Relationship between serum urate and changes in dual-energy CT monosodium urate crystal volume over 1 year in people with gout: an individual participant data analysis.

OBJECTIVES: The dynamics of monosodium urate (MSU) crystal changes across a range of serum urate concentrations in people with gout are unknown. This study aimed to systematically examine the relationship between serum urate and changes in dual-energy CT (DECT) urate volume in people with gout and stable serum urate concentrations. METHODS: Individual participant data were analysed from three studies of people with gout. The time periods for the analysis were selected to identify study participants with serial DECT scans of both feet over a 12-month epoch of stable urate-lowering therapy and serum urate concentrations. Data from 251 study participants were analysed using a mixed models analysis of covariance approach according to mean serum urate cut-points and mean serum urate bands. RESULTS: For all mean serum urate cut-points assessed (0.24, 0.30, 0.36, 0.42 and 0.48 mmol/L), reductions in DECT urate volumes were observed below the cut-point. Increased DECT urate volumes were observed at or above the 0.48 mmol/L mean serum urate cut-point. Differences in the change in DECT volume were observed for the 0.42 mmol/L cut-point (p=0.0044) and the 0.48 mmol/L cut-point (p<0.0001). Significantly reduced DECT urate volumes were observed for the mean serum urate bands<0.24 mmol/L and 0.24-0.29 mmol/L and increased DECT urate volume was observed for the mean serum urate band≥0.48 mmol/L. CONCLUSIONS: Over 1 year, MSU crystal dissolution, as measured by DECT, occurs with mean serum urate bands of<0.24 mmol/L and 0.24-0.29 mmol/L while MSU crystal formation occurs with mean serum urate≥0.48 mmol/L.

'Gout was like the boss'. A qualitative study exploring the impact of gout on employment.

OBJECTIVE: Previous research has identified that gout impacts various domains of daily life. However, there have been no qualitative studies focusing on employment. This study aimed to understand the impact of gout on employment. METHODS: Semistructured interviews were conducted in Spain and Aotearoa/New Zealand, in people with gout (according to the 2015 American College of Rheumatology/European Alliance of Associations for Rheumatology criteria) who had experienced a gout flare during their employment. The interviews were guided by questions exploring the impact on employment, job changes, disclosure and co-workers' reactions. Data were analysed thematically. RESULTS: Eighteen participants were interviewed (89% male, mean age 52.9 years). Six themes were identified. The characteristics of the disease (pain intensity, tophi and joints affected) and the job itself (including physical job requirement and workplace flexibility) determined the experience of working with gout. The experiences were divided into physical (from total incapacity to working despite pain), emotional (feeling responsible, embarrassment, guilt and depression) and social (including disclosure responses and financial impact). Gout management strategies including rapid gout flare management and urate-lowering therapy reduced the number of flares and the intensity of pain, and allowed work attendance and participation. CONCLUSION: Both gout and work characteristics influence the employment experience for people with gout. Effective management of gout led to improved work experiences in all its domains.

Updates in Ultrasound in Rheumatology.

BACKGROUND: The purpose of the authors' narrative review was to outline the current literature regarding the use of ultrasound in main rheumatic disorders and summarize the updates, specifically about rheumatoid arthritis, psoriatic arthritis, and crystal-induced arthropathies. METHODS: The authors searched on PubMed for articles discussing the major updates regarding the role of ultrasound in the previously mentioned rheumatic conditions. RESULTS: The authors have provided the updated definitions, new criteria, and diagnostic scores. CONCLUSIONS: In rheumatology's dynamic landscape, this review provides valuable insights for researchers and clinicians on ultrasound's role in improving patient care and outcomes in rheumatic diseases.

Gout risk in adults with pre-diabetes initiating metformin.

