Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd4020010

Authors: Allyson Covello Salim Zenkhri Cheongeun Oh Michael H. Pillinger Michael Toprover Fabio Becce

Prior research suggests a connection between osteoarthritis and gout at sites commonly affected by gouty attacks. Whether this connection exists at sites with known monosodium urate crystal deposition but less commonly affected by gouty attacks, such as the lumbosacral spine, has not been previously investigated. We assessed whether lumbosacral osteoarthritis is more prevalent and more severe in subjects with gout compared with controls, and whether lumbosacral osteoarthritis is associated with higher levels of spinal monosodium urate deposition. Fifty gout subjects and 25 controls underwent dual-energy computed tomography imaging of the lumbosacral spine. We assessed lumbosacral osteoarthritis using a modification of a validated computed tomography scoring system, incorporating grade of intervertebral disc narrowing and facet joint osteoarthritis, and presence of spondylolysis and spondylolisthesis. We quantified spinal monosodium urate deposition using the default post-processing algorithm, plus a maximally specific algorithm to exclude potential artefacts. Forty-six gout subjects and 25 controls, average age 62 years, were included in the final analysis. Both gout and control subjects exhibited high rates of facet joint osteoarthritis and degenerative disc disease, with no difference in prevalence or severity between groups. Gout subjects did not have differing prevalence of spondylolysis and spondylolisthesis vs. controls. Subjects with lumbosacral osteoarthritis did not have higher levels of spinal monosodium urate deposition. Overall, lumbosacral osteoarthritis was not more prevalent or more severe in gout patients compared with controls, and spinal monosodium urate crystal deposition did not differ between patients with and without lumbosacral osteoarthritis.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd4020009

Authors: Viola Klück Nienke Ponsteen Sander I. van Leuven Leo A. B. Joosten

Hyperuricemia influences several aspects of the immune system. It enhances cytokine production by monocytes and activates neutrophils and natural killer cells. Within the adaptive immune system, hyperuricemia enhances antigen presentation, skews T helper cell differentiation toward the Th17 lineage and may also activate B cells. Beyond its established role in the pathogenesis of gout, hyperuricemia may therefore contribute to other rheumatic diseases. In this review, we summarize current evidence on the role of hyperuricemia in osteoarthritis, psoriatic arthritis, axial spondylarthritis, rheumatoid arthritis, systemic sclerosis, primary Sjögren’s disease and systemic lupus erythematosus. Available data do not support a causal role for hyperuricemia in the disease onset of osteoarthritis or rheumatoid arthritis. In contrast, hyperuricemia is associated with the development of psoriatic arthritis and may be linked to a more severe disease course. Small, predominantly cross-sectional studies further suggest a potentially adverse role of hyperuricemia in systemic sclerosis, Sjögren’s disease, and systemic lupus erythematosus. Across several rheumatic diseases, hyperuricemia is associated with cardiovascular disease, renal dysfunction and interstitial lung disease. However, both mechanistic and causal evidence remain limited, underscoring the need for more studies.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd4010008

Authors: Yevetta Xiang An-Tzu Chien Christopher Hall

Gout is the most common form of inflammatory arthritis in men, driven by hyperuricemia and the deposition of monosodium urate (MSU) crystals. The innate immune response to these crystals leads to acute inflammatory episodes, called flares, characterized by intense joint pain, swelling, and temporary disability. Although gout flares are self-limiting, they impose a considerable burden on patients’ quality of life and contribute to increased healthcare utilization. A detailed understanding of the inflammatory processes triggered by MSU crystals is critical for developing targeted therapies to prevent and manage flares effectively. This review provides an overview of experimental models used to study the inflammatory phase of gout, with a focus on both in vivo and in vitro models of MSU crystal-induced inflammation. We concentrate on models that reproduce the acute inflammatory response following MSU crystal deposition, including the air pouch, intraarticular injection, and peritonitis rodent models, alongside the larval zebrafish model. In addition, we discuss in vitro approaches using primary immune cells and cell lines. We discuss the strengths, limitations, and translational relevance of these models and highlight some examples of how they have contributed to our understanding of the etiology of gout. Of note, models of hyperuricemia are not included here as these have been extensively reviewed elsewhere.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd4010007

Authors: Dorian O. Haskard

‘Irregular gout’ is an obsolete term that was used in the past to describe both trivial and serious health issues seemingly related to gouty arthritis. This article looks back at what physicians such as George Cheyne, William Oliver, William Cullen and William Heberden thought about ‘irregular gout’. It examines to what degree the concept is still relevant, knowing what we now know about uric acid and the local and systemic inflammatory effects of urate crystal formation. In parallel, the article traces the trajectory from Cullen’s ‘asthenic gout’ to nineteenth century ‘uric acid poisoning’ and thence to possible hidden consequences of asymptomatic hyperuricaemia. ‘Irregular gout’ in its various guises has greatly influenced both orthodox and unorthodox treatments over the years. Although the term is no longer used, the concept is by no means dead.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd4010006

Authors: Hervé Kempf Karolien Aelbrecht Sarah Beck-Cormier Georges Lefthériotis Lukas Nollet Flora Szeri Andras Varadi Olivier M. Vanakker

The 1st Joint Ectopic Calcification Meeting (JECM) was held in Nancy, France on 24–26 September 2025. In response to the growing need for unified scientific dialogue on soft tissue ectopic calcification, the Joint Ectopic Calcification Meeting (JECM) brought together the communities of INTEC, ISSEC, BBC, iSCCa, and the PXE Budapest meeting. This initiative emerged from concerns over fragmentation in the field, with multiple smaller meetings diluting collaborative potential. By consolidating efforts, JECM aims to foster interdisciplinary exchange, highlight cutting-edge research, and build a flagship event for the ectopic calcification community. With over 100 participants, the inaugural meeting in Nancy marks a promising step toward a more integrated and dynamic future for the field. The abstracts of this year’s meeting oral and poster presentations are collected in this conference paper, with permission from the corresponding authors.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd4010005

Authors: Edoardo Cipolletta Satveer K. Mahil Catherine H. Smith Abhishek Abhishek

Allopurinol, the most used urate-lowering drug for the treatment of gout, is associated with rare but life-threatening severe cutaneous adverse reactions (SCARs) such as Stevens–Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, but not Acute Generalised Exanthematous Pustulosis (AGEP). They are characterised by severe skin and systemic involvement and are associated with substantial morbidity and a high risk of mortality. This narrative review summarises evidence on the clinical presentation, epidemiology, risk factors, and preventive strategies for allopurinol-induced SCARs. Key risk factors include the presence of the HLA-B*58:01 allele, renal impairment, older age, female sex, heart disease, higher starting doses of allopurinol, and certain ethnicities, e.g., South Asian, Han Chinese, and African populations likely due to the higher prevalence of the HLA-B*58:01 allele. Risk mitigation strategies include genetic testing for HLA-B*58:01 in high-risk ethnic groups and avoiding allopurinol in those that are positive for the HLA-B*58:01 allele, starting allopurinol at a low-dose (e.g., 50–100 mg/day) and up-titrating it gradually at 4-week intervals, and avoiding high-dose allopurinol in those with risk factors (e.g., chronic kidney disease stage ≥3). In addition, risk stratification using prediction tools may enable a safer use of allopurinol.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd4010004

Authors: Geraldine M. McCarthy

When, as a junior doctor, Dorian Haskard made a presentation on a patient with gout to the Medical Staff Round at the London Hospital in 1981, he was told that gout was ‘yesterday’s disease and academically dead’ [...]

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd4010003

Authors: Gout, Hyperuricemia and Crystal-Associated Disease Network

The eleventh annual international G–CAN research symposium was held in Chicago, IL, on the 22nd and 23rd of October 2025. This hybrid meeting, a live face-to-face and virtual live symposium, was attended by 198 participants. Twenty-five research abstract submissions were received from early-career investigators for plenary oral and brief oral presentations. Here, we present the 24 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.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd4010002

Authors: Arthur M. Mandelin II Diane Lewis Horowitz Darren Tabechian Ami Ben-Artzi

The diagnosis of crystal-induced arthritis is routinely established by synovial fluid analysis. However, a synovial effusion is not always present, fluid aspiration is not always possible or practical, and synovial fluid analysis is occasionally subject to false negative results. When there is a high suspicion of crystal-induced arthritis, but crystals are not identified in the synovial fluid, a biopsy of the synovium in search of crystals can assist in making a diagnosis. In this manuscript, we review the utility of ultrasound-guided needle biopsy of synovial tissue in the identification of crystal-induced arthritis, briefly describe the procedure, and recommend best practices for specimen handling and tissue processing.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd4010001

Authors: Frédéric Lioté Fernando Perez-Ruiz Hang-Korng Ea Tony Merriman Tristan Pascart Alexander So

For the 16th Anniversary this year, the ECN workshop is again held in downtown Paris. Every year the ECN workshop offers a unique opportunity for clinicians and researchers interested in crystals, inflammation, and crystal-induced diseases, including gout, to present their latest results and discuss novel concepts.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3040022

Authors: Vicky Tai Charlotte Jauffret Nicola Dalbeth Tristan Pascart

Calcium pyrophosphate deposition (CPPD) disease is a consequence of the immune response to the pathological accumulation of calcium pyrophosphate (CPP) crystals within joints. This clinically heterogeneous condition can cause significant disability, yet its management remains poorly defined. New discoveries are reshaping the therapeutic landscape beyond conventional anti-inflammatory agents—which remain the cornerstone of care—justifying this review on current standard of care and treatment advances in CPPD disease. We first address the two theoretical management goals, namely inflammation control and crystal dissolution—with attempts to address the latter having failed thus far. We then summarize the evidence supporting conventional anti-inflammatory treatments and review insights into the pathophysiology of CPPD disease, which are driving the development of novel therapeutic strategies. These include the current use of biologics (IL-1 and IL-6 inhibitors) to control inflammation and highlight the need to explore new pathways to inhibit crystal formation (e.g., selective NPP1 blockers). We present the treatments in the development pipeline for CPPD disease (including JAK inhibitors), and the therapies currently undergoing clinical trials in gout for which findings could be extended to CPPD disease given their shared pathophysiology (e.g., NLRP3 inhibitors). To support and improve research on CPPD disease treatments, clinical trial design needs to be standardized, incorporating the recent ACR/EULAR classification criteria for accurate diagnosis, careful phenotypic stratification to ensure homogeneous patient groups (although this point requires consensus), and validated core outcome domains currently being developed by the OMERACT.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3040021

Authors: Elena Sansano-Muñoz María-del-Carmen López-González Cristina Rodríguez-Alvear Irene Calabuig Agustín Martínez-Sanchis Carlos Rodríguez-Navarro Eliseo Pascual Mariano Andrés

