Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) Conference 2023: Early-Career Investigators’ Abstracts

: The ninth annual international G-CAN research symposium was held in La Jolla, CA on the 7th and 8th of November 2023. This hybrid meeting, a live face-to-face and virtual live symposium, was attended by 191 participants. Over 20 research abstract submissions were received from early-career investigators, for plenary oral and poster presentations. Here, we present the 20 accepted, lightly edited abstracts from the early-career presenters consenting to have their materials published. We thank and congratulate the presenters for their work and contributions to the meeting

IL1R2 levels were measured in plasma.Genomic DNA was isolated from whole blood, and genotyping was performed using the Illumina Infinium Global Screening Array.Ex vivo functional assays were performed, consisting of PBMC stimulations with C16 + MSU (TLR2/NLRP3 inflammasome activator) or LPS (TLR4 ligand) for 24h.Cytokines were assessed by ELISA.Results: IL1R1 and IL1R2 were differentially expressed in PBMCs from gout patients compared to controls.Serum soluble IL1R1 protein levels were very low, and there were no differences in the studied groups.Plasma soluble IL1R2 concentrations were higher in both gout and hyperuricemia when compared to normouricemia.Moreover, IL1R1 expression positively correlated with serum urate levels in vivo and with ex vivo cytokine production.The IL1R1 rs17767183 SNP was not associated with changes in IL1R1 expression or cytokine production in the HINT study groups.However, the IL1R1 rs17767183 C (gout risk) allele was associated with significantly elevated IL-6 cytokine production in response to C16 + MSU crystal in 500FG healthy controls.Conclusions: Variation in expression of IL1R1 and IL1R2 is observed in primary PBMCs of patients with gout and in hyperuricemic controls thus reinforcing data implicating these loci in gout and urate-related inflammation.IL1R1 expression positively correlates with in vivo urate levels and responses to several ex vivo stimuli.Discordant results were observed for cytokine production levels in relationship to the IL1R1 rs17767183 SNP, and further analysis into the possible regulatory effects of this SNP in inflammation is currently ongoing.

1.
Neogi, T.; Jansen, T.L.   Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, 41345 Gothenburg, Sweden * Correspondence: panagiota.drivelegka@vgregion.se Abstract: Background: Patients with gout are at increased risk of acute myocardial infarction (AMI) [1].The clinical course, secondary prophylaxis and mortality after AMI has not been previously studied.The aim of this study was to investigate the in-hospital treatment, secondary prevention and all-cause and cardiovascular disease (CVD)-related mortality after the first-ever AMI in patients with gout compared to the general population.Methods: Using data from population-based registers, we identified all patients in Western Sweden with a diagnosis of gout at both primary and specialty care and a first-ever AMI in the period 2006-2016.Up to five individually matched controls with a first-ever AMI (matched on sex and admission year) were identified as comparators.Follow-up started at the date of admission for the first-ever AMI and ended at death, emigration or 365 days of follow-up after the AMI, whichever occurred first.The in-hospital treatment and secondary prevention in gout cases and controls were compared by using logistic regression analysis with adjustments for age.Cox regression analysis was used to assess the 1-year mortality with adjustments for age, baseline comorbidities, and medication within 6 months before the start of follow-up.Results: We identified 1000 patients with gout and a first-ever AMI (men, 72.7%; mean age, 70.0 years) and 4740 matched general population comparators (men, 73.5%; mean age, 71.5 years).At admission, patients with gout had significantly more comorbidities (Table 3).The in-hospital treatment differed significantly between cases and controls.Patients with gout were more likely to receive treatment with diuretics and continuous positive airway pressure and less likely to undergo coronary angiography, percutaneous coronary intervention (PCI) or any primary reperfusion (Table 4).At discharge, patients with gout were less often prescribed statins and more often prescribed nitrates, diuretics, digitalis and calcium antagonists (Table 4).The 1-year all-cause and CVD-related mortality was significantly higher in gout patients as compared to the general population (HR, 1.84; 95% CI, 1.52-2.23;and HR, 1.75; 95% CI, 1.38-2.21,respectively) (Figure 1).Conclusions: Patients with gout were less likely to undergo coronary angiography and PCI during hospitalization for the first-ever AMI and were less likely to be prescribed statins at discharge compared to the general population.The all-cause and CVD-related mortality was significantly higher in patients with gout, which might be partly related to differences in in-hospital treatment and secondary prevention.<0.0001 0.7 (0.6-0.9) § Matched on sex and admission year.* Adjusted for age.AMI, acute myocardial infarction; iv, intravenous; PCI, percutaneous coronary intervention; CABG, coronary artery by-pass grafting; CPAP, continuous positive airway pressure; PM, pacemaker; ICD, implantable cardioverter defibrillator; RAAS, renin-angiotensin-aldosterone system; OR, odds ratio; CI, confidence interval.

