Erosive Gout Research Articles

Baseline Dual-Energy Computed Tomography Urate Volume Predicts Fulfillment of Gout Remission After Two Years of Urate-Lowering Therapy.

This study aimed to identify variables that predict gout remission in people with erosive gout receiving urate-lowering therapy. We analyzed data from a two-year, double-masked randomized-controlled trial of people with erosive gout, randomized to a serum urate target of <0.20 mmol/L or <0.30 mmol/L using oral urate-lowering therapies. All participants had dual-energy computed tomography (DECT) scans of the feet and ankles at baseline. The proportion of participants achieving gout remission according to the 2016 preliminary gout remission criteria and simplified gout remission criteria (without the patient reported outcomes) was analyzed. Logistic regression models were used to evaluate predictors of gout remission in year 2. The preliminary gout remission criteria were fulfilled in 11 of 97 participants (11%) at year 1 and 21 of 92 participants (23%) at year 2. The simplified criteria were fulfilled in 26 of 97 participants (27%) in year 1 and 40 of 92 participants (44%) in year 2. In multivariable regression models, baseline DECT monosodium urate crystal volume was the only significant independent predictor of gout remission at year 2, using either criteria. Each 1-cm3 increase in the baseline DECT monosodium urate crystal volume decreased the odds of fulfilling the 2016 preliminary gout remission criteria (odds ratio [OR] 0.65, 95% confidence interval [CI] 0.46-0.93; P = 0.02) and the simplified gout remission criteria (OR 0.57, 95% CI 0.41-0.78; P < 0.001). In people with erosive gout on urate-lowering therapy, higher baseline DECT monosodium urate crystal volume is associated with lower odds of gout remission after two years of treatment, defined by either the preliminary gout remission criteria or simplified gout remission criteria.

Global, regional, and national burden of gout, 1990–2020, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021

Gout is an inflammatory arthritis manifesting as acute episodes of severe joint pain and swelling, which can progress to chronic tophaceous or chronic erosive gout, or both. Here, we present the most up-to-date global, regional, and national estimates for prevalence and years lived with disability (YLDs) due to gout by sex, age, and location from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021, as well as forecasted prevalence to 2050. Gout prevalence and YLDs from 1990 to 2020 were estimated by drawing on population-based data from 35 countries and claims data from the USA and Taiwan (province of China). Nested Bayesian meta-regression models were used to estimate prevalence and YLDs due to gout by age, sex, and location. Prevalence was forecast to 2050 with a mixed-effects model. In 2020, 55·8 million (95% uncertainty interval 44·4-69·8) people globally had gout, with an age-standardised prevalence of 659·3 (525·4-822·3) per 100 000, an increase of 22·5% (20·9-24·2) since 1990. Globally, the prevalence of gout in 2020 was 3·26 (3·11-3·39) times higher in males than in females and increased with age. The total number of prevalent cases of gout is estimated to reach 95·8 million (81·1-116) in 2050, with population growth being the largest contributor to this increase and only a very small contribution from the forecasted change in gout prevalence. Age-standardised gout prevalence in 2050 is forecast to be 667 (531-830) per 100 000 population. The global age-standardised YLD rate of gout was 20·5 (14·4-28·2) per 100 000 population in 2020. High BMI accounted for 34·3% (27·7-40·6) of YLDs due to gout and kidney dysfunction accounted for 11·8% (9·3-14·2). Our forecasting model estimates that the number of individuals with gout will increase by more than 70% from 2020 to 2050, primarily due to population growth and ageing. With the association between gout disability and high BMI, dietary and lifestyle modifications focusing on bodyweight reduction are needed at the population level to reduce the burden of gout along with access to interventions to prevent and control flares. Despite the rigour of the standardised GBD methodology and modelling, in many countries, particularly low-income and middle-income countries, estimates are based on modelled rather than primary data and are also lacking severity and disability estimates. We strongly encourage the collection of these data to be included in future GBD iterations. Bill & Melinda Gates Foundation and the Global Alliance for Musculoskeletal Health.

Proteoglycan 4 (PRG4)/Lubricin and the Extracellular Matrix in Gout

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.

Amplification of Inflammation by Lubricin Deficiency Implicated in Incident, Erosive Gout Independent of Hyperuricemia.