Objective: Monosodium urate (MSU) crystallization in human joints is poorly understood. This study aimed to investigate whether the length of MSU crystals varies in relation to organized ultrasound deposits, which may lead to longer crystals. Methods: Observational, cross-sectional study analyzing MSU crystals from synovial fluid samples of patients with crystal-proven gout. Using light microscopy, we measured crystal lengths (in µm) and noted the presence of long crystals, defined by cutoffs at the 66th, 75th, and 90th percentiles. We evaluated their association with two ultrasound-defined crystal deposition models: (1) grade 2–3 double-contour (DC) sign, tophi, and/or aggregates; and (2) grade 2–3 DC sign and/or tophi. Results: In a total of 1076 MSU crystals from 28 joints, median length was 23.3 µm (95% confidence interval 22.1–24.5). MSU crystal length was similar regardless of ultrasound deposition: in model 1 (20 joints, 71.4%), 22.5 µm in joints with deposits vs. 21.7 µm without; p = 0.42; in model 2 (15 joints, 53.6%), 22.8 µm vs. 21.2 µm, respectively; p = 0.12. Joints fulfilling model 2 criteria had more long crystals (>66th percentile), both in absolute and relative terms. Long crystals mildly correlated with serum urate levels and were numerically more frequent in patients with tophaceous gout. Conclusions: Most MSU crystals in synovial fluid gathered around a common length, regardless of ultrasound deposition. Long crystals were more common in joints with DC signs or tophi. Our finding is in keeping with two different mechanisms of MSU crystallization in humans.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3040020

Authors: Sumanth Chandrupatla Nicholas Sumpter Riku Takei Tony R. Merriman Jasvinder Singh

We conducted a two-sample Mendelian randomization (MR) study including only European men to test for a causal relationship between serum urate (SU), gout, and prostate cancer. Using genome-wide association (GWAS) data, we generated instrumental variables (IVs) associated with gout and urate. These included 20 single nucleotide polymorphisms (SNPs) associated with gout but not urate (non-hyperuricemia compartment of gout) and four SNPs from loci containing urate transporter genes for an IV representing urate levels. MR methods included the inverse-variance weighted (IVW) method, MR-Egger regression, and the weighted median method. The non-hyperuricemia compartment of gout IV showed a causal effect of gout on prostate cancer (weighted median: p = 0.01). In contrast, the SU IV showed no evidence of a causal effect of SU on prostate cancer (IVW: p = 0.83; weighted median: p = 0.97). MR-Egger showed no evidence of horizontal pleiotropy (gout: p = 0.33; urate: p = 0.80). Loci contributing most strongly to the non-hyperuricemia causal effect included three genes: IL1R1, IL1RN, and SLC30A5. There was no evidence of a causal relationship between prostate cancer and gout or SU. In conclusion, MR analysis in a European male population found evidence of a causal relationship between the non-hyperuricemia compartment of gout and prostate cancer. Implication of the IL1R1 and IL1RN genes directly implicates the gouty inflammation pathway in prostate cancer.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3040019

Authors: Michael Toprover Michael H. Pillinger

Gout is the most common inflammatory arthritis. Treatment of gout includes anti-inflammatory and urate-lowering agents. Robust guidelines by the American College of Rheumatology, the European Alliance of Associations for Rheumatology and other committees have been released regarding recommendations for urate-lowering therapy, including suggested first- and second-line medications, length of therapy with prophylaxis, and target serum urate concentration to treat patients to. Notably, the American College of Physicians guidelines do not recommend robust urate lowering and are more geared towards treating symptoms without monitoring or lowering urate. Controversies regarding the optimal management of gout patients still exist. In the following, we discuss several of these controversies and some of the most recent literature regarding potential future changes in recommended management of gout. We discuss options for prophylactic therapy and length, treating gout concomitantly with its most common comorbidities, hypertension, diabetes mellitus, and cardiovascular disease, potential debulking therapy for more severe gout, and optimal urate levels.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3030018

Authors: John D. FitzGerald Rita Kachru Chen Xie Veena K. Ranganath

Patients suffering from erosive tophaceous gout who have failed oral urate-lowering therapies and pegloticase have few therapeutic options. Pegloticase failure (infusion reaction or lack of urate lowering) is primarily due to the development of anti-drug antibodies, and once present, retreating with pegloticase is mostly unsuccessful. We postulated that rituximab pre-treatment might permit recapture of pegloticase immune tolerance. We conducted an open label, safety and feasibility study to test this hypothesis. Patients with tophaceous gout and prior pegloticase failure were recruited to receive rituximab 1000 mg (twice), methotrexate 15 mg by mouth for at least 6 weeks, and then pegloticase per standard protocol. Patients were observed for infusion reaction and serum urate lowering in response to pegloticase infusions. Two patients completed induction and received at least 1 dose of pegloticase. Patient 1 had a moderate infusion reaction, requiring treatment with oral prednisone. Patient 2 had failure to lower urate treatment after 2 infusions. Based on these 2 outcomes, the trial was stopped. With either 6- or 12-week pre-pegloticase conditioning with rituximab, we were unable to recapture immune tolerance. Future trials considering use of rituximab might consider measuring anti-uricase antibodies in real time to guide the reintroduction of pegloticase.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3030017

Authors: Robert Terkeltaub

Gout and calcium pyrophosphate crystal deposition disease (CPPD) are frequently associated with comorbid disorders, including coronary artery disease and osteoarthritis, in which ectopic calcification with basic calcium phosphate crystals commonly affects arteries and articular cartilage, respectively. Accepting the 2024 G-CAN Gold Medal, I review my research philosophy for translational etiopathogenesis investigation in gout and CPPD, atherosclerosis, responses to arterial injury, and osteoarthritis. Since molecular homeostasis points to pathophysiology and vice versa, I have followed selected molecular players and pathways to phenotypes. Typically, behind each disease target is another target. Illuminating passageways between etiopathogenic pathways is especially productive when using approaches beyond conventional “omics” to reveal the impact of specific post-translational protein modifications, and changes in protein conformation, complex assembly, and interactomes. Highlighting these concepts, I review my past studies on specific molecular pathways, and current perspectives for the following: (i) PPi, NPP1, ANKH, and transglutaminase 2 (TG2); (ii) relationships between NPP1, ANKH, Vanin-1 Pantetheinase, and ectopic chondrogenesis; (iii) intersections between adenosine, AMPK, CXCL8 and its receptor CXCR2, the receptor for advanced glycation endproducts (RAGE) and chondrocyte hypertrophy; (iv) lubricin homeostasis and proteolysis; (v) receptor for advanced glycation endproducts (RAGE) and TG2-catalyzed post-translational calgranulin modification; (vi) complement activation and C5b-9 assembly, and the nucleotide-bound conformation of TG2. The inescapable conclusion is that these molecular pathways tightly knit crystal arthropathy with both arterial and osteoarthritis comorbidity.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3030016

Authors: Yuqi Wang Jinshuo Han Jasmin Knopf Lingjiang Zhu Yi Zhao Lei Liu Martin Herrmann

Gout is a chronic inflammatory disease characterized by the deposition of monosodium urate (MSU) crystals within joints, leading to recurrent acute flares and long-term tissue damage. While various hypotheses have been proposed to explain the self-limiting nature of acute gout attacks, we posit that aggregated neutrophil extracellular traps (aggNETs) play a central role in this process. This review focuses on the mechanisms underlying MSU crystal-induced formation of neutrophil extracellular traps (NETs) and explores their dual role in the clinical progression of gout. During the initial phase of acute flares, massive NET formation is accompanied by the release of preformed inflammatory mediators, which is a condition that amplifies inflammatory cascades. As neutrophil recruitment reaches a critical threshold, the NETs tend to form high-order aggregates (aggNETs). The latter encapsulate MSU crystals and further pro-inflammatory mediators within their three-dimensional scaffold. High concentrations of neutrophil serine proteases (NSPs) within the aggNETs facilitate the degradation of soluble inflammatory mediators and eventually promote the resolution of inflammation in a kind of negative inflammatory feedback loop. In advanced stages of gout, MSU crystal deposits are often visible via dual-energy computed tomography (DECT), and the formation of palpable tophi is frequently observed. Based on the mechanisms of resolution of inflammation and the clinical course of the disease, building on the traditional static model of “central crystal–peripheral fibrous encapsulation,” we have expanded the NETs component and refined the overall concept, proposing a more dynamic, multilayered, multicentric, and heterogeneous model of tophus maturation. Notably, in patients with late-stage gout, tophi exist in a stable state, referred to as “silent” tophi. However, during clinical tophus removal, the disruption of the structural or functional stability of “silent” tophi often leads to the explosive reactivation of inflammation. Considering these findings, we propose that future therapeutic strategies should focus on the precise modulation of NET dynamics, aiming to maintain immune equilibrium and prevent the recurrence of gout flares.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3030015

Authors: Rocio Paz Gonzalez Monica Guma

This review provides an overview of the most significant developments in gout pathophysiology research published in 2024. Thirteen studies were selected based on originality, scientific rigor, and potential clinical impact and grouped into four major categories: inflammation and pain mechanisms (LRRC8 anion channels, CXCL5-CXCR2 axis, CD38 and NAD+ metabolism, PLK1 and NLRP3 inflammasome localization, and IFN1 suppression), biomarkers and proteomics (scRNA-seq reveals monocyte and T-cell flare signatures, and Olink serum profiling reveals a proinflammatory signature in hyperuricemia and also identifies TNFSF14 as a novel flare biomarker, while a multi-omics integrative study implicates TRIM46 as a key causal gene), gut virome, and novel therapies (vagus nerve stimulation, biomimetic nanosystem, and restoration of Urate Oxidase (Uox) function). The studies selected focused primarily on work on subjects other than on hyperuricemia. The findings collectively expand our understanding of gout’s complex pathophysiology and highlight potential strategies for diagnosis, management, and innovative treatments.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3030014

Authors: M. Leonor Cancela Ahmed Alouane Pietro M. Bertelli Antonio Camacho Robbe Derudder Antonella Forlino Matthew P. Harris Marta Jacinto Imre Lengyel Wolfgang Link Monzur Murshed Andreas Pasch Arun-Kumar Kaliya-Perumal Daniela Quaglino Zihan Qin Yves Sabbagh Elena Seminari Marcos M. Villar Christoph Winkler Olivier M. Vanakker