Skeletal Muscle Mass and Quality in Gout Patients Versus Non-Gout Controls: A Computed Tomography Imaging Study
Alysson Covello 1, *, Michael Toprover  3).Results: Sixty-four subjects (41 gout and 23 controls) were included in the current analysis.Gout subjects had higher BMI, greater incidence of kidney disease and hypertension, lower exercise frequency and higher mean serum urate and creatinine vs. controls.Lumbar SMRA was significantly lower in gout subjects vs. controls (gout, median 32.5 HU, IQR 20.9-39.6;controls, median 39.2 HU, IQR 31.8-43.2,p = 0.009) (Figure 4).Lumbar IMAT area was significantly higher in gout subjects vs. controls (gout, median 6.84 cm 2 , IQR 4.78-10.17;controls, median 4.88 cm 2 , IQR 3.49-6.44,p = 0.007), as was lumbar IMAT index (gout, median 2.23 cm 2 /m 2 , IQR 1.60-3.39;controls, median 1.56 cm 2 /m 2 , IQR 1.17-2.17,p = 0.008) (Figure 4).These differences persisted after adjusting for potential confounders.There was no significant difference between gout and control groups in lumbar skeletal muscle area (gout, median 73.9 cm      Results: A total of 972 studies were identified and, of these, 6 RCTs met the criteria for inclusion in the analysis.Three studies were assessed as having high risk of bias, two studies as having low risk of bias and one study with some concerns.There was a total of 445 pooled participants; 226 participants randomized to early initiation of ULT and 219 to placebo or delayed initiation of ULT.Few participants (n = 62, 13.9%) had tophaceous gout.Allopurinol was used in three studies, febuxostat in two studies and probenecid in one study.There were no statistical differences in patient-rated pain scores on days 3-4 (SMD −0.01; 95% CI −0.21-0.18;p = 0.88), days 7-8 (SMD 0.07; 95% CI −0.13-0.27;p = 0.50) or days 14-15 (SMD −0.08; 95% CI −0.36-0.20;p = 0.57).Additionally, there was no difference in time to resolution of gout flare (SMD 0.77 days; 95% CI −0.26-1.79;p = 0.14; Figure 5) or the risk of recurrent gout flare within the subsequent 28 to 30 days (RR 1.06; 95% CI 0.59-1.92;p = 0.84; Figure 6).Adverse events were similar between groups.The included studies did not examine time to achieve target serum urate, long-term adherence to ULT or patient satisfaction with treatment.Conclusions: There appears to be no indication for harm or for benefit to initiating ULT during a gout flare.These findings, however, may not be applicable to patients with more advanced gout or tophaceous gout.We recommend an individualized approach to patient management.Abstract: Background: There remains debate about the optimal time for initiating urate-lowering therapy (ULT) in the setting of a gout flare.The aim was to perform a systematic review and metaanalysis of randomized controlled trials (RCTs) assessing the initiation of ULT during a gout flare.Methods: The systematic review was conducted in accordance with PRISMA methodology.MED-LINE, EMBASE and The Cochrane Library were searched for RCTs examining the initiation of ULT during a gout flare.The quality of included studies was assessed using the Cochrane Risk of Bias 2 tool.Data were extracted for the following outcomes: patient-rated pain score, duration of gout flare, recurrent gout flares, time to achieve target serum urate, adherence to ULT, patient satisfaction with treatment and adverse events.Meta-analyses were performed using Review Manager v5.4.Results: A total of 972 studies were identified and, of these, 6 RCTs met the criteria for inclusion in the analysis.Three studies were assessed as having high risk of bias, two studies as having low risk of bias and one study with some concerns.There was a total of 445 pooled participants; 226 participants randomized to early initiation of ULT and 219 to placebo or delayed initiation of ULT.Few participants (n = 62, 13.9%) had tophaceous gout.Allopurinol was used in three studies, febuxostat in two studies and probenecid in one study.There were no statistical differences in patient-rated pain scores on days 3-4 (SMD −0.01; 95% CI −0.21-0.18;p = 0.88), days 7-8 (SMD 0.07; 95% CI −0.13-0.27;p = 0.50) or days 14-15 (SMD −0.08; 95% CI −0.36-0.20;p = 0.57).Additionally, there was no difference in time to resolution of gout flare (SMD 0.77 days; 95% CI −0.26-1.79;p = 0.14; Figure 5) or the risk of recurrent gout flare within the subsequent 28 to 30 days (RR 1.06; 95% CI 0.59-1.92;p = 0.84; Figure 6).Adverse events were similar between groups.The included studies did not examine time to achieve target serum urate, long-term adherence to ULT or patient satisfaction with treatment.Conclusions: There appears to be no indication for harm or for benefit to initiating ULT during a gout flare.These findings, however, may not be applicable to patients with more advanced gout or tophaceous gout.
We recommend an individualized approach to patient management.Abstract: Background: Although persons from underserved groups more frequently utilize the emergency department (ED) for gout flares and are more likely to be hospitalized due to gout, there is a gap in our understanding of whether these patients are retained in care after their visit to the ED.Our objective was to determine whether socioeconomic disadvantage, assessed using the area deprivation index (ADI), is associated with the rate of outpatient follow-up among people with gout treated in EDs.Methods: This cohort included patients with a confirmed gout flare at three EDs that were identified using an electronic medical record (EMR) gout alert system and manual EMR review.Medical record reviews were conducted to determine the presence or absence of an outpatient follow-up visit addressing gout.Adjudicated consensus and kappa coefficients were found to estimate interrater reliability.Each patient's nine-digit zip code was determined from addresses on file in order to calculate their ADI score with higher ADIs representing more socioeconomic deprivation.Univariable and multivariable logistic regression was used to test the association between ADI and outpatient follow-up for gout.Results: From 1 September 2021, to 31 August 2022, there were 1290 unique encounters among 981 patients identified by the gout flare alert as possibly having an acute gout flare.Of these, 63 patients were excluded due to participation in an ongoing randomized clinical trial testing a behavioral intervention to improve gout care.Of the remaining 918 patients, 159 patients (17%) (Table 7) had a true gout flare by manual EMR review by two assessors, who independently reviewed data.The kappa coefficient for agreement between the consensus determination of acute flare was 0.85.Of those with an acute gout flare, 120 (75.5%) were men and 113 (75.3%) were Black or African American.A total of 159 (53%) patients with an acute gout flare followed up with an outpatient provider in our healthcare system, and only 56 patients (35.2%) had an outpatient visit addressing gout (Table 8).In our cohort, the median state ADI score was 6.5 and the median national ADI score was 84.Overall, 41 patients (28.9%) resided in the least deprived state quartile (quartile 1) and 30 (21.1%) lived in the most deprived state quartile.State ADI and national ADI scores were not significantly associated with gout follow-up care in univariable analysis; however, higher ADI quartile correlated with unmarried status (p = 0.01).In a multivariable logistic regression model, people who reported being married were more likely to achieve outpatient follow-up gout care (OR = 2.75, 95% CI 1.28-5.93,p = 0.01).State ADI and national ADI scores were not significantly associated with gout follow-up care in this model.For every 10 years of increased age, the odds of achieving gout follow-up care increased by 43.6% (p = 0.01).Conclusions: We found that living in areas with higher socioeconomic deprivation is not associated with receipt of outpatient follow-up visits after an acute gout flare.Age and marital status are factors associated with a patient's probability of obtaining outpatient follow-up for gout.Cluster analysis was performed to measure the proximity of gout-related comorbidities, and hierarchical clustering was conducted to determine the subgroups of homogeneous gout patients.Patients with gout were followed for 1 year for acute gout flares to explore differences in prognosis between subgroups.
