between December 1, 2018, and June 1, 2019, 61 participants were included in the intention-to-treat population and randomly assigned to the intensive diet group (n = 29) or control diet group (n = 32). Participants had a mean age of 60.3 (SD 9.9) years and mean body mass index of 35.6 (SD 5.0), and 59 (97%) were men. After 16 weeks, there was a significant difference in change in body weight between the diet and control groups (-15.4 vs -7.7 kg; difference -7.7 kg [95% confidence interval -10.7 to -4.7], P < 0.001). Despite results being potentially in favor of a low-energy diet, we could not confirm differences in SU level changes and fatigue between groups. No differences in pain and gout flares were observed between groups. No serious adverse events or deaths occurred during the trial., Conclusion: An intensive dietary intervention was safe and effectively lowered body weight in people with obesity and gout, but the weight loss did not directly translate into effects on SU level, fatigue, and pain., (© 2024 American College of Rheumatology.)

Gout is a common and treatable chronic disease of monosodium urate crystal deposition. It is experienced as extremely painful episodes of joint inflammation that impact all aspects of the person's life. This Clinical Perspectives article provides an update on gout diagnosis, medications and strategies to improve the quality of gout care., (© 2024 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Colchicine has an important role in managing various conditions, including gout, familial Mediterranean fever, amyloidosis, Behçet's syndrome, recurrent pericarditis and calcium pyrophosphate deposition disease. The adverse effect profile of colchicine is well understood. However, due to its narrow therapeutic index, colchicine has been associated with overdose and fatalities. When ingested in toxic amounts, the mainstay of management is supportive care. Strategies to minimize the risk of colchicine poisoning can focus on three broad causes: unauthorized access, intentional overdose and inappropriate dosing. Culturally safe and appropriate education about storage and appropriate use of colchicine is essential to minimize the risk of overdose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

The 'treat-to target serum urate strategy' when using urate-lowering therapy has been recommended by most specialist rheumatology societies for many years. An alternative "treat-to-avoid-symptoms" in gout has been suggested, albeit without a clear definition of what this means and how it might be implemented in clinical trials or clinical practice. This has hampered efforts to design clinical trials that compare the "treat-to-target [urate]" and "treat-to-avoid-symptoms" strategies in the long-term management of gout. In this review we consider the rationale for the treat-to-target urate strategy when using urate-lowering therapy, potential definitions of a "treat-to-avoid-symptoms" strategy, or perhaps what is not "treat-to-avoid-symptoms", and approaches that might address this uncertainty., Competing Interests: Declaration of competing interest LS reports Research Funding from the New Zealand Health Research Council and consulting fees from Pharmac outside the submitted work. ND- has received consulting fees, speaker fees or grants from AstraZeneca, Novartis, Dyve Biosciences, Horizon, Selecta, Arthrosi, JW Pharmaceutical Corporation, PK Med, LG Chem, JPI, PTC Therapeutics, Protalix, Unlocked Labs, Hikma outside the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To determine the influence of patient characteristics and disease activity on adalimumab (ADA) concentrations; to assess the relationships between ADA concentrations, the presence of antidrug antibodies (ADAb), and disease activity in rheumatoid arthritis (RA); and to determine the association between cytokine concentrations and ADA concentrations., Methods: A cross-sectional study of people with RA receiving ADA for at least 4 weeks was undertaken. Disease activity was assessed by the Disease Activity Score in 28 joints (DAS28), with responders defined as DAS28 ≤ 3.2. Serum and plasma were obtained for ADA concentrations and ADAb, and a panel of cytokines were obtained for a subgroup. ADA concentrations were compared between demographic and clinical subgroups using ANOVA. The independent associations between clinical and demographic features were analyzed using a general linear model. Variables significantly associated with ADA concentrations from the univariate analyses were entered into multivariate analyses., Results: Of the 156 participants, 69.2% were female and the mean age was 57.4 (SD 12.7) years. Multivariate analysis revealed that higher C-reactive protein ( P < 0.001) and higher weight ( P < 0.004) were independently associated with lower ADA concentrations. ADA concentrations were higher in those with DAS28 ≤ 3.2 compared to those with DAS28 > 3.2 (median 10.8 [IQR 6.4-20.8] mg/L vs 7.1 [IQR 1.5-12.6] mg/L, P < 0.001). There was a significant negative correlation between interleukin 6 (IL-6) and ADA concentrations ( r = -0.04, P < 0.01)., Conclusion: ADA concentration correlates negatively with markers of inflammatory disease activity in RA, including IL-6. ADA concentration in the range 5 to 7 mg/L over the dose interval are associated with better disease control., (Copyright © 2024 by the Journal of Rheumatology.)