The 3rd Annual Meeting of the International Network on Ectopic Calcification (INTEC) was held in Faro, Portugal on 12–13 September 2024. This hybrid meeting brought together researchers and clinicians focused on the molecular, (patho)physiological, and clinical aspects of ectopic calcification in hereditary and acquired conditions, as well as in aging. The findings presented in this year’s meeting emphasised the complexity of the field, offering new insights into both mechanistic pathways and translational hurdles. The abstracts of this year’s meeting are collected in this conference paper, with permission from the corresponding authors.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3030013

Authors: Ana Beatriz Vargas-Santos Christine E. Peloquin Tuhina Neogi

The evidence regarding allopurinol’s effects on renal function among people with hyperuricemia and gout has been conflicting, though clinicians are often cautious about using allopurinol in chronic kidney disease (CKD). We sought to examine the relation between allopurinol use in those with gout and CKD and the risk of worsening renal function. We conducted a time-stratified propensity score (PS)-matched cohort study on the IQVIA Medical Research Data representative of the UK general population. Among participants 18–89 years old with gout and CKD 3–4 not on urate-lowering therapy within one year prior, we identified new users of allopurinol and matched them 1:1 with a non-user. We analyzed the relation between incident allopurinol use and the changes in the eGFR at one year of follow-up using linear regression adjusted for the potential confounders included in the PS model. We PS-matched 10,716 allopurinol initiators to 10,716 non-users, among whom 42% were female, the mean age was 74 years and 7% had CKD4. The progression to dialysis or kidney transplant was similar in both groups. The mean eGFR prior to the study entry was 48.4 mL/min among allopurinol initiators and 49.5 mL/min among non-users, while the last eGFR within one year was 49.4 and 49.7 mL/min, respectively. The allopurinol initiators had an adjusted mean increase in the eGFR of 0.81 mL/min (95% CI 0.57–1.05) greater than that of non-users. Among those with gout and CKD 3–4, allopurinol did not worsen renal function and may have slightly improved it, suggesting that allopurinol is not detrimental to patients with gout who have CKD.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3030012

Authors: Kanon Jatuworapruk Jassdakorn Suaypring Natrawee Ngamprasertsith Nattawat Watcharajittanont

Objectives: Identification of monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals in synovial fluid should ideally be performed within 24 h to ensure optimal diagnostic accuracy for gout and CPP arthritis. However, crystal identification is often delayed in community-based healthcare facilities due to limited access to specialists or necessary equipment. This study aimed to determine whether MSU and CPP crystals remain detectable in synovial fluid after two weeks of storage at 4 °C and −20 °C. Methods: Anonymized synovial fluid samples were obtained from Thammasat University Hospital between February and March 2024. All samples underwent an initial round of crystal identification using compensated polarized light microscopy, conducted by two experienced examiners blinded to the clinical diagnosis. Following the initial analysis, each sample was divided into two equal portions and placed in ethylenediaminetetraacetic acid (EDTA)-coated tubes. One portion was stored at 4 °C, while the other was frozen at −20 °C. After two weeks, all samples underwent a second round of crystal identification. Results: Forty-nine samples were included for the first evaluation; MSU and CPP crystals were identified in 14 and 6 samples, respectively. On the second examination, MSU crystals were detectable in 13/14 (92.8%) samples stored at 4 °C and 12/14 (85.7%) samples stored at −20 °C. However, CPP crystals were detectable in 2/6 (33.3%) samples stored at both temperatures. No new crystal formation in initially negative samples was observed. Conclusion: MSU crystals remain detectable in synovial fluid for up to two weeks when stored in a standard refrigerator or freezer. However, the identification rate of CPP crystals tends to decline over this period. These findings may help inform best practices for handling synovial fluid samples in cases where immediate access to a specialist or necessary equipment is unavailable.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3030011

Authors: Gabriela Sandoval-Plata Kevin Morgan Morgan Michael Doherty Abhishek Abhishek

Objectives: (1) To compare cytokine levels in participants with serum urate (SU) < 360 µmol/L, SU ≥ 360 µmol/L with and without monosodium urate (MSU) crystal deposition, respectively, and inter-critical gout. (2) To explore the association of IL-1β, IL-6 and high-sensitivity (hs) CRP with disease duration and the frequency of self-reported gout flares. Methods: Samples and data from 184 participants from studies conducted at Academic Rheumatology, Nottingham City Hospital, were included. Serum high-sensitivity CRP and cytokines involved in the pathogenesis of gouty inflammation were measured. MANCOVA and multivariate linear regression were used, as appropriate, and were adjusted for age, sex, body mass index and self-reported comorbidities. p values were adjusted for multiple testing using a 5% false-discovery rate. Results: Participants with inter-critical gout had greater levels of IL-1β (pcorr = 0.009), IL-18 (pcorr = 0.02), IL-6 (pcorr < 0.0001), IP-10 (pcorr < 0.0001), TNF-α (pcorr < 0.0001), GRO-α (pcorr = 0.0006) and hsCRP (pcorr = 0.009) compared to other groups in multivariate analyses and after correcting for multiple testing. There were no differences in cytokine and hsCRP levels in participants with SU < 360 µmol/L and in participants with SU ≥ 360 µmol/L with or without MSU crystal deposition. There was a statistically non-significant trend for association between IL-6 levels and number of self-reported gout flares. Conclusions: Our findings suggest that gout is a chronic inflammatory condition. The pre-clinical phases of gout were not associated with systemic inflammation, potentially due to the modest sample size. Further research is required to understand whether treating gout by targeting the complete dissolution of MSU crystals would reduce systemic inflammation in inter-critical gout.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3020010

Authors: Gout, Hyperuricemia and Crystal–Associated Disease Network Gout, Hyperuricemia and Crystal–Associated Disease Network

The tenth annual international G-CAN research symposium was held in Alexandria, VA on the 13th and 14th of November 2024. This hybrid meeting, a live face-to-face and virtual live symposium, was attended by 201 participants. Over 20 research abstract submissions were received from early career investigators, for plenary oral and poster presentations. Here, we present the 22 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.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3020009

Authors: Mai Sekine Kimiyoshi Ichida

Xanthine oxidoreductase (XOR) is the only enzyme responsible for uric acid production and is essential for preventing gout. While XOR inhibitors effectively reduce serum urate levels, they also influence purine salvage and de novo pathways, as well as energy metabolism, raising concerns about metabolic adaptation and rebound effects upon treatment discontinuation. In this review, we outline the fundamental regulatory mechanisms of purine metabolism and summarize the mechanisms of action of XOR inhibitors and their associated metabolic effects with reference to XOR deficiency, type I xanthinuria. Furthermore, we discuss the impact of discontinuing XOR inhibitors and examine their potential for rebound.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3020008

Authors: Fiorella Rosas-Chavez Tony R. Merriman

Background: Mendelian randomization (MR) is a genetic epidemiological method used to infer causal relationships between exposures and outcomes. Its application in hyperuricemia and gout has grown exponentially owing to the ready availability of summary statistics from genome-wide association studies and the ease of applying the two-sample MR technique. However, indications of poor study quality suggest the need for systematic evaluation. Objective: This study evaluated the quality of two-sample MR studies on hyperuricemia and gout and developed a scoring system to help reviewers and readers assess their quality and validity. Methods: A systematic review was conducted on 86 two-sample MR studies published between 2016 and 2024. Studies were assessed using a scoring system encompassing study design, statistical methods, result interpretation, and adherence to STROBE-MR guidelines. Scores could range between −9 and 21. Trends in quality over time were analyzed using regression models. Results: Study quality scores ranged from 0 to 19, with a mean of 9.1 and median of 11, demonstrating wide variability. High-quality studies adhered to MR assumptions, used independent datasets, and conducted replication analyses, while lower-quality studies often failed to correct the p-value when needed, test for confounders, address dataset overlap, or report study power. Despite the increased publication of MR studies, overall quality has not improved over time. Conclusion: There is variability in two-sample MR study quality. Our proposed scoring system offers a practical framework for evaluating MR studies, aiding researchers and clinicians in identifying robust findings while promoting higher methodological standards.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3020007

Authors: Maddalena Zangari Roberto Luisetto Roberto Pilot Paola Contessa Raffaella Signorini Stefano Masiero Anna Scanu

Monosodium urate, calcium pyrophosphate, and basic calcium phosphate crystals are the most common types of crystals found in the joints. Each type of crystal has been associated with the onset of different joint diseases. However, the mechanisms identified for one type of crystal are often generalized to the others; thus, overlooking the specific and distinct molecular and cellular responses activated by each type of crystal. This review describes the similarities and differences of the main molecules and mechanisms underlying the diseases associated with the three different types of crystals. Specifically, current knowledge on crystal properties and formation, on the induction and resolution of inflammation, on mechanisms involved in pain processing and senescence, and on the role of mitochondria and genomic instability are elucidated. A more complete and detailed study of the specific molecular mechanisms induced by different crystals is necessary to advance our understanding of the pathogenesis and to help identify innovative opportunities for prevention and treatment of crystal deposition disease.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3020006

Authors: Riku Takei Nicholas A. Sumpter Megan P. Leask Tony R. Merriman

Genetic association studies in gout have identified genetic variants in or near genes involved in the biosynthesis and transport of urate and in immunological pathways. However, the causal role of the remaining genetic variants, genes, and pathways in gout is not clear. Here, we present the results from a genetic colocalization analysis of gout-associated signals with metabolite quantitative trait loci (mQTL), shedding light on the metabolites that are likely directly affected by genetic variants associated with gout. We identified 141 candidate metabolites with evidence of colocalization with at least one gout-associated genetic signal, of which 29 showed evidence of a causal relationship with gout by Mendelian randomization. Among the 29 metabolites were lysophosphatidylcholines, which may affect the inflammatory response by binding to the TLR-2/4 receptors, providing plausible candidate metabolites for future studies that link metabolites with inflammatory processes in gout.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3020005

Authors: Natalie Anumolu Ann Rosenthal Katherine Sherman Shikha Singla

Calcium pyrophosphate deposition disease (CPPD) has been shown to be associated with inflammatory arthritis such as rheumatoid arthritis. However, few studies have investigated the correlation between CPPD and psoriatic arthritis (PsA). Our study aimed to determine whether there were higher rates of PsA in patients with CPPD than controls. A retrospective cohort study was conducted using the Veterans Affairs’ Corporate Data Warehouse. Individuals with a CPPD ICD code were matched with controls and diagnoses of PsA and psoriasis were collected. A total of 41,084 CPPD patients were matched with 119,192 controls. The proportion of CPPD patients with PsA diagnosis was more than double that of controls (1.07% vs. 0.37%; p < 0.0001), and more CPPD patients were diagnosed with psoriasis (3.05% vs. 2.52%; p < 0.0001). Those with CPPD had higher odds of a PsA diagnosis (OR 3.550, 95% CI 2.602–4.844). A total of 61.59% of PsA diagnoses preceded the CPPD diagnoses by at least one year. This is the first case–control study demonstrating an association between CPPD and PsA, potentially related to the fact that both PsA and CPPD could be triggered by trauma, and are closely associated with osteoarthritis. It also is possible that inflammatory pathways contribute to CPP crystal deposition in joints.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3010004