Results: Cluster analysis divided the eight comorbidity variables into three categories: first, type 2 diabetes, hypertension, cardiovascular disease, chronic kidney disease and cancer; second, dyslipidemia; third, obesity and increased liver enzyme levels.In the cross-sectional study, we recruited a total of 2639 people with gout, with an average age of 50.6 years and 95% male.Five groups (C1-C5) of patients with gout were identified with significantly different patient characteristics and clusters of comorbidities.C1 (n = 671, 25%) was characterized by isolated gout with few comorbidities; C2 (n = 258, 10%) were all obese, with the youngest age (mean 40 years).C3 (n = 335, 13%) was almost all diabetic patients (99.7%), and the course of gout was the longest (average 8 years).C4 (n = 938, 36%) had the largest number of patients, and all patients had dyslipidemia.C5 (n = 437, 16%) included the highest proportion of people with cardiovascular disease (53%), chronic kidney disease (56%) and cancer (7%), with the oldest age (mean 65 years).In the follow-up study, a total of 463 patients completed a 1-year follow-up on gout flares (Figures 7 and 8).Among them, C2 (gout and obesity) had the lowest rate of gout flares (52.1%) and the latest occurrence of gout flares (average 10 months).Conversely, C5 (gout with cardiovascular disease, chronic kidney disease or cancer) had the highest rate of gout flares (71.9%) and the earliest onset of gout flares (mean 3 months).Conclusions: We clustered people with gout into five groups with varying comorbidities.Gout patients with cardiovascular disease, chronic kidney disease or cancer are at the highest risk of acute gout flares and should be given more comprehensive care by clinicians.
C2 (gout and obesity) had the lowest rate of gout flares (52.1%) and the latest occurrence of gout flares (average 10 months).Conversely, C5 (gout with cardiovascular disease, chronic kidney disease or cancer) had the highest rate of gout flares (71.9%) and the earliest onset of gout flares (mean 3 months).Conclusions: We clustered people with gout into five groups with varying comorbidities.Gout patients with cardiovascular disease, chronic kidney disease or cancer are at the highest risk of acute gout flares and should be given more comprehensive care by clinicians.flares (average 10 months).Conversely, C5 (gout with cardiovascular disease, chronic kidney disease or cancer) had the highest rate of gout flares (71.9%) and the earliest onset of gout flares (mean 3 months).Conclusions: We clustered people with gout into five groups with varying comorbidities.Gout patients with cardiovascular disease, chronic kidney disease or cancer are at the highest risk of acute gout flares and should be given more comprehensive care by clinicians.Abstract: Background: Gout has traditionally been thought of as a male disease.This may have resulted in an under-diagnosis of gout in women.Given that gout definitions vary substantially in the literature and that serum urate levels in women are about 1 to 1.5 mg/dL lower than those in men, it is possible that women with gout are underrepresented in research.Here, we aimed to determine the sex ratios for gout associated with different gout definitions.We then aimed to identify gout definitions that are more or less likely to include women with gout.Methods: We identified studies that included both men and women with gout, restricting to those with at least 50 women published since the year 2000.We then used the number of reported incident/prevalent cases to calculate male:female sex ratios.
To validate our findings, we calculated sex ratios for various gout definitions in both the UK Biobank and All of Us cohorts.Results: The median sex ratio for gout was 3.0, ranging from 1.2 to 17.1 (Table 9).We found that with more stringent gout definitions, fewer women were included in studies relative to men.This was especially apparent for clinical trials that only included individuals above a serum urate threshold, resulting in the highest sex ratios of all studies.In the UK Biobank and All of Us cohorts, we were able to reproduce these results, with the least stringent criteria (self-reported gout or gout code or ULT) resulting in sex ratios of 8.0 and 1.7, respectively, and the most stringent criteria (self-reported gout and gout code and ULT) resulting in sex ratios of 13.0 and 3.3, respectively (Table 10).
Conclusions: Disease definitions are important to consider when attempting to include under-represented groups in research.With increasing stringency for definitions of gout, we found that fewer women were included relative to men.Most importantly, this resulted in few female gout cases being included in clinical trials.Caution should be taken when considering inclusion in gout research to not further bias research toward over-represented groups.A second interesting finding was the dramatic difference in sex ratio between the US-based All of Us cohort and the UK-based UK Biobank.There are several possibilities for why this may have occurred, including the restricted age range of the UK Biobank (40-70 years) compared to All of Us (>18 years) and the ethnicity differences between cohorts.However, when applying different gout criteria to White All of Us participants between 40 and 70, we found similar results to the full cohort.It could therefore be the case that female gout is relatively less common in the UK compared to the US, or perhaps it is less likely to be ascertained in a population-based research cohort.Abstract: Background: Hyperuricemia definitions are highly variable, often defined based on the distribution of urate in the population of interest or the reported urate solubility threshold of 6.8 mg/dL.This solubility threshold was derived at a temperature of 37 • C in a 1972 publication, in which the author highlighted the extreme dependence of urate solubility on temperature.In the 2019 G-CAN consensus statement, hyperuricemia was defined as "elevated blood urate concentration over the saturation threshold."Here, we aimed to investigate the evidence for using different hyperuricemia definitions in gout research, with a focus on the 6.8 mg/dL definition.Methods: Publications were reviewed to identify serum urate thresholds for hyperuricemia and their reported justifications.Publications of intra-articular temperatures were reviewed to identify the appropriate temperature to derive urate solubility.Finally, we reproduced the results of Loeb 1972 using the data from Allen 1965 to calculate urate solubility at internal joint temperatures.Results: Hyperuricemia was defined as serum urate levels above thresholds of 5.7 to 8 mg/dL (Table 11).Where justifications were given, the majority stated that they had arbitrarily chosen that threshold or referenced another study that arbitrarily defined hyperuricemia.In some cases, the justification was related to urate solubility, suggesting that urate was saturated above the stated threshold.Additionally, in many cases different thresholds were proposed for men vs women.Intra-articular temperatures ranged from 29.7 • C to 37 • C, in most cases measured in the knee joint, with a mean of approximately 33 • C (Table 12).At this temperature, the urate solubility threshold in the presence of physiological sodium levels (140mM) would be 5.3 mg/dL based on data from Allen 1965 and Loeb 1972 (Figure 9).Conclusions: Hyperuricemia was arbitrarily defined in almost all reviewed publications.When serum urate thresholds were based on urate solubility, they all cited the Loeb 1972 publication (or other publications citing this study), which highlighted the extreme variability of urate solubility based on temperature.Using the data presented in this paper, an estimated internal joint temperature of 33 • C would result in a urate solubility threshold of approximately 5.3 mg/dL.Importantly, this solubility threshold represents the point at which solid urate is in equilibrium with its dissolved form, and as such lower urate levels would further encourage crystal dissolution and suppress crystal growth.Sodium concentration, pH and other variables have also been shown to have large effects on urate solubility and nucleation/crystal growth.We propose that serum urate should be analyzed as a continuous variable wherever possible, in men and women separately, with results presented per unit change in serum urate.This would reflect the observation that gout risk exponentially increases with increasing urate levels.When a serum urate threshold is required for the purpose of gout treatment, we would suggest that one should aim for serum urate levels below 6 mg/dL as an upper limit, with lower levels more likely to improve crystal dissolution.