Objective: In 2019, the Gout and Crystal Arthritis Network (G-CAN) published consensus statements for the nomenclature of disease elements and states in gout. The aim of this study was to determine adherence to the G-CAN consensus nomenclature statements since publication., Methods: American College of Rheumatology and EULAR conference abstracts were searched using online databases for the keywords 'gout,' 'urate,' 'uric acid,' 'hyperuricaemia,' 'tophus,' and/or 'tophi' before and after publication of the consensus statements (January 1, 2016 to December 31, 2017 and January 1, 2020 to December 31, 2021, respectively). Abstracts were manually searched for labels used to reference gout disease elements and states. Use of the G-CAN-agreed labels, as well as alternatives, were compared between the two time periods., Results: There were 988 abstracts included in the analysis: 596 in 2016 to 2017 and 392 in 2020 to 2021. Use of the agreed labels 'urate' and 'gout flare' increased between the two periods. There were 219 of 383 abstracts (57.2%) with the agreed label 'urate' in 2016 to 2017 compared with 164 of 232 (70.7%) in 2020 to 2021 (P = 0.001). There were 60 of 175 abstracts (34.3%) with the agreed label 'gout flare' in 2016 to 2017 compared with 57 of 109 (52.3%) in 2020 to 2021 (P = 0.003). Consistent with the G-CAN statement, use of the label 'chronic gout' reduced between the two time periods. There were 29 of 596 abstracts (4.9%) in 2016 to 2017 that used the label 'chronic gout' compared with 8 of 392 abstracts (2.0%) in 2020 to 2021 (P = 0.02)., Conclusion: Use of G-CAN-agreed gout labels has increased, but gout nomenclature remains imprecise. Additional efforts are needed to ensure consistent use of agreed nomenclature for gout in the scientific literature., (© 2023 American College of Rheumatology.)

Background: Alcohol consumption is a risk factor for hyperuricaemia and gout. Multiple single-nucleotide polymorphisms (SNPs) have been identified as associated with both alcohol consumption and serum urate or gout in separate genome-wide association studies (GWAS). This study aimed to identify and characterise interactions between these shared signals of genetic association and alcohol consumption for serum urate level, hyperuricaemia, and gout., Methods: This research was conducted using the UK Biobank resource. The association of alcohol consumption with serum urate and gout was tested among 458,405 European participants. Candidate SNPs were identified by comparing serum urate, gout, and alcohol consumption GWAS for shared signals of association. Multivariable-adjusted linear and logistic regression analyses were conducted with the inclusion of interaction terms to identify SNP-alcohol consumption interactions for association with serum urate level, hyperuricaemia, and gout. The nature of these interactions was characterised using genotype-stratified association analyses., Results: Alcohol consumption was associated with elevated serum urate and gout. For serum urate level, non-additive interactions were identified between alcohol consumption and rs1229984 at the ADH1B locus (P = 3.0 × 10 -44 ) and rs6460047 at the MLXIPL locus (P = 1.4 × 10 -4 ). ADH1B also demonstrated interaction with alcohol consumption for hyperuricaemia (P = 7.9 × 10 -13 ) and gout (P = 8.2 × 10 -9 ). Beer intake had the most significant interaction with ADH1B for association with serum urate and gout among men, while wine intake had the most significant interaction among women. In the genotype-stratified association analyses, ADH1B and MLXIPL were associated with serum urate level and ADH1B was associated with hyperuricaemia and gout among consumers of alcohol but not non-consumers., Conclusions: In this large study of European participants, novel interactions with alcohol consumption were identified at ADH1B and MLXIPL for association with serum urate level and at ADH1B for association with hyperuricaemia and gout. The association of ADH1B with serum urate and gout may occur through the modulation of alcohol metabolism rate among consumers of alcohol., (© 2024. The Author(s).)