Authors: Renaud Felten Laura Widawski Pierre-Marie Duret Lionel Spielmann Laurrent Messer

This review examines the concept of “psout”, an overlap syndrome of hyperuricemic psoriatic arthritis (HU-PsA) and co-existing gout and PsA. The manuscript explores its epidemiology, pathophysiology, clinical implications, and treatment strategies, focusing on emerging data since its first description in 2020. The psout concept is sustained by shared inflammatory and metabolic pathways between gout and PsA, contributing to a broad spectrum of phenotypes and moderate-to-severe clinical manifestations. Monosodium urate crystals and hyperuricemia are central to this overlap, influencing cytokine production, keratinocyte activation, and immune responses, being able to activate both innate and acquired immunity. Clinical management is complex due to diagnostic challenges and therapeutic considerations not yet implemented in international recommendations. Emerging data from clinical trials underscore the significance of hyperuricemia in worsening PsA outcomes while highlighting the potential of personalized treatments. Future research into shared pathophysiological mechanisms, the accurate description of the diversity of phenotypes, innovative imaging assessments, and therapeutic strategies could provide insights into the interplay of these two conditions and enhance patient outcomes.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3010003

Authors: Anusha Moses Martijn Oude Voshaar Mart van de Laar Tim L. Th. Jansen

Gout management strategies remain a topic of debate, particularly regarding the efficacy of treat-to-target (T2T) and treat-to-avoid-symptoms (T2S) approaches. T2T, endorsed by major rheumatology societies, involves systematic serum urate (sUA) monitoring and urate-lowering therapy (ULT) dose escalation to maintain sUA below a predefined threshold. In contrast, T2S, which focuses on symptom relief rather than routine sUA monitoring, is supported by alternative guidelines. Despite the widespread adoption of T2T in other chronic diseases, its clinical benefits beyond biochemical parameters, such as serum urate reduction, remain uncertain in gout. This study evaluates current evidence on T2T and T2S, analyzing data from a pragmatic multicenter trial comparing both strategies. Findings suggest that while T2T is effective in reducing sUA levels, its superiority in preventing flares and improving patient-reported outcomes remains inconclusive. Some studies report reduced tophus burden and better adherence with T2T, whereas others find negligible differences in pain relief and functional improvement between the two strategies. The lack of high-quality comparative trials underscores the need for further investigation. Future research should prioritize long-term, patient-centered outcomes and pragmatic implementation strategies.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3010002

Authors: Pascal Richette Marcel Flendrie Leo A. B. Joosten Noortje van Herwaarden

Lifelong urate-lowering therapy (ULT) is recommended for gout to prevent flares and urate deposition. However, concerns about its adherence, long-term side effects, and the necessity of continuous treatment after achieving remission raise critical questions. Two randomised controlled trials (RCTs), GO TEST Finale and STING, aim to evaluate the safety and feasibility of ULT discontinuation in gout patients in remission. The GO TEST Finale is a superiority trial involving 310 patients in the Netherlands, comparing a treat-to-target (T2T) ULT continuation strategy with ULT discontinuation. Patients in the discontinuation arm resume ULT only after flare recurrence or tophi development. The primary outcomes focus on remission criteria failure over 24 months, while the secondary outcomes explore predictors of successful discontinuation and cost-effectiveness. The STING study, a non-inferiority trial in France, includes 450 patients without ultrasound (US) evidence of urate deposits. Patients in the discontinuation group resume ULT if a US detects urate deposition during follow-up, minimising flare risk. The primary outcomes measure the proportion of patients experiencing flares at two years, with the secondary outcomes examining the long-term health impacts and cost-effectiveness. These trials provide an opportunity for translational research into the immunological and epigenetic effects of rising serum urate levels. The results could inform personalised strategies for a drug-free period and address the critical question of whether lifelong ULT is necessary for gout management. The complementary findings from both trials are expected to contribute significantly to resolving this ongoing clinical debate.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd3010001

Authors: Aichang Ji Zibin Tian Yongyong Shi Riku Takei Shun-Jen Chang Ronald M. L. Yip Huiyong Yin Changgui Li

Gout is a common inflammatory joint disease in China. In recent years, the prevalence of gout in China has been increasing and the onset age of gout has been trending younger. The common risk factors for gout in China include hyperuricemia, age, sex, obesity, hypertension, metabolic syndrome, use of drugs (e.g., diuretics), dietary factors, chronic kidney disease (CKD), ethnicity, and income. Chinese clinical guidelines recommend the diagnosis of subclinical gout, refractory gout, and clinical classification of hyperuricemia in gout patients with early-onset or family history. Maintaining a consistently low level of serum urate is crucial for the effective long-term treatment of gout. However, the Chinese guidelines recommend paying special attention to allopurinol hypersensitivity when considering urate-lowering drugs. The adherence rate to urate-lowering therapy (ULT) in Chinese patients with gout ranges from 9.6% to 40.7%. Patient education and reducing drug side effects are effective approaches to improve the adherence to ULT and the rate of achieving the target urate level. The development of new treatment principles based on clinical trials, such as ULT based on the classification of hyperuricemia and urine alkalization, is recommended to improve patient outcomes and reduce potential side effects. The study of genetics, metabolites, and intestinal microbiota has yielded new findings that may aid in the diagnosis, classification, and pathogenesis of gout in China.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2040025

Authors: Greg Challener Chio Yokose

Gout is the most common inflammatory arthritis, with a growing global disease burden. This conference report summarizes nine impactful publications dating from 11/2022 to 10/2023 to inform and improve clinical care in gout. The articles we present here collectively address diverse facets of gout research, including gout epidemiology, predictive biomarkers, the occurrence of complications relating to gout flares, and gout management strategies.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2040024

Authors: Ira Khanna Venkatesh Mani Renata Pyzik Audrey Kaufman Weiwei Chi Emilia Bagiella Philip Robson Yousaf Ali

We assessed changes in vascular inflammation and monosodium urate (MSU)-coded deposits after administration of Pegloticase in the vasculature of tophaceous gout patients using 18F-fluorodeoxyglucose (18F-FDG) Positron emission tomography/computed tomography (PET/CT) and dual-energy CT (DECT). Ten patients with tophaceous gout, intolerant or refractory to urate-lowering therapy (ULT), were treated with Pegloticase every two weeks for six months. 18F-FDG PET/CT and DECT were performed at baseline and after Pegloticase therapy to detect vessel wall inflammation (Standard uptake value, SUVmean, and SUVmax) and vascular MSU-coded deposition (MSU volume). Data were summarized using means and standard deviations. Baseline and follow-up values were compared for each variable using mixed-effect models. Significant decreases in SUVmean (p = 0.0003) and SUVmax (p = 0.009) were found with a trend towards a decrease in vessel wall MSU volume after treatment. There was a significant decrease in serum urate, correlating with reduction in SUVmean (R2 = 0.65), with a trend towards a decrease in CRP and blood pressure in all patients. Despite the small sample size, we were able to demonstrate a decrease in vessel wall inflammation and a trend towards a decrease in MSU volume by intensively lowering serum urate. These findings suggest that MSU-coded deposits and hyperuricemia may play a role in vascular wall inflammation. It remains to be seen whether this correlates with a decrease in adverse cardiovascular outcomes.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2040023

Authors: Ancuta Straton Brenda Kischkel Tania Crișan Leo Joosten

Gout is a crystal-induced arthropathy in which monosodium urate (MSU) crystals precipitate within joints as a result of persistent hyperuricemia and elicit an inflammatory response. An intriguing aspect is the occurrence of gout in only 10–15% of hyperuricemic individuals, suggesting the presence of additional risk factors. Although MSU crystal deposition is widely recognized as the cause of gout flares, the variability in initiating the inflammatory response to hyperuricemia and MSU deposition is not well understood. Several studies bring up-to-date information about the environmental and genetic influences on the progression towards clinical gout. Elevated urate concentrations and exposure to different external factors precipitate gout flares, highlighting the potential involvement of epigenetic mechanisms in gouty inflammation. A better understanding of the alteration of the epigenetic landscape in gout may provide new perspectives on the dysregulated inflammatory response. In this review, we focus on understanding the current view of the role of epigenomic reprogramming in gout and the mechanistic pathways of action.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2040022

Authors: John D. FitzGerald Chesca Barrios Tairan Liu Ann Rosenthal Geraldine M. McCarthy Lillian Chen Bijie Bai Guangdong Ma Aydogan Ozcan

Background: The gold standard for crystal arthritis diagnosis relies on the identification of either monosodium urate (MSU) or calcium pyrophosphate (CPP) crystals in synovial fluid. With the goal of enhanced crystal detection, we adapted a standard compensated polarized light microscope (CPLM) with a polarized digital camera and multi-focal depth imaging capabilities to create digital images from synovial fluid mounted on microscope slides. Using this single-shot computational polarized light microscopy (SCPLM) method, we compared rates of crystal detection and raters’ preference for image. Methods: Microscope slides from patients with either CPP, MSU, or no crystals in synovial fluid were acquired using CPLM and SCPLM methodologies. Detection rate, sensitivity, and specificity were evaluated by presenting expert crystal raters with (randomly sorted) CPLM and SCPLM digital images, from FOV above clinical samples. For each FOV and each method, each rater was asked to identify crystal suspects and their level of certainty for each crystal suspect and crystal type (MSU vs. CPP). Results: For the 283 crystal suspects evaluated, SCPLM resulted in higher crystal detection rates than did CPLM, for both CPP (51%. vs. 28%) and MSU (78% vs. 46%) crystals. Similarly, sensitivity was greater for SCPLM for CPP (0.63 vs. 0.35) and MSU (0.88 vs. 0.52) without giving up much specificity resulting in higher AUC. Conclusions: Subjective and objective measures of greater detection and higher certainty were observed for SCPLM over CPLM, particularly for CPP crystals. The digital data associated with these images can ultimately be incorporated into an automated crystal detection system that provides a quantitative report on crystal count, size, and morphology.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2030021

Authors: Frédéric Lioté Fernando Perez-Ruiz Hang-Korng Ea Tristan Pascart Tony Merriman Alexander So