Both
Mean SU was 8.2 mg/dL among those with crystal-proven gout vs 6.05 among those without crystals.Also 89% male in crystal proven vs 62% male in non-crystal proven 5.7 Women Does not state where these came from 7. 1 Men Abstract: Background: Uniform terminology with standardized definitions for the various elements and states of a disease ensure accurate and consistent technical communication.In 2019 the Gout and Crystal Arthritis Network (G-CAN) published consensus statements for the nomenclature of disease elements and disease states in gout.The aim of this study was to determine adherence to the G-CAN consensus statements since the G-CAN publication.Methods: ACR 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 (1 January 2016-31 December 2017 and 1 January 2020-31 December 2021, respectively).Abstracts were manually searched for labels used to reference gout disease elements and states.Labels were extracted from text, figures and tables.Use of the G-CAN agreed labels, as well as alternatives, were compared between the two time periods and between abstracts that included a G-CAN consensus statement author and those that did not in 2020/2021.Use of the term "chronic gout," which G-CAN advised should be avoided, was also compared between the two time periods.Results: There were 988 abstracts included in the analysis; 596 in 2016/2017 and 392 in 2020/2021 (Figure 10).G-CAN agreed labels were used in 445/596 (74.9%) of abstracts in 2016/2017, increasing to 311/392 (79.4%) in 2020/2021 (p = 0.006).Use of the agreed labels "urate," "gout flare" and "chronic gouty arthritis" increased between the two periods.There were 219/383 (57.2%) abstracts with the agreed label "urate" in 2016/2017 compared to 164/232 (70.7%) in 2020/2021 (p = 0.001).There were 60/175 (34.3%) abstracts with the agreed label for "gout flare" in 2016/2017 compared with 57/109 (52.3%) in 2020/2021 (p = 0.003).Only 1/49 (2.0%) abstract used the agreed label for "chronic gouty arthritis" in 2016/2017 compared to 6/39 (15.4%) in 2020/2021 (p = 0.022).Abstracts with consensus statement authors used the correct labels in 87.4% compared to 74.5% without in 2020/2021 (p < 0.001).Use of the label "chronic gout" declined between the two time periods.There were 29/49 (59.1%) abstracts in 2016/2017 that used the label "chronic gout" compared with 8/39 (20.5%) abstracts in 2020/2021 (p ≤ 0.001).Conclusions: Use of the 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.