Background: Rheumatoid arthritis associated interstitial lung disease (RA-ILD), is an important extra-articular manifestation of rheumatoid arthritis (RA). The frequency, risk factors, and prognosis of RA-ILD are incompletely understood., Aims: To determine the prevalence and incidence, clinical characteristics and risk factors for development, and outcomes of persons with RA-ILD in the population of the Canterbury District Health Board (CDHB) catchment area., Methods: Individuals aged ≥ 18 years with RA, resident in the CDHB catchment area between 1 January 2006 and 31 December 2008 (Period One), and 1 January 2011 to 31 December 2013 (Period Two) were identified by medical record review and followed until 30 June 2019. Individuals with RA-ILD as defined by pre-specified criteria were identified. The association between demographic and clinical characteristics and RA-ILD development and mortality was examined using Cox-proportional hazards models., Results: The prevalence of RA-ILD per 100,000 was 10.97 (95 % CI 7.53,14.42) for Period One, and 14.74 (95 % CI 10.84,18.63) for Period Two. Among individuals evaluated for risk factors for RA-ILD development, the estimated cumulative incidence of ILD at 10 years was 4.47 % (95 % CI 3.14, 6.14). After adjusting for age, rheumatoid factor positivity (HR 3.73, 95 % CI, 1.32,10.56), extra-articular manifestations other than RA-ILD (HR 4.48, 95 % CI 2.36,8.48), and subcutaneous rheumatoid nodules (HR 4.66, 95 % CI 2.34, 9.26) were associated with increased risk of developing RA-ILD. The standardised mortality ratio for RA-ILD was 3.90 (95 % CI 2.55,5.72) compared to the general population. Extent of ILD on CT chest was associated with mortality (HR for >20% vs. < 20 % 4.47, 95 % CI 1.67,11.96)., Conclusions: Clinically evident RA-ILD occurred in approximately 5 % of individuals with RA. Mortality was increased almost fourfold compared to the general population. Radiologic extent was the most important prognostic factor., Competing Interests: Declaration of Competing Interest LKS has received grants or contracts to from Health Research Council of New Zealand paid to their institution, royalties or licenses from UpToDate, and payments for participation on a data safety monitoring board or advisory Board from Pharmac paid to them and their institution. DB has received a scholarship grant from University of Otago funded by Arthritis New Zealand. ELM has received grants from Abbvie Inc, royalties or licenses from UpToDate, consulting fees from Beohringer-Ingelheim GmBH, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Beohringer-Ingelheim GmBH, Participation on a Data Safety Monitoring Board or Advisory Board for Horizon Therapeutics and National Institute of Health, Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for The American College of Rheumatology., (Copyright © 2023. Published by Elsevier Inc.)

Background: Dual energy computed tomography (DECT) allows direct visualization of monosodium urate crystal deposition in gout. However, DECT urate volume data are often highly skewed (mostly small volumes with the remainder considerably larger), making statistical analyses challenging in longitudinal research. The aim of this study was to explore the ability of various analysis methods to normalise DECT urate volume data and determine change in DECT urate volumes over time., Methods: Simulated datasets containing baseline and year 1 DECT urate volumes for 100 people with gout were created from two randomised controlled trials. Five methods were used to transform the DECT urate volume data prior to analysis: log-transformation, Box-Cox transformation, log(X-(min(X)-1)) transformation; inverse hyperbolic sine transformation, and rank order. Linear regression analyses were undertaken to determine the change in DECT urate volume between baseline and year 1. Cohen's d were calculated as a measure of effect size for each data treatment method. These analyses were then tested in a validation clinical trial dataset containing baseline and year 1 DECT urate volumes from 91 people with gout., Results: No data treatment method successfully normalised the distribution of DECT urate volumes. For both simulated and validation data sets, significant reductions in DECT urate volumes were observed between baseline and Year 1 across all data treatment methods and there were no significant differences in Cohen's d effect sizes., Conclusions: Normalising highly skewed DECT urate volume data is challenging. Adopting commonly used transformation techniques may not significantly improve the ability to determine differences in measures of central tendency when comparing the change in DECT urate volumes over time., Competing Interests: Declaration of Competing Interest Lisa Stamp reports grants or contracts from Health Research Council of New Zealand, personal royalties or licenses from UptoDate, and consulting fees from Pharmac. Nicola Dalbeth reports grants or contracts from Health Research