Gout, Urate, and Crystal Deposition Disease

The crystal arthropathies gout and calcium pyrophosphate deposition (CPPD) disease represent a significant subset of rheumatic and musculoskeletal diseases, yet their overlap with common entities such as osteoarthritis (OA), rheumatoid arthritis (RA), and psoriatic arthritis (PsA) remains underrecognized. We conducted a structured narrative review of studies published through August 2025, exploring the epidemiology, clinical presentation, imaging characteristics, and treatment implications of these overlapping conditions. We particularly examine how crystal deposition may mimic or complicate the clinical course of OA, RA, and PsA, especially in older adults with multimorbidity. Recognizing these overlaps is critical to avoid misdiagnosis, inappropriate escalation of immunomodulatory therapy, and missed opportunities for targeted crystal-directed treatment. Full article

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. Full article

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. Full article

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. Full article

‘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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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) PP_i, 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. Full article

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. Full article

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. Full article