OBJECTIVE: Despite the strong association between gout and pre-diabetes, the role of metformin in gout among individuals with pre-diabetes remains uncertain. We compared the incidence rates of gout in adults with pre-diabetes starting metformin with those not using antidiabetic treatments. METHODS: We conducted a new-user, propensity score-matched cohort study using electronic health records from an academic health system (2007-2022). Pre-diabetes was defined based on haemoglobin A1c levels. Metformin users were identified and followed from the first metformin prescription date. Non-users of antidiabetic medications were matched to metformin users based on propensity score and the start of follow-up. The primary outcome was incident gout. Cox proportional hazards models estimated the HR for metformin. Linear regression analyses assessed the association between metformin use and changes in serum urate (SU) or C-reactive protein (CRP). RESULTS: We identified 25 064 individuals with pre-diabetes and propensity score-matched 1154 metformin initiators to 13 877 non-users. Baseline characteristics were well balanced (all standardised mean differences <0.1). The median follow-up was 3.9 years. The incidence rate of gout per 1000 person-years was lower in metformin users 7.1 (95% CI 5.1 to 10) compared with non-users 9.5 (95% CI 8.8 to 10.2). Metformin initiation was associated with a reduced relative risk of gout (HR 0.68, 95% CI 0.48 to 0.96). No relationship was found between metformin and changes in SU or CRP. CONCLUSIONS: Metformin use was associated with a reduced risk of gout among adults with pre-diabetes, suggesting that metformin may be important in lowering gout risk in individuals with pre-diabetes.

Identifying the association between serum urate levels and gout flares in patients taking urate-lowering therapy: a post hoc cohort analysis of the CARES trial with consideration of dropout.

OBJECTIVE: To investigate gout flare rates based on repeated serum urate (SU) measurements in a randomised controlled trial of urate-lowering therapy (ULT), accounting for dropout and death. METHODS: We performed a secondary analysis using data from Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout, which randomised participants to febuxostat or allopurinol, titrated to target SU <6 mg/dL with flare prophylaxis for 6 months. SU was categorised as ≤3.9, 4.0-5.9, 6.0-7.9, 8.0-9.9 or ≥ 10 mg/dL at each 3-6 month follow-up. The primary outcome was gout flare. Poisson regression models, adjusted for covariates and factors related to participant retention versus dropout, estimated gout flare incidence rate ratios by time-varying SU category. RESULTS: Among 6183 participants, the median age was 65 years and 84% were male. Peak gout flare rates for all SU categories were observed in months 0-6, coinciding with the initiation of ULT and months 6-12 after stopping prophylaxis. Flare rates were similar across SU groups in the initial year of ULT. During months 36-72, a dose-response relationship was observed between the SU category and flare rate. Lower flare rates were observed when SU ≤3.9 mg/dL and greater rates when SU ≥10 mg/dL, compared with SU 4.0-5.9 mg/dL (p for trend <0.01). CONCLUSION: Gout flare rates were persistently higher when SU ≥6 mg/dL after the first year of ULT after accounting for censoring. The spike in flares in all categories after stopping prophylaxis suggests a longer duration of prophylaxis may be warranted.

Calcium pyrophosphate deposition disease: historical overview and potential gaps.

CPPD disease can affect patients' quality of life through its various clinical presentations. This mini-review discusses the evolution of CPPD from its discovery to current knowledge of its pathogenesis, genetic associations, diagnostics, and treatment options. Despite extensive research, the exact mechanisms of CPPD are not well understood, and there is a notable lack of knowledge about psychosocial impacts and patient experiences. This study aims to present a CPPD Disease Timeline identifying gaps in current knowledge and potential directions for future research. These findings contribute to a broader understanding of CPPD disease and emphasize the importance of continued research and innovation in this field.

Development and validation of a self-updating gout register from electronic health records data.