15th Anniversary this year: the ECN workshop is set up in Paris, down town. Every year ECN workshop offers a unique opportunity for clinicians and researchers interested in crystals, inflammation, crystal-induced diseases including gout, to present their latest results and discuss novel concepts. Twenty nine out of 52 accepted abstracts are reported here.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2030020

Authors: Romain Dalla-Torre Benoit Le Goff Christelle Darrieutort-Laffite

Periarticular calcifications are a common condition for rheumatologists. They are characterized by deposition of carbonated apatite in tendons or connective tissues around joints. It most commonly affects patients between 30 and 60, and the main location is the shoulder (rotator cuff tendons), followed by the hip. Although the disease is frequent, factors associated with the appearance of the deposits or their spontaneous resorption remain unclear. In this review, we will summarize the available data about mechanisms underlying the constitution of the deposits and their resorption and describe the various affected sites and the associated symptoms. In the last part, we will discuss current treatment options.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2030019

Authors: Andrew P. Giromini Sonia R. Salvatore Brooke A. Maxwell Sara E. Lewis Michael R. Gunther Marco Fazzari Francisco J. Schopfer Roberta Leonardi Eric E. Kelley

Many preclinical reports have coalesced to identify a strong association between obesity and increased levels of uric acid (UA) in tissues and, importantly, in the circulation (hyperuricemia). Unfortunately, nearly all these studies were conducted with male mice or, in one case, female mice without a side-by-side male cohort. Therefore, the relationship between obesity and hyperuricemia in female mice remains undefined. This lack of clarity in the field has considerable impact as the downstream effects of obesity and allied hyperuricemia are extensive, resulting in many comorbidities including cardiovascular dysfunction, chronic kidney disease, and nonalcoholic fatty liver disease (NAFLD). Herein we begin to address this issue by revealing phenotypic and metabolic responses to diet-induced obesity (DIO) in a side-by-side male vs. female C57BL/6J study. Beginning at 6 weeks of age, mice were exposed to either an obesogenic diet (60% calories from fat) or control diet (10% calories from fat) for 19 weeks. Similar to numerous reported observations with the 60% diet, male mice experienced significant weight gain over time, elevated fasting blood glucose, impaired glucose tolerance and significantly elevated circulating uric acid levels (2.54 ± 0.33 mg/dL) compared to age-matched lean male controls (1.53 ± 0.19 mg/dL). As expected, the female mice experienced a slower rate of weight gain compared to the males; however, they also developed elevated fasting blood glucose and impaired glucose tolerance compared to age-matched lean controls. Countervailing our previous report whereby the control diet for the female-only study was vivarium standard chow (18% calories from fat), the obese female mice did demonstrate significantly elevated circulating UA levels (2.55 ± 0.15 mg/dL) compared to the proper control (1.68 ± 0.12 mg/dL). This affirms that the choice of control diet is crucial for reaching durable conclusions. In toto, these results, for the first time, reveal elevated circulating UA to be a similar long-term response to obesogenic feeding for both males and females and mirrors clinical observations demonstrating hyperuricemia in obesity for both sexes.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2030018

Authors: Sonia Nasi Mario Romani Nathalie Busso

Calcification refers to the deposition of calcium-containing crystals either intracellularly or within the extracellular matrix. Physiologic calcification is a normal process occurring during bone and tooth development and growth. In contrast, pathologic calcification occurs in soft tissues that typically do not undergo mineralization, such as blood vessels, cartilage, tendons, and skin. Pathological calcification is significantly associated with tissue impairment and the development of secondary diseases, such as atherosclerosis, osteoarthritis, tendinopathy, and skin ulcers. Aging, a natural process linked to numerous pathologic conditions, is one of the most recognized risk factors for pathological calcification. In this manuscript, we review the current state of knowledge regarding the role of aging in calcification across different tissues. We focus on the mechanisms activated during normal aging, including cellular senescence, decreased pyrophosphate levels, increased secretion of extracellular vesicles, elevated oxidative stress, and higher levels of pro-mineralizing cytokines, all of which can contribute to pathological calcification. Finally, we discuss the available animal models used to study the impact of aging on calcification.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2030017

Authors: Maria Muntiu Leo A. B. Joosten Tania O. Crişan

Gout is a prevalent form of inflammatory arthritis caused by the crystallization of uric acid in the joints and soft tissues, leading to acute, painful attacks. Activation of the NLRP3 inflammasome in mononuclear cells, along with inflammasome-independent pathways, is responsible for the inflammatory phenotype in gout. Research into the different aspects of gout pathophysiology and potential treatment options is ongoing. This review highlights some of the basic research published in the 12 months following the 2022 Gout, Hyperuricemia, and Crystal-Associated Disease Network (G-CAN) conference and focuses on mechanisms of inflammation, encompassing pro- and anti-inflammatory pathways, as well as the exploration of various biological systems, such as single-cell transcriptomics, proteomics, metabolomics, and microbiome analyses.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2020016

Authors: Tappei Takada Hiroshi Miyata Yu Toyoda Akiyoshi Nakayama Kimiyoshi Ichida Hirotaka Matsuo

Uric acid is the final purine metabolite in humans. Serum urate levels are regulated by a balance between urate production, mainly in the liver, and its excretion via the kidneys and small intestine. Given that uric acid exists as a urate anion at physiological pH 7.4, membrane transporters are required to regulate urate homeostasis. In the kidney, urate transporter 1, glucose transporter 9, and organic anion transporter 10 contribute to urate reabsorption, whereas sodium-dependent phosphate transport protein 1 would be involved in urate excretion. Other transporters have been suggested to be involved in urate handling in the kidney; however, further evidence is required in humans. ATP-binding cassette transporter G2 (ABCG2) is another urate transporter, and its physiological role as a urate exporter is highly demonstrated in the intestine. In addition to urate, ABCG2 regulates the behavior of endogenous substances and drugs; therefore, the functional inhibition of ABCG2 has physiological and pharmacological effects. Although these transporters explain a large part of the urate regulation system, they are not sufficient for understanding the whole picture of urate homeostasis. Therefore, numerous studies have been conducted to find novel urate transporters. This review provides the latest evidence of urate transporters from pathophysiological and clinical pharmacological perspectives.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2020015

Authors: Gout, Hyperuricemia and Crystal-Associated Disease Network Gout, Hyperuricemia and Crystal-Associated Disease Network

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.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2020014

Authors: Ava M. Zapf Owen M. Woodward

A relationship between metabolic disorders and hyperuricemia is well established. The nature of the relationship—risk factor, causal agent, or byproduct—remains unclear. Recent studies of sodium–glucose transporter 2 inhibitors (SGLT2i’s) have established that this pharmacological intervention is beneficial to patients with hyperglycemia and type 2 diabetes mellitus (T2D) and also against the common cardio and renal comorbidities associated with diabetes. Hyperuricemia, or high plasma uric acid levels, is one of the comorbidities mitigated with SGLT2i treatment, raising the potential for using SGLT2i’s as part of the treatment for gout and hyperuricemia. However, the mechanisms underlying the lower plasma urate levels and increased uricosuria produced with SGLT2i’s remains poorly understood. Here, we review the renal physiology of glucose and uric acid transport, the renal consequences of hyperglycosuria and diabetes, the benefits and physiology of SGLT2i use, and discuss several potential mechanisms that may be responsible for the favorable uricosuric effect observed in those treated with SGLT2i’s.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2020013

Authors: Panagiota Drivelegka Lennart TH Jacobsson Mats Dehlin

Population-based databases in Nordic countries offer unique opportunities for large-scale population-based epidemiological studies. The personal identity number enables researchers to link different registers at the individual level, which can be used for large-scale epidemiological population-based studies. This review outlines how these opportunities have been used so far in the field of gout research, as well as the potential challenges and limitations. Their major advantage is that they cover the entire population, minimizing problems such as selection bias and loss to follow-up. This has enabled us to provide information on gout regarding risk factors; occurrence; association with comorbidities in relation to gout onset; treatment patterns; as well as its effect on other outcomes, such as sick leave and mortality. Validity issues, missing data, and legal issues are some of the challenges that researchers need to deal with. Choosing the most appropriate combination of databases to use for a specific question is crucial in order to maximize validity and adjust for confounders. Despite challenges and potential limitations, the Swedish registers have provided valuable epidemiological results and will continue to play an important role in the years to come.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2020012

Authors: Medeea Badii Orsolya I. Gaal Ioana Hotea Valentin Nica Andreea M. Mirea Dragoş Mărginean HINT Consortium HINT Consortium Cristina Pamfil Simona Rednic Radu A. Popp Tania O. Crişan Leo A. B. Joosten

Gout, an inflammatory disease orchestrated by interleukin-1β activation and release, is more prevalent in men. The clinical profiles of patients with gout report differences by sex. This study aims to investigate sex-specific cytokine profiles in circulation and in stimulated peripheral blood mononuclear cells (PBMCs) of patients with gout and controls. Participants included in the gout group met the criteria of the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR). The control group included individuals with varying levels of serum urate and absence of gout. PBMCs were stimulated in vitro for 24 h with various TLR ligands. Cytokines were determined in culture supernatants and plasma. Plasma IL-1Ra and high-sensitivity C-reactive protein (hsCRP) were higher in men with gout compared to men without gout whereas no significant differences in circulating cytokines were observed in women. PBMCs of patients with gout showed higher cytokine production of IL-1β, IL-1Ra, and TNF-α following 24 h stimulation, predominantly observed in women. We identified sex-specific cytokine production in gout in response to in vitro stimulation. While men with gout had higher levels of circulating cytokines, stimulated PBMCs of women with gout show an enhanced capacity for cytokine production. These data may suggest potentially different regulatory mechanisms of inflammation in men and women with gout.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2020011

Authors: Raewyn C. Poulsen Nicola Dalbeth

Gout flares more frequently start late at night or in the early morning compared to during the day. The reasons for this are unknown. Activation of the NLRP3 inflammasome in monocytes/macrophages is central to initiation of gout flares. Here, we review the mechanisms by which circadian clocks control the NLRP3 inflammasome and the implications of this for the nighttime pattern of gout flares. Several hormones involved in inflammation regulation, e.g., glucocorticoids, melatonin and melanocortins, are under circadian control, with both circulating hormone levels as well as the expression of their receptors on target tissues showing time-of day differences. In addition, the NLRP3 inflammasome is also under the control of the macrophage circadian clock, leading to time-of-day differences in expression of NLRP3 inflammasome components and susceptibility to inflammasome-activating stimuli. MSU crystal exposure leads to altered expression of circadian clock components in macrophages, leading to time-of-day-specific loss of repression of NLRP3 inflammasome activity. Taken together, there is clear evidence that circadian clocks regulate the NLRP3 inflammasome and that this regulation may be compromised by MSU crystal exposure in gout. Circadian control of the inflammasome may be one of the factors contributing to nighttime susceptibility to gout flares.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2020010

