Gout Urate Cryst. Depos. Dis., Volume 3, Issue 3 (September 2025) – 8 articles

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

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. Full article

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. Full article

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. Full article

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 (p_corr = 0.009), IL-18 (p_corr = 0.02), IL-6 (p_corr < 0.0001), IP-10 (p_corr < 0.0001), TNF-α (p_corr < 0.0001), GRO-α (p_corr = 0.0006) and hsCRP (p_corr = 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. Full article