OBJECTIVE: To develop an automatic gout register from electronic health records (EHRs) data. METHODS: We analysed the EHR of all patients >18 years old from a tertiary academic hospital (2013-2022) based on six criteria: International Classification of Diseases 10 gout diagnosis, urate-lowering therapy prescription, monosodium urate crystals in joint aspiration and gout-related terms in problem lists, clinical or imaging reports. We assessed the positive and negative predictive value (PPV and NPV) of the query by chart reviews. RESULTS: Of 2 110 902 outpatients and inpatients, 10 289 had at least one criterion for gout. The combination of joint aspiration OR diagnostic in the problem list OR≥2 other criteria created a register of 5138 patients, with a PPV of 92.4% (95% CI 88.5% to 95.0%) and an NPV of 94.3% (95% CI 91.9% to 96.0%). PPV and NPV were similar among outpatients and inpatients. Incidence was 2.9 per 1000 person-year and dropped by 30% from the COVID-19 pandemic onward. Patients with gout were on average 71.2 years old (SD 14.9), mainly male (76.5%), overweight (69.5%) and polymorbid (mean number of comorbidities of 3, IQR 1-5). More than half (57.4%) had received a urate-lowering treatment, 6.7% had a gout that led to a hospitalisation or ≥2 flares within a year and 32.9% received a rheumatology consultation. CONCLUSION: An automatic EHR-based gout register is feasible, valid and could be used to evaluate and improve gout management. Interestingly, the register uncovered a marked underdiagnosis or under-reporting of gout since the COVID-19 pandemic.

Optimising gout treatment: insights from a nurse-led cohort study.

OBJECTIVES: Currently, gout management, particularly urate-lowering therapy (ULT), is often suboptimal. Nurses successfully manage various diseases including gout. As gout prevalence is rising, and rheumatologists and general practitioners face shortages, a new approach is imperative. This real-life prospective cohort study evaluated the effectiveness of nurse-led care employing a treat-to-target strategy for gout management over a 2-year period. METHODS: All consecutively confirmed gout patients were included. The nurse-led clinic provided a structured treatment plan with consultations, patient leaflets, telephone contacts and laboratory monitoring. After a year of nurse-led care, patients transitioned to continued care in general practice. Follow-up data were complete through registries. The primary outcome was achieving target p-urate levels (<0.36 mmol/L) at 2 years after diagnosis. Secondary outcomes included treatment continuation and achievement of target p-urate levels in specific subgroups. The results were compared with patients diagnosed in the same clinic but followed up in 'usual care'. RESULTS: In the nurse-led group (n=114), 83% achieved target p-urate levels and ULT was continued by 98%. This trend persisted across various patient subgroups. Only 44% of patients in usual care achieved target p-urate and with insufficient doses of allopurinol . Nurse-led care involved an average of two visits and three telephone contacts over 336 days. The 2-year mortality rate was 15%. CONCLUSIONS: Nurse-led gout care, employing a targeted approach, was associated with a very high uptake of and adherence to ULT. The encouraging results were not achieved in usual care although a direct comparison might be influenced by selection bias.

Chances and challenges of photon-counting CT in musculoskeletal imaging.

In musculoskeletal imaging, CT is used in a wide range of indications, either alone or in a synergistic approach with MRI. While MRI is the preferred modality for the assessment of soft tissues and bone marrow, CT excels in the imaging of high-contrast structures, such as mineralized tissue. Additionally, the introduction of dual-energy CT in clinical practice two decades ago opened the door for spectral imaging applications. Recently, the advent of photon-counting detectors (PCDs) has further advanced the potential of CT, at least in theory. Compared to conventional energy-integrating detectors (EIDs), PCDs provide superior spatial resolution, reduced noise, and intrinsic spectral imaging capabilities. This review briefly describes the technical advantages of PCDs. For each technical feature, the corresponding applications in musculoskeletal imaging will be discussed, including high-spatial resolution imaging for the assessment of bone and crystal deposits, low-dose applications such as whole-body CT, as well as spectral imaging applications including the characterization of crystal deposits and imaging of metal hardware. Finally, we will highlight the potential of PCD-CT in emerging applications, underscoring the need for further preclinical and clinical validation to unleash its full clinical potential.

Giant Tophaceous Gout: The Importance of Therapeutic Compliance.