Authors: Augustin Latourte Hang-Korng Ea Pascal Richette

Calcium-containing crystal deposition diseases are extremely common in rheumatology. However, they are under-explored compared to gout or other inflammatory rheumatic diseases. Major advances have been made in 2023 that will undoubtedly stimulate and facilitate research in the field of calcium pyrophosphate (CPP) deposition disease (CPPD): the ACR/EULAR classification criteria for CPPD and a semi-quantitative OMERACT score for ultrasound assessment of the extent of CPP deposition have been validated and published. A large randomized controlled trial compared the efficacy and safety of colchicine and prednisone in acute CPP arthritis. Preclinical studies have elucidated the pro-inflammatory and anti-catabolic effects of basic calcium phosphate (BCP) crystals on mononuclear cells and chondrocytes. The association between osteoarthritis (OA) and IA calcifications has been the subject of several epidemiological publications, suggesting that calcium crystals are associated with a greater risk of progression of knee OA. Research in the field of calcium crystal deposition diseases is active: the areas of investigation for the coming years are broad and promising.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2020009

Authors: Emilio Filippucci Edoardo Cipolletta Silvia Sirotti Georgios Filippou

The use of ultrasonography (US) has considerable potential for the diagnosis and monitoring of gout due to its capacity to detect monosodium urate deposits. In the last decade, a critical amount of scientific data has become available. Consensus-based definitions for ultrasonographic elementary lesions in gout have been developed, tested, and validated, as well as a semiquantitative scoring system for their quantification. Many scanning protocols have been proposed in different clinical scenarios. In this review, we formulate a set of practical suggestions for the use of the US in daily practice. We discuss the current knowledge to indicate which joints and structures are to be scanned and which elementary findings are to be evaluated according to the clinical scenario. While for some clinical settings, a quite definite scanning protocol can be indicated, others still need to be further investigated, and how to obtain the best out of the US is still entrusted to the individual experience.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2010008

Authors: Leonard Stern Richard J. Johnson Payam Shakouri Amod Athavale Lissa Padnick-Silver Brian LaMoreaux Brad A. Marder Sreedhar Mandayam

Gout patients have higher mortality, heavier comorbidity burden, and lower quality of life than non-gout patients, but information is sparse on how gout affects advanced CKD patients. This study examined the prevalence and potential health impacts in stage 3–5 CKD patients. Gout was defined as being listed as a comorbidity, ULT use, and/or reported gout symptoms (tophi, >1 flare). Uncontrolled gout was defined as hyperuricemia (serum urate >6 mg/dL) with tophi, ≥2 gout flares/year, or ≥1 swollen/tender joint. This study included 746 patients (55% men, age: 56.2 ± 18.3 years, CKD-duration: 4.0 ± 4.8 years, eGFR: 32.2 ± 15.5 mL/min/1.73 m2), of which 23% met the gout criteria. Prevalence was highest in patients with stage 3b and 4 CKD. Gout patients had a significantly higher prevalence of cardiovascular comorbidities, CKD-mineral bone disorder, and back pain than non-gout patients. Uncontrolled gout patients had more hypertension, joint issues, chronic pain, febuxostat use, and colchicine use than controlled patients. Compared to those without gout, gout patients had higher rates of cardiovascular and bone diseases, with uncontrolled patients having an even higher burden. In conclusion, these data suggest that identifying and monitoring gout in CKD patients provides health benefits. However, more than one-third of gout patients did not have a formal gout diagnosis in their medical record.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2010007

Authors: Lisa K. Stamp Robin Christensen Melanie B. Morillon

In gout research, serum urate has been widely accepted as the primary endpoint in clinical trials of urate-lowering therapies by both the FDA and EMA for many years. However, for serum urate to be a meaningful outcome measure, it should reflect at least one important patient-centered clinical outcome, such as gout flares. The relationship between achieving a pre-specified “target” serum urate and a corresponding improvement in patient-centered outcomes has been difficult to show due to variation in reporting of both serum urate and gout flares in clinical trials; a paradoxical rise in gout flares after starting urate-lowering therapy and a delay after achieving the pre-specified target serum urate before gout flares settle coupled with the relatively short duration of the trials. However, recent evidence from individual-level patient data from two, two-year randomized controlled trials clearly shows that achieving target urate is associated with a subsequent reduction and cessation of gout flares. In this review, we examine the evidence supporting serum urate as a surrogate outcome for gout flares, the methods, and the challenges of showing the validity of surrogacy.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2010006

Authors: Frédéric Lioté Fernando Perez-Ruiz Hang-Korng Ea Tony Merriman Tristan Pascart Alexander So

The 14th annual international European Crystal Network was held in Paris on 2 and 3 March 2023. This in-person meeting was attended by 93 participants. Over 40 research abstract submissions were received from investigators, ranging from early career investigators to senior researchers, for plenary oral and poster presentations. Here, we present the accepted, lightly edited abstracts from the presenters consenting to have their work published. We thank and congratulate the presenters for their work and contributions to the meeting.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2010005

Authors: Sara K. Tedeschi

Calcium pyrophosphate deposition (CPPD) disease is a crystalline arthritis that was described more than 60 years ago, yet our knowledge about this condition greatly lags behind other forms of arthritis. This is an exciting era for CPPD disease as a robust framework for CPPD clinical research has been established. The American College of Rheumatology (ACR) and EULAR co-sponsored the development of the first-ever classification criteria for CPPD. The Outcomes Measures in Rheumatology (OMERACT) CPPD Ultrasound Subtask Force developed and validated definitions for ultrasonographic findings of CPPD, and the OMERACT CPPD Working Group is establishing a core outcome domain set for this crystalline arthritis. This review focuses on key elements of the 2023 ACR/EULAR CPPD disease classification criteria and considerations for measuring outcomes in CPPD disease.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2010004

Authors: Tom Niessink Matthijs Janssen Tim L. Jansen Cees Otto

Due to health concerns, the European Union has banned the use of titanium dioxide nanoparticles in consumables in February 2022, with a 6-month transitional period ending in August 2022. We studied the prevalence of titanium dioxide nanoparticles in synovial fluid samples during and after the transitional period. A total of 302 samples were collected as a consecutive series between 1 April 2022 and 15 June 2023 from patients visiting the department of rheumatology at VieCuri Medical Centre in Venlo, The Netherlands. The samples were primarily collected for diagnostic purposes and only clinical waste material was used for this study. From each sample, up to 40 μl of fluid was analysed with Raman spectroscopy for the presence of titanium dioxide particles. The trend in prevalence was calculated with a 3-month wide moving average. A total of 13 out of 302 samples (4.3%) contained titanium dioxide (TiO2). The prevalence of TiO2 decreased between the transitional period and the period after the ban (p = 0.0154, with a relative risk ratio of 4.9 (95% CI 1.35–17.74). There was no significant difference in patient characteristics between the TiO2 positive and the TiO2 negative group. These results are hinting towards a possible relationship between the EU-ban and the identified decrease in prevalence.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2010003

Authors: Sébastien Ottaviani

Imaging modalities such as ultrasonography (US) and dual-energy computed tomography (DECT) have been recognized for their abilities to detect monosodium urate (MSU) crystals. The main described features of gout detected by DECT (tophus) or US (tophus, double contour [DC] sign and aggregates) are very specific for the diagnosis of gout, but the impact of imaging on the follow-up of MSU deposits is not well known. US and DECT allow for visualization of the disappearance of MSU crystals under adequate urate-lowering therapy (ULT). An OMERACT US score and a DECT urate score have been described. The dissolution of the DC sign is detectable on US after 3 months, whereas a decreased size or volume in tophus can be observed on US or DECT after 6 months of ULT. Serum urate level decrease is associated with a reduction in MSU crystal deposition. Finally, the risk of gout flare is associated with the baseline MSU burden and with the degree of dissolution of crystal deposition. All these data confirm that imaging could be useful in managing gout, even if its exact place in routine practice remains unclear.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2010002

Authors: Georgios Filippou Silvia Sirotti Edoardo Cipolletta Emilio Filippucci

Ultrasound is a pivotal exam in calcium pyrophosphate deposition (CPPD) identification. It has been demonstrated to be feasible, accurate, and reliable for CPPD diagnosis. Even if standardized definitions and a scoring system for CPPD have been established by the OMERACT ultrasound working group, ultrasound is still considered one of the most operator-dependent techniques. This is because in ultrasound, both the acquisition and the interpretation phases of the diagnostic process are in the hands of one operator and are performed simultaneously, in contrast to what happens with other imaging exams, where the acquisition process is standardized and independent from the interpretation process. Therefore, the scanning technique and machine setting acquire a central role, almost as important as the interpretation of the images, as erroneous scanning may lead to interpretative mistakes. In this review, we will delve into the appearance of CPPD on ultrasound, based on the latest research findings, passing through its pathogenesis, and focusing on machine settings and ultrasound scanning techniques, providing some tips and tricks to facilitate accurate CPPD recognition in the most frequently affected sites.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd2010001

Authors: Jennifer Lee Nicholas Sumpter Tony R. Merriman Ru Liu-Bryan Robert Terkeltaub

Gout is at least three times more prevalent in males than in females. However, concurrent with rising total gout prevalence, complex factors, including comorbidities, diet, lifestyle, and aging, have promoted higher gout prevalence in females. This narrative review focuses on summarizing recent developments in the landscape of gout in females and the mechanisms involved. New knowledge on sex hormone effects on both urate-excreting and urate-reabsorbing transporters and higher hypertension and chronic kidney disease prevalence in females compared to males may help explain why gout incidence rises robustly after menopause in females, to approach that in males. Racial and ethnic factors, risk profiles based on heritable genetic polymorphisms of urate transporters, diet, body mass index, and lifestyle factors differ according to sex. In addition, sex differences in clinical phenotypes, outcomes of gout, and non-gout illnesses include more frequent comorbidities, more pain and disability during gout flares, different perceptions of disease burden, and more frequent severe cutaneous hypersensitivity reaction to allopurinol in females. Collectively, such findings support the potential clinical benefits of tailoring gout and hyperuricemia treatment according to sex.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1040019