In gout, hyperuricemia promotes urate crystal deposition, which stimulates the NLRP3 inflammasome and interleukin-1β (IL-1β)-mediated arthritis. Incident gout without background hyperuricemia is rarely reported. To identify hyperuricemia-independent mechanisms driving gout incidence and progression, we characterized erosive urate crystalline inflammatory arthritis in a young female patient with normouricemia diagnosed as having sufficient and weighted classification criteria for gout according to the American College of Rheumatology (ACR)/EULAR gout classification criteria (the proband). We conducted whole-genome sequencing, quantitative proteomics, whole-blood RNA-sequencing analysis using serum samples from the proband. We used a mouse model of IL-1β-induced knee synovitis to characterize proband candidate genes, biomarkers, and pathogenic mechanisms of gout. Lubricin level was attenuated in human proband serum and associated with elevated acute-phase reactants and inflammatory whole-blood transcripts and transcriptional pathways. The proband had predicted damaging gene variants of NLRP3 and of inter-α trypsin inhibitor heavy chain 3, an inhibitor of lubricin-degrading cathepsin G. Changes in the proband's serum protein interactome network supported enhanced lubricin degradation, with cathepsin G activity increased relative to its inhibitors, SERPINB6 and thrombospondin 1. Activation of Toll-like receptor 2 (TLR-2) suppressed levels of lubricin mRNA and lubricin release in cultured human synovial fibroblasts (P < 0.01). Lubricin blunted urate crystal precipitation and IL-1β induction of xanthine oxidase and urate in cultured macrophages (P < 0.001). In lubricin-deficient mice, injection of IL-1β in knees increased xanthine oxidase-positive synovial resident M1 macrophages (P < 0.05). Our findings linked normouricemic erosive gout to attenuated lubricin, with impaired control of cathepsin G activity, compounded by deleterious NLRP3 variants. Lubricin suppressed monosodium urate crystallization and blunted IL-1β-induced increases in xanthine oxidase and urate in macrophages. The collective activities of articular lubricin that could limit incident and erosive gouty arthritis independently of hyperuricemia are subject to disruption by inflammation, activated cathepsin G, and synovial fibroblast TLR-2 signaling.

Rat Bite Erosion of the Knee.

Erosive gout is a hallmark of severe disease and an indication to begin urate-lowering therapy, which can be started concurrently during a gout flare, to prevent further articular damage and flare recurrence.1 A 56-year-old male refugee presented to clinic with several days of left knee pain and swelling.

Intensive Serum Urate Lowering With Oral Urate-Lowering Therapy for Erosive Gout: A Randomized Double-Blind Controlled Trial.

To determine whether a therapeutic approach of intensive serum urate lowering results in improved bone erosion scores in patients with erosive gout. We undertook a 2-year, double-blind randomized controlled trial of 104 participants with erosive gout who were receiving serum urate-lowering therapy orally and who had serum urate levels of ≥0.30 mmoles/liter at baseline. Participants were randomly assigned to either an intensive serum urate target of <0.20 mmoles/liter or a standard target of <0.30 mmoles/liter (considered the standard according to rheumatology guidelines). Oral serum urate-lowering therapy was titrated to target using a standardized protocol (with the maximum approved doses of allopurinol, probenecid, febuxostat, and benzbromarone). The primary end point was the total computed tomography (CT) bone erosion score. Outcome Measures in Rheumatology (OMERACT) gout core outcome domains were secondary end points. Although the serum urate levels were significantly lower in the intensive target group compared to the standard target group over the study period (P = 0.002), fewer participants in the intensive target group achieved the randomized serum urate target level by year 2 (62% versus 83% of patients in the standard target group; P < 0.05). The intensive target group required higher doses of allopurinol (mean ± SD 746 ± 210 mg/day versus 497 ± 186 mg/day; P < 0.001) and received more combination therapy (P = 0.0004) compared to the standard target group. We observed small increases in CT bone erosion scores in both serum urate target groups over 2 years, with no between-group difference (P = 0.20). OMERACT core outcome domains (gout flares, tophi, pain, patient's global assessment of disease activity, health-related quality of life, and activity limitation) improved in both groups over 2 years, with no between-group differences. Adverse event and serious adverse event rates were similar between the groups. Compared to a serum urate target of <0.30 mmoles/liter, more intensive serum urate lowering is difficult to achieve with an oral urate-lowering therapy. Intensive serum urate lowering leads to a high medication burden and does not improve bone erosion scores in patients with erosive gout.

Gout, Hyperuricaemia and Crystal-Associated Disease Network (G-CAN) consensus statement regarding labels and definitions of disease states of gout

ObjectiveThere is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease...