Gout is a metabolic disease resulting from the deposition of monosodium urate crystals in joints, tissues, and organs. Nowadays, the treatment of hyperuricemia is easily accessible and widespread and mainly consists of xanthine oxidase inhibitors and uricosurics. In refractory and advanced cases of gout, amputation surgery may be required. The authors present the case of an 85-year-old man who is non-compliant with hypouricemic medication, has exuberant gout, and has refused amputation surgery several times. The patient went to the emergency department with a triad of acute kidney injuries, acute gout, and poorly controlled pain. Cases of tophaceus gout such as the one presented are very rare nowadays.

2023 EULAR recommendations on imaging in diagnosis and management of crystal-induced arthropathies in clinical practice.

OBJECTIVE: To formulate evidence-based recommendations and overarching principles on the use of imaging in the clinical management of crystal-induced arthropathies (CiAs). METHODS: An international task force of 25 rheumatologists, radiologists, methodologists, healthcare professionals and patient research partners from 11 countries was formed according to the EULAR standard operating procedures. Fourteen key questions on the role of imaging in the most common forms of CiA were generated. The CiA assessed included gout, calcium pyrophosphate deposition disease and basic calcium phosphate deposition disease. Imaging modalities included conventional radiography, ultrasound, CT and MRI. Experts applied research evidence obtained from four systematic literature reviews using MEDLINE, EMBASE and CENTRAL. Task force members provided level of agreement (LoA) anonymously by using a Numerical Rating Scale from 0 to 10. RESULTS: Five overarching principles and 10 recommendations were developed encompassing the role of imaging in various aspects of patient management: making a diagnosis of CiA, monitoring inflammation and damage, predicting outcome, response to treatment, guided interventions and patient education. Overall, the LoA for the recommendations was high (8.46-9.92). CONCLUSIONS: These are the first recommendations that encompass the major forms of CiA and guide the use of common imaging modalities in this disease group in clinical practice.

Systemic inflammatory cytokine profiles in patients with gout during flare, intercritical and treat-to-target phases: TNFSF14 as new biomarker.

INTRODUCTION: Untreated gout is characterised by monosodium urate (MSU) crystal accumulation responsible for recurrent flares that are commonly separated by asymptomatic phases. Both phases are inflammatory conditions of variable intensity. Gout flares are self-limited inflammatory reactions involving multiple mediators. This study aimed to characterise the inflammatory profiles of gout at different phases. METHODS: Using the Olink targeted proteomics, levels of 92 inflammation-related proteins were measured in plasma samples of a prospective gout population (GOUTROS), collected at gout flare (T1), the intercritical phase (T2) and after reaching the target serum urate level under urate-lowering therapy (T3). Results were validated in an independent cohort (OLT1177-05) with plasmas collected at T1 and T2. Ex vivo and in vitro experiments were performed to assess the inflammatory properties of new biomarkers. RESULTS: In total, 21 inflammatory new biomarkers were differentially expressed during the three time-points of gout disease. The levels of four of these proteins (interleukin 6 (IL-6), colony-stimulating factor 1, vascular endothelial growth factor A and tumour necrosis factor superfamily 14 (TNFSF14)) were increased during gout flare in an independent cohort. IL-6 and TNFSF14 had the highest fold change in expression during T1 versus T2 or T3. TNFSF14 was produced at the inflamed joint and enhanced the inflammatory response induced by lipopolysaccharide and MSU crystal stimulation. Conversely, TNFSF14 blockade reduced the inflammatory response. Additionally, single nucleotide polymorphisms of TNFSF14 affected the ability of myeloid cells to produce inflammatory cytokines. CONCLUSION: Gout flare involves multiple inflammatory mediators that may be used as potential therapeutic targets.

Changes in alcohol intake and serum urate changes: longitudinal analyses of annual medical examination database.