Authors: Geraldine Mary McCarthy

Calcium-containing crystal deposition diseases are a common cause of pain and disability but remain relatively under-investigated. No drug has been identified that can prevent deposition or effect dissolution of either calcium pyrophosphate (CPP) or basic calcium phosphate (BCP) crystals. In comparison to the field of gout and urate biology, published research in relation to calcium crystal deposition diseases in 2022 was relatively modest in quantity. In CPP deposition (CPPD) disease, progress was made mainly in epidemiology, imaging, surgical management and Gitelman’s syndrome. In relation to BCP crystals, the effect on tenocytes in vitro was explored and results indicate that BCP crystals likely reduce tendon matrix integrity via their interaction with tenocytes. The involvement of calcification in the progression of osteoarthritis (OA) was elegantly demonstrated contributing to further discovery of the process of OA progression. There was a paucity of mechanistic and genetic studies in calcium crystal deposition diseases published in 2022, nor any breakthrough in therapy, showing that there is abundant scope for investigation under these themes in the future.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1040018

Authors: Nellissa Y. Ling Siân E. Halcrow Hallie R. Buckley

Gout has been part of human history for thousands of years. Skeletal evidence of the disease among past people in Europe is often associated with high-status individuals whose lifestyles comprised risk factors for gout, including increased sedentism and greater access to rich, high-caloric, food. A growing body of evidence, however, has shown that multiple factors other than lifestyle also contribute to gout development. In 2011, Buckley presented a review of modern and pre-modern gout cases in which she proposed that selective pressures may partly underlie the high prevalence of gout in the population history of the Pacific region. In this paper, we provide an update on Buckley’s 2011 review of gout in human history. We also review early life stress as a potential underlying factor to consider for gout development, particularly among small prehistoric communities where opulent lifestyles traditionally associated with gout were unlikely to have occurred.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1030017

Authors: Tristan Pascart Jean-François Budzik

Cardiovascular disease in gout is a central issue, but the underlying mechanisms linking the two are unclear. The existence of monosodium (MSU) crystal deposition directly inflaming vessel walls has been recurrently suggested and challenged since the 1950s and is again a matter of active debate since recent studies using dual-energy computed tomography (DECT) suggested a higher prevalence of plaques considered to be containing MSU crystals in patients with gout. The objective of this review is to critically cover the evidence gathered on MSU crystal deposition in the cardiovascular system. In patients affected with gout, histological evidence of MSU crystals in arteries lacks a biochemical characterization supporting the observation in polarized light microscopy, while current knowledge on vascular lesions identified in DECT as containing MSU crystals suggests that they may be only artifacts, including in cadaveric and phantom studies. In individuals without gout, MSU crystal deposition in vessel walls have not been demonstrated, despite higher urate local plaque concentrations and increased xanthine oxidase activity. Gout is associated with increased arterial calcification and atherosclerosis, both being potential confounders of suspected MSU crystal deposition for the analysis of DECT scans and histopathology, respectively. In summary, the reality of the presence of MSU crystals in vascular plaques has not been demonstrated so far, and needs further investigation as it represents a potential outcome for cardiovascular complications of gout.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1030016

Authors: Ru Liu-Bryan Tracy Guo Jennifer Lee Robert Terkeltaub

Gout is strongly associated with atherosclerosis and other cardiovascular comorbidities. Furthermore, sites of extra-articular monosodium urate (MSU) crystal deposits in gout can include heart valves and atherosclerotic artery plaques, but with unclear effects therein. Hence, we seminally explored cultured vascular smooth muscle cell (VSMC) responsiveness to MSU crystals. To limit confounding effects, we cultured human aortic VSMCs under serum-free conditions to assess MSU crystal effects on VSMC differentiation and function, differentially expressed genes (DEGs) via RNA sequencing, and selected atherogenic changes in cytokines and the lipidome. MSU crystals induced p38 phosphorylation, IL-6, and VSMC vacuolization with dysregulated autophagy. MSU-crystal-induced DEGs included decreased late-stage autophagosome maturation mediator GABARAPL1, decreased physiologic VSMC differentiation regulators (LMOD1 and SYNPO2), increased ATF4, CHOP, and the intrinsic apoptosis signaling pathway in response to ER stress, and neointimal atherogenic nuclear receptors (NR4A1 and NR4A3). MSU crystals alone increased the levels of cholesterol biosynthetic intermediates 14-demethyl-lanosterol (14-DML), desmosterol, and zymosterol. Adding MSU crystals increased oxidized LDL’s capacity to increase intracellular 27-OH cholesterol, and MSU crystals and oxidized LDL synergistically induced a marked release of arachidonate. In conclusion, MSU crystals deposited in arterial media and neointima have the potential to dysregulate VSMC differentiation and proteostasis, and to induce further atherogenic effects, which include enhanced VSMC loading of oxidized cholesterol intermediates and release of IL-6 and arachidonic acid (AA).

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1030015

Authors: Gout, Hyperuricemia and Crystal-Associated Disease Network Gout, Hyperuricemia and Crystal-Associated Disease Network

The eighth annual international G-CAN research symposium was held in Alexandria, VA on 21st and 22nd October 2022. This hybrid meeting, live face-to-face and virtual live symposium, was attended by over 150 participants. Over 20 research abstract submissions were received from early-career investigators, for plenary oral and poster presentations. Here, we present the accepted, lightly-edited abstracts from the presenters consenting to have their materials published. We thank and congratulate the presenters for their work and contributions to the meeting.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1030014

Authors: Mariano Andrés

Gout is intimately associated with cardiovascular disease—especially in cases of an atherosclerosis origin, but also with others such as heart failure, atrial fibrillation, or aortic valve stenosis. Besides the common presence of vascular comorbidities in gout sufferers, the disease is—in itself—an independent cardiovascular risk factor, with disease events and mortality attributable to having this condition. This review aims to update the current knowledge regarding several grey areas of the gout–cardiovascular disease spectrum—particularly in terms of risk variations across sex or ancestries, potential monosodium urate crystal deposition in the artery tree as a pathogenic pathway, the efforts undertaken to assess risk estimations in the gout population, and recent controversies surrounding the effects of gout therapies on cardiovascular disease.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1030013

Authors: Isidoro Cobo Jessica Murillo-Saich Mohnish Alishala Monica Guma

The analysis of metabolite mediators has allowed a broader understanding of disease mechanisms. Experimental evidence indicates that metabolic rewiring is a key feature of inflammatory cells to restore tissue homeostasis upon damage. Over the last two decades, next-generation sequencing techniques have offered the possibility of looking at the genome-wide effect of the exposure of inflammatory cells to external stimuli. During gout flares, monosodium urate crystals activate a distinct metabolic profile and inflammatory transcriptional program in inflammatory cells. The extracellular signals are transduced through distinct signalling pathways, which are regulated by non-coding RNA and DNA sequences, and modification of histones. During response to inflammatory stimuli, changes in the abundance of metabolic mediators can regulate the activation of histones and of chromatin remodellers. The interplay between metabolic changes by MSUc, the regulation of epigenetic changes and the activation of transcription factor networks in inflammatory cells remains unknown. A better understanding of the interplay between metabolites and how it alters inflammatory response may provide novel insights into disease mechanisms during gout. In this review, we aim to provide a deeper understanding of the current view of how metabolic deregulation could alter the epigenetic landscape of inflammatory cells during gout.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1030012

Authors: Khaled A. Elsaid Gregory D. Jay Ru Liu-Bryan Robert Terkeltaub

Proteoglycan 4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and superficial zone chondrocytes, released into synovial fluid, and adsorbed on cartilage and synovial surfaces. PRG4′s roles include cartilage boundary lubrication, synovial homeostasis, immunomodulation, and suppression of inflammation. Gouty arthritis is mediated by monosodium urate (MSU) crystal phagocytosis by synovial macrophages, with NLRP3 inflammasome activation and IL-1β release. The phagocytic receptor CD44 mediates MSU crystal uptake by macrophages. By binding CD44, PRG4 limits MSU crystal uptake and downstream inflammation. PRG4/CD44 signaling is transduced by protein phosphatase 2A, which inhibits NF-κB, decreases xanthine oxidoreductase (XOR), urate production, and ROS-mediated IL-1β secretion. PRG4 also suppresses MSU crystal deposition in vitro. In contrast to PRG4, collagen type II (CII) alters MSU crystal morphology and promotes the macrophage uptake of MSU crystals. PRG4 deficiency, mediated by imbalance in PRG4-degrading phagocyte proteases and their inhibitors, was recently implicated in erosive gout, independent of hyperuricemia. Thus, dysregulated extracellular matrix homeostasis, including deficient PRG4 and increased CII release, may promote incident gout and progression to erosive tophaceous joint disease. PRG4 supplementation may offer a new therapeutic option for gout.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1030011

Authors: Rachel D. King Eric E. Kelley

The past year generated significant change and advancement of the urate field with novel insights regarding the role of uric acid (UA) in multiple pathophysiologic processes from gout to COVID-19. While these contributions continue to move the field forward, the basic biochemistry and biology of UA is often overlooked, being lost in the shadow of clinical associations and omics. However, the seminal impact of UA begins with biochemistry and the associated interplay with cell biology. In these basic reactions and resultant impacts on physiology, UA mediates its influence on clinical outcomes. As such, this review focuses on published advances in UA biochemistry and biology in 2022 and associates these advances with downstream consequences.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1020010

Authors: Natalie McCormick Chio Yokose Hyon K. Choi

Together with the substantial role of genetic factors, serum urate levels and the occurrence of gout are also heavily driven by environmental and clinical factors, including adiposity, dietary patterns, alcohol, kidney function, and diuretic medication use. These are, in turn, greatly influenced by the social determinants of health, which encompass access to health care, availability of healthy foods, and opportunities for physical activity but also education, income, social norms, and racism, among other forces. Gout-related health disparities have been described for Māori and Pacific people in New Zealand, but racial disparities in gout prevalence and outcomes between Black and White Americans have been under-recognised, and particularly, sex-specific data are scarce. In this article we review evidence from prior cohort studies and contemporary national-level data which show the incidence and prevalence of gout and hyperuricemia in Black adults in the US have come to exceed that in White adults and are disproportionately greater in Black women. Importantly, this emerging disparity can be attributed entirely to social determinants of health, including higher levels of adiposity and poverty in Black women compared to White women and lower kidney function and poorer quality diet among Black men compared to White men. Furthermore, Black patients with gout have received poorer quality gout-related care and experienced higher levels of healthcare use, especially Black women. While identifying targets for culturally safe interventions for addressing risk factor disparities is essential, evidence gaps remain about potential disparities in longer-term outcomes of gout, including cardio-metabolic-kidney endpoints and premature mortality. Sociodemographically diverse, population-based longitudinal cohort studies, research on implementation strategies for improved gout care delivery models for underserved groups, and efforts to minimise structural racism and its effects are key to achieving health equity in gout.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1020009