Council of New Zealand and Novotech, personal consulting fees from AstraZeneca, Dyve Biosciences, Horizon, Selecta, Arthrosi, JW Pharmaceutical Corporation, PK Med, PTC Therapeutics, Protalix, Cello Health, JPI, Unlocked Labs, and LG, payment or honoraria from Novartis and Hikma. The other authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Objective: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease., Methods: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort., Results: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score >56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers)., Conclusion: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: The gouty tophus is an organized structure composed of monosodium urate (MSU) crystals and chronic inflammatory soft tissue. This dual-energy computed tomography (DECT) study aimed to determine whether the composition of the tophus changes during urate-lowering therapy., Methods: Serial DECT scans from 32 people with gout were obtained over 2 years of allopurinol therapy, dose-escalated to serum urate of <0.36 mmoles/liter. Up to 5 index tophi were selected for each patient, with 103 separate tophi included in the analysis. Using manual outlining methods of conventional CT and DECT scans, the same index tophi were serially measured for total tophus volume and urate volume. For each tophus, the soft tissue volume was then calculated by subtracting the urate volume from the total tophus volume., Results: The mean ± SD serum urate reduced from 0.43 ± 0.03 mmoles/liter at baseline to 0.31 ± 0.02 mmoles/liter at year 2. The mean ± SD total tophus volume reduced over the 2-year period from 5.17 ± 5.55 cm 3 to 2.61 ± 2.73 cm 3 (P < 0.0001). Greater reductions in tophus urate volumes than tophus soft tissue volumes were observed; the tophus urate volume decreased by 70.6%, and tophus soft tissue volume decreased by 37.8% (P < 0.0001). The mean tophus urate:soft tissue ratio reduced from 0.15 at baseline to 0.05 at year 2 (P < 0.001)., Conclusion: The composition of the tophus is dynamic and changes during urate-lowering therapy for gout management. The soft tissue component of the tophus is slower to respond and may persist without measurable MSU crystal deposition., (© 2023 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Clinical trials are a critical element of a modern, high-functioning, learning healthcare system. Clinical trials provide access to novel, as yet unfunded treatments, and deliver cutting-edge healthcare. Evidence from clinical trials ensures appropriateness of healthcare, allows disinvestment from practices that are found not to improve outcomes or be cost-effective, and supports the introduction of new approaches, all of which leads to improvement in health outcomes. In 2020, Manatū Hauora - Ministry of Health and The Health Research Council of New Zealand funded a project to understand the current state of clinical trial activity in Aotearoa New Zealand and to propose the infrastructure required to support equitable clinical trial activity, in order to ensure that trials benefiting from publicly funded infrastructure are responsive to the needs of New Zealanders and ultimately enable equitable delivery of the best healthcare we can achieve to all New Zealanders. This viewpoint reports the process that was undertaken to develop the final proposed infrastructure and the rationale for the approach. The restructuring of the Aotearoa New Zealand health system into Te Whatu Ora - Health New Zealand and Te Aka Whai Ora - Māori Health Authority that will both operate hospital services and commission primary and community healthcare at a national level provides the ideal opportunity to integrate and embed research into Aotearoa New Zealand's healthcare system. Integration of clinical trials and research more broadly into the public healthcare system will require a significant shift in the culture within our healthcare system. Research must be recognised and promoted as a core activity for clinical staff at all levels of the healthcare system, rather than something to be tolerated or even hindered. Strong leadership will be required from the top of Te Whatu Ora - Health New Zealand down to ensure the required cultural shift to recognise the value of clinical trials to all aspects of the healthcare system, and to grow capability and capacity of the health research workforce. The investment required by the Government to implement the proposed clinical trial infrastructure will be substantial, but now is the ideal time for investment in clinical trials infrastructure in Aotearoa New Zealand. We urge the Government to be bold and invest now to ensure the benefits can be reaped for all New Zealanders in years to come., Competing Interests: Lisa K Stamp, Matire Harwood, Stuart Dalziel, Katrina Sharples, and Frank Bloomfield are active clinical triallists. Funding from Health Research Council of New Zealand and the Ministry of Health., (© PMA.)