INTRODUCTION: Despite the established cross-sectional association between alcohol intake and serum urate (SU), its longitudinal association remains unknown. This study aimed to determine whether changes in alcohol intake have a clinically relevant association with SU change. METHOD: We conducted retrospective analyses using systematically collected annual medical examination data from October 2012 to October 2022 in a Japanese preventive medicine centre. The exposure was changes in alcohol intake between two consecutive visits. The association of SU changes with alcohol intake changes was estimated by mixed-effect linear regression with adjustment for relevant covariates. RESULTS: We analysed 63 486 participants (median age, 47.0 years; 55% women; 58.6% regular alcohol drinkers with a median of 1.4 drinks/day) with 370 572 visits. The median SU level was 5.3 mg/dL, and 506 (0.8%) participants had diagnoses of gout or hyperuricemia without medication use during the study period. Decreasing one daily alcohol intake had a clinically small association with SU changes (-0.019 (95% CI: -0.021 to -0.017) mg/dL). Beer had the largest association with SU (-0.036 (95% CI: -0.039 to -0.032) mg/dL for one beer decrease). Complete discontinuation of any alcohol from a mean of 0.8 drinks/day was associated with -0.056 mg/dL (95% CI: -0.068 to -0.043) decrease in SU; the association became larger in hyperuricemic participants (-0.110 mg/dL (95% CI: -0.154 to -0.066) for alcohol discontinuation from a mean of 1.0 drinks/day). CONCLUSIONS: This study revealed changes in alcohol intake had small associations with SU change at the general Japanese population level. Complete discontinuation of alcohol in hyperuricemic participants had only modest improvement in SU.

The Hepatokine RBP4 Links Metabolic Diseases to Articular Inflammation.

OBJECTIVES: This study investigates the role of retinol binding protein 4 (RBP4) in an articular context. RBP4, a vitamin A transporter, is linked to various metabolic diseases. METHODS: Synovial fluid RBP4 levels were assessed in crystalline arthritis (CA) patients using ELISA. RBP4's impact on articular cell types was analysed in vitro through RT-PCR and flow cytometry. Proteomic analysis was conducted on primary human osteoarthritis chondrocytes (hOACs). RESULTS: Synovial fluid RBP4 concentrations in CA patients correlated positively with glucose levels and negatively with synovial leukocyte count and were elevated in hypertensive patients. In vitro, these RBP4 concentrations activated neutrophils, induced the expression of inflammatory factors in hOACs as well as synoviocytes, and triggered proteomic changes consistent with inflammation. Moreover, they increased catabolism and decreased anabolism, mitochondrial dysfunction, and glycolysis promotion. Both in silico and in vitro experiments suggested that RBP4 acts through TLR4. CONCLUSIONS: This study identifies relevant RBP4 concentrations in CA patients' synovial fluids, linking them to hypertensive patients with a metabolic disruption. Evidence is provided that RBP4 acts as a DAMP at these concentrations, inducing robust inflammatory, catabolic, chemotactic, and metabolic responses in chondrocytes, synoviocytes, and neutrophils. These effects may explain RBP4-related metabolic diseases' contribution to joint destruction in various rheumatic conditions like CA.

Safety and efficacy of colchicine in crystal-induced arthritis flare in 54 patients with severe chronic kidney disease.

INTRODUCTION: Colchicine, commonly used in gout flare, is contraindicated in severe chronic kidney disease (CKD) (estimated glomerular filtration rate <30 mL/min). However, in this context, there are few alternatives, and colchicine use persists. We evaluated the tolerance of colchicine and its efficacy in patients with severe CKD. PATIENTS AND METHODS: All prescriptions of colchicine for managing crystal-induced arthritis flare (gout or calcium pyrophosphate deposition (CPPD) disease) in a hospitalised patient with severe CKD were screened from September 2020 to September 2021. After patient consent and treatment information, clinical and biological safety and efficacy data were prospectively collected from day 1 (D1) to D11. RESULTS: We included 54 patients (median age 75 years (IQR 67-83)) with 62 colchicine prescriptions (cases). Twelve (22%) patients were on dialysis. The main reason for hospitalisation was heart failure (31.5%), acute renal failure (22.2%), infection (18.5%) or an acute joint episode (9.3%). In total, 59.3% of patients had diabetes. The prescriptions concerned 58 cases of gout flares, 1 case of CPPD and 3 cases of both. Initial colchicine dosages were ≤0.5 mg/day in 47/62 (75.8%) cases; no dosage exceeded 1 mg/day (median duration of 6 days (IQR 3-11)). Colchicine was well tolerated in 47/61 (77%) cases. No serious adverse event was reported. Colchicine was considered completely effective by the medical team in 48/58 (83%) of cases. CONCLUSION: The use of colchicine, at reduced doses, was mostly effective to treat crystal-induced arthritis flare in 54 patients with severe CKD and was well tolerated, without any serious adverse events.