Authors: Surbhi Gupta Elizabeth Miller Sharon Stein Merkin Maureen McMahon Karol E. Watson John D. FitzGerald

(1) The Multi-Ethnic Study of Atherosclerosis (MESA) is a multi-center longitudinal cohort study designed to investigate the risk factors associated with the incidence of CVD. The purpose of this study is to examine the impact of gout on incident CVD. (2) Participants reporting the use of gout-specific medications (urate lowering drugs or colchicine) were compared with non-users. Kaplan–Meier survival curves and multivariable models to control for known CV risk factors evaluated hazard ratios (HR) between participants taking gout medications versus those not taking gout medications. (3) For the 6734 participants, analyses were stratified by gender owing to a gout-gender interaction. For the 164 male and 59 female participants taking gout medications, Kaplan–Meier (unadjusted) survival curves demonstrate that participants taking gout medications have higher rates of CVD than participants not taking gout medications, particularly for women. After controlling for known CV risk factors, the adjusted HR for female participants taking gout medications was 1.79 (0.99, 3.23), p = 0.05; the adjusted HR for male participants on gout medications was 1.20 (0.81, 1.77), p = 0.36; (4) Participants treated for gout in this study have many comorbid conditions with known CVD risk factors, making it difficult to confirm the independent effect of gout on CVD. There are a paucity of data on women with gout. These findings suggest that there is a clinically meaningful and potentially greater risk of CVD among women with gout as compared to men.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1020008

Authors: Eric Liu Nicola Dalbeth Bregina Pool Andrea Ramirez Cazares Veena K. Ranganath John D. FitzGerald

Aggregates are one of the elementary lesions seen on musculoskeletal ultrasound (US) in gout patients as defined by Outcome Measures in Rheumatology (OMERACT). The aim of this study was to evaluate the threshold of detection of aggregate findings on ultrasound and to analyze these findings with corresponding compensated light microscope (CPLM) images in vitro. Patient derived monosodium urate (MSU) crystals were obtained from two separate patients with gout during routine clinical care. In addition, fabricated in-house synthetic MSU crystals were used for comparison. Each sample was scanned using a GE Logic ultrasound machine and corresponding CPLM images obtained. As the aggregates became imperceptible by ultrasound, MSU clumping by CPLM examination was no longer detectable and crystal density per high power field fell markedly. Aggregates on US images are present only from patient-derived samples likely representing MSU crystal clustering or packing. Thus, when synovial aspiration is considered, a joint with aggregates on US would be a more suitable target with a higher likelihood of noting MSU crystals.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1020007

Authors: Adrian Buchholz Sina Stücker Franziska Koßlowski Christoph H. Lohmann Jessica Bertrand

The detection and differentiation of BCP and CPP crystals in calcified tissue is an important factor in the context of research and potential future treatment of osteoarthritis and chondrocalcinosis. Current standard methods originate from clinical practice and often lack precision in the correct identification of the calcium crystal type. In this work, a step-by-step guide for the use of the high-resolution imaging methods of tissue sections, Raman spectroscopy and scanning electron microscopy (SEM) in combination with energy-dispersive X-ray spectroscopy (EDS), for calcium crystal identification is presented. Sample preparation including Von Kossa staining, measurement and measurement parameters, data processing and data analysis methods are discussed and described. Furthermore, the different methods are compared to show advantages and disadvantages. Overall, Raman spectroscopy is a reasonable method from an economic point of view and regarding the time/effort required for acquiring highly reliable data in calcium crystal identification. Potentially, semi-quantitative results can be obtained with little effort and without the destruction of the respective test sample. The analysis/penetration depth during the Raman measurements, which is not precisely defined, poses a potential problem for accuracy. SEM can also be used for this task but requires more time, advanced technical knowledge and a pre-treatment of the samples using, e.g., gold sputtering, which may distort further analysis on the specific specimen. Therefore, this technique yields additional value compared to Raman spectroscopy only with additional research questions needed to be answered in the same sample, such as analysis of the sample topography or analysis of other unknown particles/deposits using EDS. The methods described in this manuscript are helpful for retrospective analyses in the context of research, but can also be used for potential future treatment strategies to discriminate between osteoarthritis and chondrocalcinosis patients.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1010006

Authors: Rui Li Ningning Liang Yongzhen Tao Huiyong Yin

Urate is one of the key metabolites of purine metabolism, and the overproduction of urate in the liver or decreased excretion in the kidney in humans may lead to elevated levels of urate in the circulation, termed hyperuricemia (HU). The formation of monosodium urate (MSU) crystals in the joint or surrounding tissues may trigger inflammatory responses and gout attacks, which is the most common inflammatory arthritis. In addition to gout, HU has also been associated with many other metabolic diseases, such as cardiovascular disease, obesity, diabetes, fatty liver diseases, kidney diseases, hypertension, and various cancers. Overwhelming evidence indicates that HU and gout lead to systematic metabolic alterations underlying these metabolic disorders. As one of the most powerful omics techniques, metabolomics systematically analyzes all small-molecule metabolites in a biological system that directly reflect the physiological and pathological conditions. In recent years, metabolomics has been increasingly employed in clinical and experimental research in HU and gout. Emerging studies have developed predictive models to differentiate HU from gout based on metabolomics and machine-learning algorithms. In this review, we systematically summarize recent advances in metabolomic research in gout and HU in animal and human clinical studies. A comprehensive understanding of systemic metabolic changes caused by HU and gout may provide unprecedented insights into the pathological mechanisms in HU, gout, and related metabolic diseases, which may have a profound impact on the prevention, diagnosis, and treatment of HU and gout.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1010005

Authors: Mariana Urquiaga Angelo L. Gaffo

Gout is a prevalent and burdensome condition despite the advances in our knowledge of its underlying mechanisms, prevention, and treatment. There is still work to be done to elucidate relevant questions that could lead to better patient care. This conference report summarizes eight impactful publications which inform and improve clinical care in gout from October 2021 to October 2022. The articles we present here address innovative management approaches, the use of serum urate as a surrogate marker, the occurrence of complications such as cardiovascular events and lower extremity amputation, the evaluation of mortality in patients with chronic kidney disease and gout, the effect of intensive serum urate control on radiographic outcomes, and the impact of COVID-19 infection in patients with gout. The conclusions reached by these publications are noteworthy. Some of them are potentially practice-changing, and all provide exciting follow-up questions.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1010004

Authors: Thomas Bardin Emmanuel Letavernier Jean-Michel Correas

This review re-examines the role of crystal deposition in the kidney in view of recent clinical and experimental findings. The involvement of the renal system in gout seems frequent. Indeed, recent studies showed that approximately 25% of patients with gout experience renal failure, defined by estimated glomerular filtration rate <60 mL/min/1.73 m2. The pathophysiology is complex and involves several factors, their respective roles being difficult to dissect. The role of crystal deposition in the kidney was the first suspected, and the concept of gouty microcrystalline nephropathy, also called gouty nephropathy, has been popular, supported by early autopsy studies demonstrating uric acid and urate crystal deposition in the renal medulla of patients with gout, together with features of tubulointerstitial nephritis. Crystal deposition was first considered an important source of renal involvement in gout. After the introduction of urate-lowering drugs and the performance of kidney biopsies, which mainly involved the renal cortex and did not reveal much crystal deposition but rather vascular changes, this concept has been criticized and even dismissed. Thereafter, kidney involvement in gout was considered mainly vascular, related to hypertension and associated comorbidities and later to hyperuricemia. The toxic effects of non-steroidal anti-inflammatory drugs is also an important factor. Modern imaging, especially renal ultrasonography, allows for atraumatic exploration of the kidney and has revealed hyperechogenicity of the renal medulla, suggesting crystalline deposits, in approximately one-third of patients with tophaceous gout. Experimental models of gouty nephropathy have recently demonstrated the pathogenic role of microcrystal deposition in the collecting ducts and parenchyma of the renal medulla. Taken together, these recent findings lead to the re-examination of the pathogenic role of crystal deposition in the renal medulla and testing the effect of urate-lowering drugs on renal features of gouty patients with evidence of renal crystal deposition.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1010003

Authors: Gary H. Ho Michael Toprover Daria B. Crittenden Binita Shah Michael H. Pillinger

Background: Despite colchicine’s proven efficacy in the non-gout population, the effects of colchicine on the risk of major adverse cardiovascular events (MACE) among high-risk patients with gout remain to be determined. The purpose of this study is to evaluate the association between colchicine use and MACE in gout patients with preexisting coronary artery disease (CAD). Methods: This retrospective cohort study followed patients with gout and established CAD within the VA New York Harbor Healthcare System who did or did not use colchicine regularly (>30 continuous days prescription with at least 1 refill). The primary outcome was first MACE, defined as a composite of non-fatal myocardial infarction, coronary artery bypass graft, non-fatal stroke, and all-cause mortality. Part I of the primary analysis compared MACE between colchicine users and nonusers. Part II of the study compared MACE within the colchicine-use group, divided into quartiles based on consistency of colchicine use (i.e., percentage of time on colchicine). Results: Among 1638 patients with gout, 355 had established CAD (239 colchicine users and 116 nonusers). In this cohort, the odds of MACE were similar between any colchicine use compared to nonuse (OR 1.14; 95% CI (0.59–2.20)); however, colchicine users overall had a higher baseline cardiovascular risk profile than nonusers, suggesting that colchicine may have served to equilibrate risk between the two groups. Moreover, patients in the highest continuous colchicine-use quartile (>70% of observation period on colchicine) demonstrated lower odds of MACE compared to those in the lowest three quartiles (OR 0.35; 95% CI (0.13–0.93)), with no difference in baseline risk. Additionally, colchicine users had a numerically lower rate of MACE during periods of active use compared with periods of lapse. Kaplan–Meier analysis revealed a difference in cumulative MACE over time, favoring the subgroup with the most consistent colchicine use (plog-rank = 0.01). Conclusions: Despite higher CV risk, gout patients with CAD receiving colchicine had no higher rates of MACE than those not receiving colchicine. Among all patients with gout and CAD treated with colchicine, those with the most consistent colchicine use had lower odds of MACE, and event rates were lower during active use. Colchicine protection against cardiovascular events may require maintenance of colchicine bloodstream levels.

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1010002

Authors: Chanaka Dahanayake Kelsey M. Jordan Edward Roddy

Gout is the most common inflammatory arthritis and causes significant pain and disability [...]

Gout, Urate, and Crystal Deposition Disease doi: 10.3390/gucdd1010001

Authors: Tristan Pascart Tony R. Merriman Hyon K. Choi Robert Terkeltaub

Gout and crystal deposition-associated disorders are among the leading causes of inflammation and arthritis throughout the world [...]