Calcium pyrophosphate deposition disease: a frequent finding in patients with long-standing erosive gout

Objective: To characterize patients with both monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals in their synovial fluid (SF).Method: Forty-nine gout patients with acute arthritis were included. Those patients with MSU crystals only in their SF were compared to those patients with both MSU and CPP crystals in their SF.Results: A total of 36 out of 49 patients (73.5%) had only MSU crystals, whereas 13 out of 49 (26.5%) had both MSU and CPP crystals in their SF. Co-deposition of CPP crystals was associated with long-standing gout disease (p = 0.022), kidney dysfunction (p = 0.024), and erosive arthritis (p = 0.049), but not with age.Conclusion: Long-standing gout may be a risk factor for CPP deposition disease, and the frequency of CPP co-deposition may be higher than expected.

Advanced erosive gout as a cause of Fever of unknown origin.

A 61-year-old man was referred to our hospital due to a 3-month history of fever of unknown origin, and with right knee and ankle joint pains. At another hospital, extensive investigations had produced negative results, including multiple sterile cultures of blood and joint fluids, and negative autoantibodies. His serum uric acid level was not elevated. However, after admission to our hospital, we performed right knee arthrocentesis, which revealed uric acid crystals. These findings, combined with the results of imaging tests, which showed joint degeneration, led to a diagnosis of advanced erosive gout. After receiving a therapeutic non-steroidal anti-inflammatory drug and a maintenance dose of colchicine for prophylaxis against recurrence, the patient's symptoms subsided and did not return. Advanced erosive gout should be considered a possible cause of fever of unknown origin and diagnostic arthrocentesis should be performed in patients with unexplained arthritis.

Analysis of bone in POMC knockout mice

Abstracts for 2nd Joint Meeting of the International Bone and Mineral Society and The Australian & New Zealand Bone & Mineral Societys for 2nd Joint Meeting of the International Bone and Mineral Society and The Australian & New Zealand Bone & Mineral Society Category 1. Systemic and Local Regulation of Skeletal Metabolism Analysis of bone in POMC knockout mice J.L. Costa, M. Watson, K.E. Callon, U. Hochgeschwender, J. Cornish Department of Medicine, University of Auckland, Auckland, New Zealand Neurobiology, Duke University, Durham, North Carolina, USA The proopiomelanocortin (POMC) gene encodes numerous peptide hormones secreted by the CNS, the pituitary, and other tissues in the periphery. These hormones include α-, βand γ-melanocyte stimulating hormones (MSH), adrenocorticotropin (ACTH), β-lipotrophin, and β-endorphin. Roles for these hormones have been demonstrated in pigmentation, body weight and metabolism regulation, steroid hormone production, and pain modulation. In the hypothalamus and in the peripheral circulation, α-MSH is secreted in response to elevated leptin levels. Several types of bone cells express subsets of the melanocortin receptors as well as the ACTH receptor. In vitro, α-MSH has been shown to increase bone turnover, increasing both osteoblast proliferation and osteoclastogenesis, while systemic administration of α-MSH reduces bone volume in vivo. There are few recent studies of the direct effects of ACTH on bone cells, and its activities in vivo are often confounded by the numerous steroid hormones it stimulates. βendorphin is one of several endogenous opioids and this family has generally been shown to be anabolic to bone. POMC knockout mice have non-functional adrenal glands with reduction or loss of all adrenal hormones, show increased linear growth, are morbidly obese and develop pituitary tumors with age. In this pilot study, we examined tibia from POMC null mutants for changes in their bone characteristics before the onset of obesity (aged 810 weeks, 3 females per group) using computer assisted microtomography. Cortical thickness was significantly increased in POMC null mice (0.18mm±0.009SEM vs. 0.13±0.003, p=0.0139) versus controls. Changes in trabecular bone in POMC null mice did not reach significance in several measurements: trabecular thickness (0.046mm±0.002 vs. 0.044mm±0.001), trabecular separation (0.20mm±0.006 vs. 0.23mm±0.03) or bone surface (12.1mm2± 2.1 vs. 10.83mm2±0.37). Average femur length (13.9mm±0.15 vs. 13.4mm±0.23) and growth plate thickness also did not reach significance in this small number of animals, although interesting trends were again seen in the POMC null animals. This preliminary study shows that ablation of POMC signaling results in changes in bone morphology consistent with some but not all of the constituent POMC hormones. We suggest that the combined loss of α-MSH and reduction of steroid hormone signaling may be responsible for increasing the rate of osteoblast proliferation and/or reducing the rate of osteoclast formation or function in bones, potentially leading to increased linear length. Changes in POMC hormone signaling impact bone formation during mammalian development and warrant further investigation for possible links to central control of bone metabolism. doi:10.1016/j.bone.2009.12.012 Category 4. Clinical Disorders other than Osteoporosis, Mechanisms of erosive gout: Monosodium urate monohydrate crystals reduce osteoblast viability A. Chhana, K.E. Callon, B. Pool, J. Cornish, N. Dalbeth Medicine, University of Auckland, Auckland, New Zealand Gout is an inflammatory arthritis that is triggered by monosodium urate monohydrate (MSU) crystals within the joint. MSU crystals interact with surrounding cells and tissue within the joint causing inflammation. Bone erosion is a frequent manifestation of chronic gout, and leads to joint damage and deformity, with subsequent disability. We have recently shown that patients with erosive gout have disordered osteoclastogenesis and that MSU crystals indirectly promote osteoclast formation through interactions with stromal cells. Bone 46 (2010) 1465–1466