Aims: This study aimed to develop and evaluate an allopurinol adherence tool based on steady-state oxypurinol plasma concentrations, allopurinol's active metabolite., Methods: Plasma oxypurinol concentrations were simulated stochastically from an oxypurinol pharmacokinetic model for allopurinol doses of 100-800 mg daily, accounting for differences in renal function, diuretic use and ethnicity. For each scenario, the 20th percentile for peak and trough concentrations defined the adherence threshold, below which imperfect adherence was assumed. Predictive performance was evaluated using both simulated low adherence and against data from 146 individuals with paired oxypurinol plasma concentrations and adherence measures. Sensitivity and specificity (S&S), negative and positive predictive values (NPV, PPV) and receiver operating characteristic (ROC) area under the curve (AUC) were determined. The predictive performance of the tool was evaluated using adherence data from an external study (CKD-FIX)., Results: The allopurinol adherence tool produced S&S values for trough thresholds of 89-98% and 76-84%, respectively, and 90%-98% and 76-83% for peak thresholds. PPV and NPV were 79-84% and 88-94%, respectively, for trough and 80-85% and 89-98%, respectively, for peak concentrations. The ROC AUC values ranged from 0.84 to 0.88 and from 0.86 to 0.89 for trough and peak concentrations, respectively. S&S values for the external evaluation were found to be 75.8% and 86.5%, respectively, producing an ROC AUC of 0.8113., Conclusion: A tool to identify people with gout who require additional support to maintain adherence using plasma oxypurinol concentrations was developed and evaluated. The predictive performance of the tool is suitable for adherence screening in clinical trials and may have utility in some clinical practice settings., (© 2022 British Pharmacological Society.)

The fat mass and obesity associated (FTO) locus consistently associates with higher body mass index (BMI) across diverse ancestral groups. However, previous small studies of people of Polynesian ancestries have failed to replicate the association. In this study, we used Bayesian meta-analysis to test rs9939609, the most replicated FTO variant, for association with BMI with a large sample (n = 6095) of Aotearoa New Zealanders of Polynesian (Māori and Pacific) ancestry and of Samoan people living in the Independent State of Samoa and in American Samoa. We did not observe statistically significant association within each separate Polynesian subgroup. Bayesian meta-analysis of the Aotearoa New Zealand Polynesian and Samoan samples resulted in a posterior mean effect size estimate of +0.21 kg/m 2 , with a 95% credible interval [+0.03 kg/m 2 , +0.39 kg/m 2 ]. While the Bayes Factor (BF) of 0.77 weakly favors the null, the BF = 1.4 Bayesian support interval is [+0.04, +0.20]. These results suggest that rs9939609 in FTO may have a similar effect on mean BMI in people of Polynesian ancestries as previously observed in other ancestral groups., (© 2023. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Objective: The selection and reporting of core outcome measures in clinical trials is essential for patients, researchers, and healthcare providers for clinical research to have an impact on healthcare. In this systematic scoping review, we aimed to quantify the extent to which gout clinical trials are collecting and reporting data in accordance with the core outcome domains from Outcome Measures in Rheumatology (OMERACT) published in 2009 applicable for both acute and chronic trials and evaluate the reporting according to the core domains before and after the 2009 OMERACT endorsement., Methods: We searched multiple databases PubMed, EMBASE, the Cochrane Library including the Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Database of Systematic Reviews (CDSR) and www., Clinicaltrials: gov for randomized controlled trials (RCTs) allocating people with gout versus an active pharmacological gout treatment or a control comparator (no date limitation). We extracted the data in accordance with the core outcome sets, focusing individually on core outcome domains and the core outcome measurements for acute and chronic trials, respectively. In this study 'Acute trials' reflect studies that describe interventions for short term management of gout flares, and 'chronic trials' describe interventions for long-term urate lowering