Silvia Sirotti * and Georgios Filippou
Rheumatology Department, IRCCS Galeazzi-Sant'Ambrogio Hospital, 20157 Milan, Italy * Correspondence: silvia.sirotti@gmail.comAbstract: Background: The knees and wrists are considered to be the most frequently involved joints in calcium pyrophosphate deposition (CPPD) disease, but to date there is limited evidence regarding the extent of crystal deposition in these sites.Recently the OMERACT ultrasound working group-CPPD subgroup validated a semiquantitative scoring system for assessing CPPD extent, allowing an evaluation of the burden of CPPD.The aim of this study was to assess the extent of CPPD and the frequency of involvement of different anatomical structures in the knees and wrists in different CPPD disease phenotypes.Methods: This was a cross-sectional study conducted between April 2023 and July 2023.Consecutive patients diagnosed with CPPD disease based on the 2023 ACR/EULAR classification criteria were prospectively enrolled.The ultrasonographic assessment was carried out by two rheumatologists expert in CPPD and ultrasound, whose reliability has been tested previously.The OMERACT scoring system for CPPD was used to evaluate the extent of CPPD.Descriptive statistical analyses were performed to analyze the collected data.Results: Twenty-eight patients were enrolled (17 female), with a mean age of 76 years (±9 SD).The patients were classified into three clinical subsets according to the 2011 EULAR recommendations: 11 had acute CPP crystal arthritis, 13 had chronic CPP crystal inflammatory arthritis and 4 had osteoarthritis with CPPD (Figure 11).In all patients, at least one medial meniscus (MM), one lateral meniscus (LL) and one triangular fibrocartilage complex (TFCC) of the wrist was affected.MM showed the highest bilateral involvement (93% of cases), followed by the LL and TFCC (86% of bilaterality in both cases).No significant differences were found regarding the frequency of involvement of the various sites by subsets of disease.Regarding the extent of deposition, at the patient level, the overall mean score (ranging from 0 to 24) was 14.2 (SD 4.3, median 14).Patients with acute CPP crystal arthritis had a mean score of 13.5 (SD 3.8, median 13), those with chronic CPP crystal inflammatory arthritis had a mean score of 13.8 (SD 4.9, median 13) and patients with osteoarthritis with CPPD had the highest mean score of 17.5 (SD 1.3, median 17.5) (Table 13).At the tissue level, the mean extent of CPPD was 2 (SD 0.8, median 2) at the level of menisci, 1.9 (SD 0.8, median 2) at the TFCC and 1 (SD 0.9, median 1) at the level of the HC.Conclusions: In patients who satisfy the new ACR/EULAR criteria for CPPD disease, at least one wrist and one knee are involved in 100% of patients.These data could reflect some limitations in the ACR/EULAR criteria to capture initial cases with a lower burden of deposition.When analyzing the extent of CPPD according to the 2011 EULAR subsets, a higher load of crystals was found in patients with the subset of OA plus CPPD than in patients with acute CPP flares or with chronic arthritis.These data suggest that release of crystals in joint space (and thus fewer deposits in tissues) in patients with frequent acute or chronic forms of arthritis is a key player in the development of inflammation.Finally, fibrocartilage appears to be more frequently and also more severely involved in CPPD.Abstract: Background: Calcium crystals, including both basic and pyrophosphate, are frequently observed in patients with osteoarthritis (OA).The processes underlying their formation and their role in OA pathogenesis remain unclear, and basic studies performed on hyaline cartilage (HC) provided partial and in some cases contrasting data.On the other hand, imaging studies demonstrated that fibrocartilage (FC) is at least equally involved in CPPD as HC, but much less is known about the changes of this tissue during the CPPD course.The objective was to use a combined approach from clinical, imaging and histological data from both HC and FC in order to identify potential promoters and mechanisms of calcium crystals formation in joints.In this abstract, we present the preliminary histological findings in menisci of patients with CPPD.Methods: Both menisci of a patient who underwent total knee replacement with CPPD identified at X-rays of the knee and at an advanced stage of osteoarthritis were retrieved during surgery.For conventional light microscopy studies, meniscal specimens were fixed 24h in 10% neutral buffered formalin, dehydrated in a graded ethanol series and cleared with xylene, embedded in paraffin and cut into 4µm sections.Abstract: Background: Calcium crystals, including both basic and pyrophosphate, are frequently observed in patients with osteoarthritis (OA).The processes underlying their formation and their role in OA pathogenesis remain unclear, and basic studies performed on hyaline cartilage (HC) provided partial and in some cases contrasting data.On the other hand, imaging studies demonstrated that fibrocartilage (FC) is at least equally involved in CPPD as HC, but much less is known about the changes of this tissue during the CPPD course.The objective was to use a combined approach from clinical, imaging and histological data from both HC and FC in order to identify potential promoters and mechanisms of calcium crystals formation in joints.In this abstract, we present the preliminary histological findings in menisci of patients with CPPD.Methods: Both menisci of a patient who underwent total knee replacement with CPPD identified at X-rays of the knee and at an advanced stage of osteoarthritis were retrieved during surgery.For conventional light microscopy studies, meniscal specimens were fixed 24h in 10% neutral buffered formalin, dehydrated in a graded ethanol series and cleared with xylene, embedded in paraffin and cut into 4µm sections.Samples were stained with hematoxylin and eosin (H&E) and analyzed.Histological slides were also analyzed by compensated polarized light microscopy to identify the presence of crystalline material.For immunohistochemistry, meniscal slices were treated, after antigen retrieval, for 10 min with 0.1% H 2 O 2 and blocked with normal serum.Immunostaining was performed overnight at 4 • C with anti-Collagen X (10µg/mL) but in negative controls; detection was performed with a streptavidin-biotin system and diaminobenzidine.Counterstaining of nuclei was performed with Meyer's hematoxylin.
Results: Polarized microscopy shows circumscribed structures filled with rhomboid-shaped crystals, characteristic of CPPD (Figure 12).H&E staining detected the same deposits of CPP crystals (foci) often surrounded by putative hypertrophic chondrocyte clusters.These foci were partially but strongly positive to collagen X, a marker of hypertrophic chondrocytes.Its presence in these structures suggests a role of hypertrophic chondrocytes in the process of formation/deposition of CPP crystals.Conclusions: Although the exact order of different structure involvement in CPPD is not yet known, fibrocartilaginous tissues might play a significant role in the development of both CPPD and OA.These preliminary results raise several questions on the pathogenic mechanisms underlying CPP formation, and further investigation could provide important insights into several processes in both diseases.
crystals (foci) often surrounded by putative hypertrophic chondrocyte clusters.These foci were partially but strongly positive to collagen X, a marker of hypertrophic chondrocytes.Its presence in these structures suggests a role of hypertrophic chondrocytes in the process of formation/deposition of CPP crystals.Conclusions: Although the exact order of different structure involvement in CPPD is not yet known, fibrocartilaginous tissues might play a significant role in the development of both CPPD and OA.These preliminary results raise several questions on the pathogenic mechanisms underlying CPP formation, and further investigation could provide important insights into several processes in both diseases.Abstract: Background: Calcium pyrophosphate deposition (CPPD) disease is a complex nosologic entity that may present with various clinical manifestations, ranging from acute monoarthritis of a large joint to axial inflammatory involvement.Further, calcium pyrophosphate crystals may be found in joints of asymptomatic patients or also in association with other diseases, such as osteoarthritis (OA), making symptom attribution challenging.This complexity has led to a large variety of names for CPPD disease in the past, resulting in several "pseudo-"syndromes, like pseudo-gout, pseudo-rheumatoid arthritis, etc.In 2011, a EULAR task force attempted to mediate this semantic issue by publishing a consensus paper on the nomenclature of CPPD.Here we examine the impact of the 2011 EULAR recommendations on the international literature regarding the terms (labels and acronyms) used to define CPPD and calcium pyrophosphate crystals.Methods: This is an ancillary study of the G-CAN project on the nomenclature for CPPD.In brief, a systematic literature review was carried out in order to extrapolate all labels and acronyms used for CPPD from 2000 to 2022 (included).The articles were then divided into before and after 2011, year of publication of the recommendations, and the frequencies of the terms suggested by the EULAR taskforce were calculated to assess the impact of the 2021 EULAR terminology.Results: A total of 2376 papers were included in the review, 972 from 2000 to 2011 and 1401 after (4 papers with missing data).Regarding crystal's label and acronym, CPP (calcium pyrophosphate crystals) was used in 12 papers (out of 261 that provided an acronym, 4-5%) and CPPD (calcium pyrophosphate dihydrate) was used in 235 (90%) before 2011 while after publication of the terminology 217 papers (out of 380 who provided an acronym) used the term CPP (57%) and 149 the term CPPD (39%).Regarding the acronym of the disease, the term CPPD as proposed in 2011, defined as all instances of occurrence of CPP deposition including also the asymptomatic form, was used in 6 out of 90 papers that provided an acronym (7%) before 2011 and 24% after (78/324).Conclusions: The 2011 EULAR recommendations on CPPD nomenclature had only a moderate impact on disease label, but they demonstrated a greater influence regarding the acronym used for crystal (CPP).A reason for this could be the lack of an exact definition of the letters of the acronym CPPD in the paper that could be associated with different words, especially regarding the D that could be read as "dehydrate," "deposition" or even "disease."It is quite urgent and important to make uniform the terms used to define the disease and its clinical states and to identify strategies that could drive a substantial implementation of these new definitions in research and clinical practice.