Inhibiting Lysyl Oxidases prevents pathologic cartilage calcification.

Lysyl oxidases (LOX(L)) are enzymes that catalyze the formation of cross-links in collagen and elastin fibers during physiologic calcification of bone. However, it remains unknown whether they may promote pathologic calcification of articular cartilage, an important hallmark of debilitating arthropathies. Here, we have studied the possible roles of LOX(L) in cartilage calcification, related and not related to their cross-linking activity. We first demonstrated that inhibition of LOX(L) by ß-aminoproprionitrile (BAPN) significantly reduced calcification in murine and human chondrocytes, and in joint of meniscectomized mice. These BAPN's effects on calcification were accounted for by different LOX(L) roles. Firstly, reduced LOX(L)-mediated extracellular matrix cross-links downregulated Anx5, Pit1 and Pit2 calcification genes. Secondly, BAPN reduced collagen fibrotic markers Col1 and Col3. Additionally, LOX(L) inhibition blocked chondrocytes hypertrophic differentiation (Runx2 and COL10), pro-inflammatory IL-6 release and reactive oxygen species (ROS) production, all triggers of chondrocyte calcification. Through unbiased transcriptomic analysis we confirmed a positive correlation between LOX(L) genes and genes for calcification, hypertrophy and extracellular matrix catabolism. This association was conserved throughout species (mouse, human) and tissues that can undergo pathologic calcification (kidney, arteries, skin). Overall, LOX(L) play a critical role in the process of chondrocyte calcification and may be therapeutic targets to treat cartilage calcification in arthropathies.

Factors influencing the kinetics of MSU crystal depletion measured with dual-energy CT in patients with gout.

OBJECTIVE: To examine factors influencing the kinetics of monosodium urate (MSU) crystal dissolution measured with dual-energy computed tomography (DECT) during follow-up of patients with gout. METHODS: Patients with a diagnosis of gout with baseline knees and feet DECT scans exhibiting MSU crystal volumes ≥0.1 cm3 and at least one follow-up DECT were included. Spearman's correlation coefficient was used to search for association between change from baseline MSU crystal volume at 6, 12, 18 and 24 months and serum urate (SU) level. Associations between percentage change from the baseline volume of MSU crystal deposits and explanatory variables were assessed using linear mixed models. RESULTS: Sixty-two patients (age 67.3±12.8 years; 53 (85%) males) cumulating 104 follow-up DECT scans were included. Overall, SU target levels (<6.0 and <5.0 mg/dL) were achieved by 48 (77%) and 36 (58%) patients, respectively. There was a good correlation (r=0.66; p<0.0001) observed between SU level and percentage change in MSU crystal volume. The median decrease from baseline MSU crystal volume was greater in patients reaching the <5.0 mg/dL SU target than in those reaching ≥5.0 SU <6.0 mg/dL: -85% (95% CI: -94% to -72%) versus -40% (-57% to -22%; p<0.05) at 12 months. In multivariable analysis, time (in days) with a multilevel coefficient of -0.06 (95% CI: -0.08 to -0.03, p<0.001), hypertension (coefficient: 41.87, 95% CI: 16.38 to 67.18, p<0.01) and SU level <5.0 mg/dL (coefficient: -39.46, 95% CI: -70.93 to -8.34, p=0.02) were the only variables significantly associated with MSU crystal volume change. CONCLUSION: In patients with DECT-measured MSU crystal deposition, reaching the <5.0 mg/dL SU target provides more extensive and rapid crystal dissolution than reaching the <6.0 mg/dL SU target.