therapy in the management of gout., Results: From 8,522 records identified in the database search, 134 full text papers were reviewed, and 71 trials were included, of which 36 were acute and 35 were chronic. Only 3 of 36 (8%) acute trials reported all five core domains and none of the 35 included chronic trials reported all 7 core domains. In the acute trials, twenty-seven unique measurement instruments across the 5 core domains were identified. For chronic trials there were 31 unique measurement instruments used across the 7 core domains. Serum urate was reported in 100% of the chronic trials and gout flares in 80%. However, other core domains were reported in <30% of chronic trials. In particular the patient-important domains such as HR-QOL, patient global assessment and activity limitations were rarely reported. A broad variety of different measurement instruments were used to assess each endorsed core domain, a minority of trials used the OMERACT endorsed instruments. For acute trials, the number reporting on all core domains was consistently low and no change was detected before and after the endorsement of the core domains in 2009. None of the included chronic trials reported on all 7 endorsed core domains at any time., Conclusion: In this study we found a low adherence with the intended endorsed (i.e., core) outcome domains for acute and chronic gout studies which represents a poor uptake of the global OMERACT efforts for the minimum of what should be measured in clinical trials. In addition, there is a significant variation in how the OMERACT endorsed outcome domains have been measured. This systematic review demonstrates the need for continuous encouragement among gout researchers to adhere to OMERACT core domains as well as further guidance on outcome measurements reporting., Registration: Prospero: CRD42019151316., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Urate-lowering therapies for the management of gout lead to a reduction in serum urate levels, monosodium urate crystal deposition, and the clinical features of gout, including painful and disabling gout flares, chronic gouty arthritis, and tophi. Thus, disease remission is a potential goal of urate-lowering therapy. In 2016, preliminary gout remission criteria were developed by a large group of rheumatologists and researchers with expertise in gout. The preliminary gout remission criteria were defined as: serum urate < 0.36 mmol/L (6 mg/dL); an absence of gout flares; an absence of tophi; pain due to gout < 2 on a 0-10 scale; and a patient global assessment < 2 on a 0-10 scale over a 12-month period. In this critical review, we describe the development of the preliminary gout remission criteria, the properties of the preliminary gout remission criteria, and clinical studies of gout remission in people taking urate-lowering therapy. We also describe a future research agenda for gout remission.

Aims: Monogenic diabetes accounts for 1-2% of diabetes cases yet is often misdiagnosed as type 2 diabetes. The aim of this study was to examine in Māori and Pacific adults clinically diagnosed with type 2 diabetes within 40 years of age, (a) the prevalence of monogenic diabetes in this population (b) the prevalence of beta-cell autoantibodies and (c) the pre-test probability of monogenic diabetes., Methods: Targeted sequencing data of 38 known monogenic diabetes genes was analyzed in 199 Māori and Pacific peoples with BMI of 37.9 ± 8.6 kg/m 2 who had been diagnosed with type 2 diabetes between 3 and 40 years of age. A triple-screen combined autoantibody assay was used to test for GAD, IA-2, and ZnT8. MODY probability calculator score was generated in those with sufficient clinical information (55/199)., Results: No genetic variants curated as likely pathogenic or pathogenic were found. One individual (1/199) tested positive for GAD/IA-2/ZnT8 antibodies. The pre-test probability of monogenic diabetes was calculated in 55 individuals with 17/55 (31%) scoring above the 20% threshold considered for diagnostic testing referral., Discussion: Our findings suggest that monogenic diabetes is rare in Māori and Pacific people with clinical age, and the MODY probability calculator likely overestimates the likelihood of a monogenic cause for diabetes in this population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Toomata, Leask, Krishnan, Cadzow, Dalbeth, Stamp, de Zoysa, Merriman, Wilcox, Dewes and Murphy.)