Genetic Colocalization of Gout with Plasma and Urine Metabolites
Riku Takei

Genetic Colocalization of Gout with Plasma and Urine Metabolites
Riku Takei Abstract: Objective: To investigate the genetic colocalization of gout-associated genetic loci with genetic control of the metabolome and to investigate the causal role of metabolites in gout.Methods: GWAS data for 1083 plasma metabolites were downloaded [1] and tested for genetic colocalization with gout genetic association data from a recent GWAS [2].Restricting the locus region to lead SNP ±500kb, genetic colocalization analysis was carried out for 276 gout loci (291 independent SNPs) for each of the 1083 metabolite GWAS data using the 'coloc' R package.Colocalization occurred if the posterior probability of colocalization was ≥0.8.Ten metabolites with the highest number of loci colocalized with gout were then tested for a causal role in gout by Mendelian randomization (MR) using the 'MendelianRandomization' package in R. The inverse variance-weighted (IVW) and weighted median (WM) methods were used to test for causality, and the MR-Egger method was used to test for pleiotropy.Results: Ten metabolites colocalized with gout genetic association signals in at least five loci: urate (positive control), retinol (vitamin A), diacylglycerol, androstenediol disulfate, androsterone sulfate, threonine, glutamine, pyroglutamine, serine and alanine.Four of these metabolites showed evidence of causality for gout in at least one of the MR methods used; urate (IVW-estimate = 1.48,P IVW = 6.01 × 10 −5 and WM-estimate = 1.65,P WM = 3.19 × 10 −25 ), androsterone sulfate (C, P IVW = 7.71 × 10 −3 and WM-estimate = −0.09,P WM = 5.87 × 10 −10 ), diacylglycerol (IVW-estimate = 0.18, P IVW = 1.42 × 10 −2 and WM-estimate = 0.10, P WM = 3.96 × 10 −5 ) and glutamine (IVW-estimate = −0.03,P IVW = 0.46 and WM-estimate = −0.08,P WM = 3.95 × 10 −3 ).Urate and androsterone sulfate showed evidence of pleiotropy (MR-Egger intercept P = 2.19 × 10 −2 and 5.13 × 10 −3 , respectively).Conclusions: Diacylglycerol, glutamine and androsterone sulfate showed evidence of causality for gout.There was a positive relationship between risk of gout with diacylglycerol and an inverse relationship with glutamine and androsterone sulfate.Glutamine is involved in the formation of phosphoribosylamine in de novo purine biosynthesis, a key precursor molecule of urate synthesis.Furthermore, glutamine can be converted into glutamate via glutaminolysis and fed into the tricarboxylic acid cycle, which produces substrate for trained immunity of innate immune cells [3].There is increased macrophage responsiveness with loss of diacylglycerol kinase α [4] (an enzyme responsible for converting diacylglycerol into phosphatidic acid), and it has been hypothesized that the abundance of diacylglycerol species causes increased activation of protein kinase C, which in turn contributes to macrophage responsiveness.Androsterone sulfate is a breakdown metabolite of testosterone.How it could play a causal role in gout is not clear, although it could indicate a causal role for testosterone.