Enhanced osteoclastogenesis in patients with tophaceous gout: Urate crystals promote osteoclast development through interactions with stromal cells

To analyze cellular mechanisms of bone erosion in gout. Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) from patients with gout were analyzed for the presence of osteoclast precursors. Fixed tophus and bone samples were analyzed by immunohistochemistry. Mechanisms of osteoclastogenesis were studied by culturing murine preosteoclast RAW 264.7 cells, bone marrow stromal ST2 cells, and human synovial fibroblasts with monosodium urate monohydrate (MSU) crystals. PBMCs from patients with severe erosive gout had the preferential ability to form osteoclast-like cells in culture with RANKL and monocyte colony-stimulating factor (M-CSF). The number of PBMC-derived tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells strongly correlated with the number of tophi (r = 0.6296, P = 0.630). Patients with severe erosive and tophaceous gout also had higher circulating concentrations of RANKL and M-CSF. Furthermore, greater numbers of TRAP-positive multinucleated cells were cultured from SFMCs derived from gouty knee effusions than from paired PBMCs (P = 0.004). Immunohistochemical analysis demonstrated numerous multinucleated cells expressing osteoclast markers within tophi and at the interface between soft tissue and bone. MSU crystals did not directly promote osteoclast formation from RAW 264.7 cells in vitro. However, MSU crystals inhibited osteoprotegerin gene and protein expression in ST2 cells and human synovial fibroblasts, without significantly altering RANKL gene expression. Conditioned medium from ST2 cells cultured with MSU crystals promoted osteoclast formation from RAW 264.7 cells in the presence of RANKL. Chronic tophaceous and erosive gout is characterized by enhanced osteoclast development. These data provide a rationale for the study of osteoclast-targeted therapies for the prevention of bone damage in chronic gout.

Renal complications of nonsteroidal anti-inflammatory drugs

A 63-year-old, hypertensive, nondiabetic man with a 4-year history of gout was hospitalized because of painful swelling of his right foot. His blood pressure had been treated with nifedipine, 20 mg orally, three times daily. On admission, the patient was normotensive (blood pressure, 140/85 mm Hg) and had no clinical signs of congestive heart failure or volume depletion. Physical examination revealed erythema and soft-tissue swelling of the dorsum of the right foot with metatarsal tenderness. Laboratory data showed mild azotemia with a BUN level of 23 mg/dl; serum creatinine, 1.8 mg/dl; creatinine clearance, 70 mllmin; serum potassium, 4.1 mEq/liter; serum bicarbonate, 24 mmol/liter; and serum uric acid, 13.2 mg/dl. Roentgenographic findings were consistent with erosive gout, and a diagnosis of acute gouty attack was made. Indomethacin, 50 mg orally three times daily, was begun. The patient's symptoms improved rapidly, but within 4 days, the BUN rose to 51 mg/dl; serum creatinine, 2.4 mg/dl; serum potassium, 6.6 mEq/liter; and serum bicarbonate, 27 mmollliter; the creatinine clearance decreased to 36 mI/mm, with a fractional excretion of sodium of 0.06% and a urinary potassium concentration of 21 mEq/liter. The urinary sediment was unremarkable. The patient's blood pressure ranged from 140/85 to 150/90 mm Hg and no major changes in urinary output were noted. Indomethacin treatment was discontinued and replaced by colchicine. The patient's renal function and serum potassium level returned to baseline values within 4 days.