Background: Colchicine has been suggested for osteoarthritis treatment, but evidence is contradictory. We aimed to investigate colchicine's efficacy and safety compared with placebo in people with hand osteoarthritis., Methods: In this single-centre, double-blind, randomised, placebo-controlled trial we recruited adults with symptomatic hand osteoarthritis and finger pain of at least 40 mm on a 100 mm visual analogue scale from an outpatient clinic in Denmark. The hand with the most severe finger pain at inclusion was the target hand. Participants were randomly assigned (1:1) to 0·5 mg colchicine or placebo taken orally twice a day for 12 weeks, stratified by BMI (≥30 kg/m 2 ), sex, and age (≥75 years). Participants, outcome assessors, and data analysts were masked to treatment allocation. The primary endpoint was change from baseline to week 12 in target hand finger pain, assessed on a 100 mm visual analogue scale with a pre-specified minimal clinically important difference of 15 mm, in the intention-to-treat population. Safety was assessed at week 12 in the intention-to-treat population. The study was registered with ClinicalTrials.gov, NCT04601883, and with EudraCT, 2020-002803-20., Findings: Between Jan 15, 2021, and March 3, 2022, 186 people were screened for eligibility, and 100 were randomly assigned to receive colchicine (n=50) or placebo (n=50). Participants had a mean age of 70·9 (SD 7·5) years, 69 (69%) of 100 were women and 31 (31%) were men. All participants completed the study. The mean change from baseline to week 12 in finger pain were -13·9 mm (SE 2·8) in the colchicine group and -13·5 mm (2·8) in the placebo group, with a between-group difference (colchicine vs placebo) of -0·4 mm (95% CI -7·6 to 6·7; p=0·90). In the colchicine group, there were 76 adverse events in 36 (72%) of 50 participants and one serious adverse advent (migraine attack leading to hospital admission). In the placebo group, there were 42 adverse events in 22 (44%) of 50 participants and two serious adverse events (cholecystitis and elevated alanine aminotransferase concentrations, in the same patient)., Interpretation: In people with painful hand osteoarthritis, treatment with 0·5 mg of colchicine twice day for 12 weeks did not effectively relieve pain, and treatment with colchicine was associated with more adverse events., Funding: The Oak Foundation, IMK Almene Fond, Minister Erna Hamilton's Scholarship for Science and Art, AP Moller and Wife Chastine McKinney Moller's Foundation for Medical Science Advancement, The Danish Medical Association, the Velux Foundation, Aase and Ejnar Danielsen's Foundation, and Director Emil C Hertz and Wife Inger Hertz's foundation., Competing Interests: Declaration of interests The Parker Institute is supported by a core grant from the Oak Foundation (OCAY-18–774-OFIL). AD has received grants to this project from IMK Almene Fond, Erna Hamilton's Foundation (Minister Erna Hamilton's Scholarship for Science and Art), the AP Møller Foundation (AP Møller and wife Chastine McKinney Møller's Foundation for Medical Science Advancement), The Danish Medical Association, the Velux Foundation, Aase and Ejnar Danielsen's Foundation and Director Emil C Hertz and wife Inger Hertz's foundation. FB has received consulting fees from Horizon Therapeutics. FCM has received grants from Innovation Fund Denmark; and payment or honoraria from Varian and Siemens Healthineers. IKH has received grants from Pfizer and Lily; and payment or honoraria from Novartis and GSK. LT has received payment or honoraria from Eli Lilly, Novartis, and Janssen; and is on the advisory board for Bristol Meyers Squibb and Janssen. MH is on the European Advisory Board for Thuasne Group. MK has received grants from the Innovative Medicines Initiative (APPROACH project) and Dutch Arthritis Society; royalties or licenses from Wolters Kluwer and Springer Verlag; consulting fees for Abbvie, Pfizer, Kiniksa, Flexion, Galapagos, Centre for Human Drug Research, Novartis, and UCB; payment or honoraria from Galapagos and Jansen; and is a member of the Osteoarthritis Research Society International board, a member of the European Alliance of Associations for Rheumatology (EULAR) council and President for the Dutch Society for Rheumatology. PGC has received consulting fees from AbbVie, AstraZeneca, Eli Lilly, Galapagos, GlaxoSmithKline, Grunenthal, Janssen, Levicept, Merck, Novartis, Pfizer, Regeneron, Stryker, and UCB; payment or honoraria from AbbVie; and support from AbbVie to congress attendance. LKS has received grants from the Health Reserach Council of New Zealand amd consulting fees from Pharmac. GMM has received support for attending meeting from Janssen; and is president for the Irish Society of Rheumatology. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)