Figure 1 .
Figure 1.All cause and CVD-related mortality at 1 year after the first-ever AMI in patients with gout compared to the general population.*Adjusted for age, baseline comorbidities and medication within 6 months before the start of follow-up.HR, hazard ratio; CI, confidence interval; CVD, cardiovascular disease.

Figure 1 .
Figure 1.All cause and CVD-related mortality at 1 year after the first-ever AMI in patients with gout compared to the general population.*Adjusted for age, baseline comorbidities and medication within 6 months before the start of follow-up.HR, hazard ratio; CI, confidence interval; CVD, cardiovascular disease.

Figure 3 .
Figure 3. Representative CT images of lumbar muscle quantity and quality metrics in a gout subject vs. a control subject.

Figure 4 .
Figure 4. Lumbar skeletal muscle index, skeletal muscle radiation attenuation (density) and intermuscular adipose tissue index in gout vs. control subjects.

Figure 3 .Figure 3 .
Figure 3. Representative CT images of lumbar muscle quantity and quality metrics in a gout subject vs. a control subject.

Figure 4 .
Figure 4. Lumbar skeletal muscle index, skeletal muscle radiation attenuation (density) and intermuscular adipose tissue index in gout vs. control subjects.

Figure 4 .
Figure 4. Lumbar skeletal muscle index, skeletal muscle radiation attenuation (density) and intermuscular adipose tissue index in gout vs. control subjects.

Figure 5 .
Figure 5. Forest plot of the days to gout flare resolution between the experimental group (early initiation of ULT) and control group (placebo or delayed initiation of ULT).

Figure 5 .
Figure 5. Forest plot of the days to gout flare resolution between the experimental group (early initiation of ULT) and control group (placebo or delayed initiation of ULT).

Figure 7 .
Figure 7. Incidence rate of gout flare within 1 year.

Figure 8 .
Figure 8. Kaplan-Meier curve for time to first gout flare in group C2 and C5.

Figure 7 .
Figure 7. Incidence rate of gout flare within 1 year.

Figure 7 .
Figure 7. Incidence rate of gout flare within 1 year.

Figure 8 .
Figure 8. Kaplan-Meier curve for time to first gout flare in group C2 and C5.

Figure 8 .
Figure 8. Kaplan-Meier curve for time to first gout flare in group C2 and C5.11.Sex Ratios in Gout Nicholas Sumpter *, Tony R. Merriman Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA * Correspondence: nicholassumpter@uabmc.edu

Figure 11 .
Figure 11.Overall distribution of all the scores (grade 0-1-2-3) in CPPD patients.The values above the bars are number of patients.TFCC, triangular fibrocartilage complex.

Figure 13 .
Figure 13.Cumulative hazard of opioid exposure leading to chronic use in patients with gout (vs.non-gout).

Figure 14 .
Figure 14.Factors associated with initiating chronic opioid use in patients with gout.*All variables in multivariable model with p-value < 0.05 are shown in the figure.White/Caucasian race was referent value; Other race includes composite of Asian, Native Hawaiian/Pacific Islander and American Indian.Adequate ULT indicates ≥2 fills of ULT -AND-at least ≥90 days covered by dispensing.Adequate SU control indicates average SU < 6 mg/dL.Age reported in years; Rheumatology visit reported as presence of any visit throughout follow-up period; RDCI (rheumatic disease comorbidity index) including lung disease, myocardial infarction, other cardiovascular disease, stroke, hypertension, fracture, depression, diabetes mellitus, ulcer or stomach problem and cancer.Abbreviations: ULT, urate-lowering therapy; CKD, chronic kidney disease; SU, serum urate.

Table 2 .
Results of the SVM classification model predicting CPP and MSU.Measures calculated with respect for the newly developed criteria set for CPPD (positive above 57 points or with identified CPP crystals in SF) and the 2015 ACR/EULAR criteria set for gout (positive above 8 points or with identified MSU crystals in SF).Ninety-five percent confidence intervals are given for each performance measure.

Table 3 .
Patient characteristics and comorbidities in gout patients and general population comparators at admission for the first-ever AMI.Matched on sex and admission year.*Adjusted for age.¤ Vasodilator drugs, anti-hypertensive drugs, diuretics, beta-blockers, calcium antagonists and renin-angiotensin-aldosterone inhibitors.AMI, acute myocardial infarction; CHD, coronary heart disease; CVD, cardiovascular; OR, odds ratio; CI, confidence interval.

Table 4 .
In-hospital treatment and medication prescribed at discharge after the first-ever AMI in gout patients and general population comparators.

Table 4 .
In-hospital treatment and medication prescribed at discharge after the first-ever AMI in gout patients and general population comparators.

Table 5 .
Agreement between raters for all MSU or CPP crystals identified by either rater by either method.

Table 6 .
Certainty of crystal by rater and method.

Table 5 .
Agreement between raters for all MSU or CPP crystals identified by either rater by either method.

Table 6 .
Certainty of crystal by rater and method.

Table 7 .
Demographic characteristics of participants who presented to the emergency department with an acute gout flare and further characterized by presence or absence of outpatient gout follow-up care.

Table 8 .
Healthcare utilization among participants following an emergency department encounter for acute gout flare including emergency department visits, hospitalizations, follow-up with type of provider and interval to follow-up and proportion of patients with outpatient visits that addressed gout.

Clustering of Gout-Related Comorbidities and Their Relationship with Gout Flares: A Data-Driven Cluster Analysis of Eight Comorbidities Shuang Lui *, Hang Sun, Shen Qu, Haibing Chen
School of Medicine, Tongji University, Shanghai 200092, China * Correspondence: liushuang08@126.comAbstract: Objective: To study the aggregation of multiple comorbidities in people with gout and explore differences in the prognosis of gout flares among different subgroups.Methods: The retrospective study included gout patients from the Department of Endocrinology and Metabolism of the Tenth People's Hospital Affiliated to Tongji University as the research subjects.Eight comorbidity variables such as obesity, type 2 diabetes, hypertension, cardiovascular disease, chronic kidney disease, dyslipidemia, increased liver enzyme levels and cancer were used as research indicators.

Table 9 .
Sex ratios for various gout definitions in reviewed literature including both men and women with gout published since the year 2000.Publications with fewer than 50 women with gout excluded.Included the most recent publication for each cohort.Sex ratios all calculated as ratio of number of incident or prevalent gout cases, rather than using the incidence/prevalence rates.

Table 10 .
Sex ratios for various gout definitions in the UK Biobank and All of Us cohorts.

Table 13 .
Score distribution in different CPPD phenotypes.

Disease and Sequelae in Individuals with Gout, Diabetes, or Both: A US Veterans Population-Based Study Nicole Leung *, Michael Toprover, Charles Fang, Michael H. Pillinger, Craig Tenner and Jay Pendse
Division of Rheumatology, NYU Grossman School of Medicine, New York, NY 10003, USA * Correspondence: nicole.leung@nyulangone.org

Gateway to Chronic Opioid Use? Lindsay Helget 1, *, Bryant R. England 1 , Punyasha Roul 1 , Harlan Sayles 1 , Tuhina Neogi 2 , James R. O'Dell 1 and Ted R. Mikuls 1
Background: Painful gout flares often lead to healthcare visits, which, based on prior reports, result in the use of opioid therapy for management, despite opioids not being a preferred treatment.Opioid use for flares raises concerns that uncontrolled gout may serve as a "gateway" to chronic opioid use.The objectives of this study were to (1) compare the risk of initiating chronic opioid use in Veteran's Health Administration (VHA) patients with and without gout and (2) to examine determinants of initiating chronic opioid use in gout patients.Methods: We performed a matched cohort study, identifying patients with gout using national VHA data from January 1999 to January 2015 based on ≥2 ICD-9 codes for gout (274.X).Gout cases were matched to patients without gout (up to 1:10) based on birth year, sex and VA enrollment year, then followed from the index date (fulfillment of gout algorithm) until the earliest date of incident chronic opioid use, death or 5 years after the index date.Individuals with a fill of an opioid in the year prior to the index date were excluded.Chronic opioid use was defined as 90 cumulative days' supply with at least two dispenses occurring in a 6-month window with no gap >32 days.Associations of gout (vs.non-gout) with chronic opioid use were quantified using a cumulative hazard curve and multivariable Cox proportional hazards regression.Associations between patient characteristics and time-to-initiating chronic opioid use among patients with gout were examined.Covariates in both models included race, comorbidities, body mass index (BMI) and smoking status.In the gout-only model, additional covariates included age, sex, Rheumatic Disease Comorbidity Index (RDCI), time-varying serum urate (SU) control (average SU <6 mg/dL in prior year) and urate-lowering treatment (ULT; ≥2 fills of ULT with ≥90 days covered by dispensing in prior year).Results:Over 16.7 million patientyears of follow-up (median follow-up 5 years), 6.9% of gout patients initiated chronic opioids vs. 3.8% of non-gout patients (Figure13, Table14).After adjusting for covariates, patients with gout were significantly more likely than non-gout patients to initiate chronic opioid use (aHR 1.36; 95% CI 1.34 to 1.39).Factors associated with gout-related chronic opioid exposure are summarized in Figure14.Among those with gout, factors positively associated with chronic opioid use included Black/African American race, comorbidities, ULT use and rheumatology encounter.Factors negatively associated with chronic opioid use in those with gout included male sex, CKD, urban residence, SU control, age and Asian, Native Hawaiian/Pacific Islander and American Indian race.Conclusions: In the VHA, we found that patients with gout were 36% more likely than those without gout to initiate chronic opioid use, after accounting for potential confounders, despite opioids not being recommended for management of gout flares.Associations between patient characteristics and time-to-initiating chronic opioid use highlight potential gaps in care, particularly among underserved Black/African American and rural populations as well as the potential for adequate urate control to reduce the risk of chronic opioid use in gout.
* Covariates include age, index year, race (Black/African American, Other or Missing vs. White), BMI, smoking status (Former, Current or Missing vs. Never), chronic lung disease, past myocardial infarction, cardiovascular disease, stroke, hypertension, diabetes, fracture, depression, stomach ulcer or cancer.*