Prednisolone Versus Colchicine for Acute Gout in Primary Care: statistical analysis plan for the pragmatic, multicenter, randomized, and double-blinded COPAGO non-inferiority trial.

BACKGROUND: To date, colchicine and prednisolone are two effective therapies for the treatment of acute gout but have never been compared directly in a randomized clinical trial. In addition, in previous trials of treating acute gout patients with concomitant comorbidities were often excluded due to contraindications to naproxen. STUDY DESIGN: This pragmatic, prospective, double-blind, double-dummy, parallel-group, randomized, non-inferiority trial compares prednisolone with colchicine in terms of non-inferiority in patients with acute gout. Patients presenting to their general practitioner with acute gout can be included if the gout attack has occurred within the last 2 days. A total of 60 practices in the vicinity of three university medical centers (Greifswald, Göttingen, and Würzburg) participate in the study. The intervention group receives 30 mg prednisolone for 5 days, while the group of standard care receives low-dose colchicine (day 1: 1.5 mg; days 2-5: 1 mg). The first dose of treatment is provided at day 0 when patients present to the general practitioner due to an acute gout attack. From day 0 to day 6, patients will be asked to complete a study diary on daily basis regarding pain quantification. For safety reasons, potential side effects and the course of systolic blood pressure are also assessed. STATISTICAL ANALYSIS PLAN: N = 314 patients have to be recruited to compensate for 10% of dropout and to allow for showing non-inferiority of prednisolone compared to colchicine with a power of 90%. We use permuted block randomization with block sizes of 2, 4, and 6 to avoid imbalanced treatment arms in this multi-center study; patients are randomized in a 1:1 ratio. The absolute level of pain on day 3 (in the last 24 h) is the primary outcome and measured on a numerical rating scale (NRS: 0-10). Using a multiple linear regression model adjusted for age, sex, and pain at baseline, prednisolone is considered non-inferior if the effect estimate including the confidence intervals is lower than a margin of 1 unit on the NRS. Average response to treatment, joint swelling and tenderness, physical function of the joint, and patients' global assessment of treatment success are secondary outcomes. DISCUSSION: The trial will provide evidence from a direct comparison of colchicine and prednisolone regarding their efficacy of pain reduction in acute gout patients of primary care and to indicate possible safety signals. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05698680 first posted on January 26, 2023 (retrospectively registered).

Estimation of the spatial pattern of gout prevalence across China by wastewater-based epidemiology.

Gout is a metabolic arthritis caused by hyperuricemia. In recent years, the prevalence of gout has been increased significantly in China due to the improvement of the living standards, and gout has become another common metabolic disease following diabetes mellitus. Gout severely affects the health status and life quality of human. In order to monitor the near real-time prevalence of gout, a wastewater-based epidemiology (WBE) approach was carried out in 257 Chinese cities using febuxostat as the biomarker. Febuxostat in wastewater was measured by a LC-MS/MS method with satisfactory results of method validation. The average concentration of febuxostat in wastewater was 53.05 ± 31.76 ng/L, with the estimated per capita consumption of 124.40 ± 73.37 mg/day/1000 inhabitant. The calculated prevalence of febuxostat was 0.41 % ± 0.24 %, and the prevalence of gout was finally estimated to be 1.30 % ± 0.77 % (0.60 % to 2.11 %), which was nearly consistent with value of 1.10 % obtained from the Guideline for the diagnosis and management of hyperuricemia and gout in China (2019). The results indicated that the febuxostat-based WBE approach might be reasonable to assess the near real-time gout prevalence in China.

Describing calcium pyrophosphate deposition: undoing the tower of Babel!

PURPOSE OF REVIEW: In 1977, McCarty astutely observed, 'The variety of names suggested for the condition associated with deposits of calcium pyrophosphate dihydrate crystals is exceeded only by the variations of its clinical presentation'. Fast forward to 2024, a standardized nomenclature for calcium pyrophosphate deposition (CPPD) is still lacking. This review aims to delineate the challenges in characterizing CPPD through nomenclature and imaging. RECENT FINDINGS: Despite the effort of nomenclature standardization in 2011 by the EULAR, confusion persists in the literature and clinical practice, with pseudo-forms and obscure abbreviations. The Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) has launched a project to redefine CPPD nomenclature and formulate a user-friendly language for effective communication with patients and other stakeholders. Additionally, recent advancements in imaging, have shed light on various aspects of the disorder. SUMMARY: Almost 60 years from the first description of a clinical manifestation related to calcium pyrophosphate crystals, a common language describing the disorder is still lacking. A redefined CPPD nomenclature, together with lay-friendly terminology, would significantly contribute to the uniformity of CPPD research, enhance public understanding and awareness and improve doctor-patient communication and therefore disease outcomes. Imaging can provide deep insights into CPPD elements, promoting comprehension of this disorder.

Middle Ear Tophi: A Case Series of Two Unusual Lesions and a Report of Facial Weakness and Review of the Literature.

OBJECTIVE: Tophaceous lesions of the middle ear from calcium pyrophosphate deposition disease (CPPD, or pseudogout) and gout are infrequently reported. Recognizing its characteristic findings will allow clinicians to accurately narrow the differential diagnosis of bony-appearing middle ear lesions and improve management. PATIENTS: Two consecutive cases of tophaceous middle ear lesions presenting to a tertiary care center between January 2021 and December 2021. Neither with previous rheumatologic history. INTERVENTIONS: Surgical excision of tophaceous middle ear lesions. MAIN OUTCOME MEASURE: Improvements in facial weakness and conductive hearing loss. RESULTS: The first case was a 66-year-old gentleman with progressive conductive loss, ipsilateral progressive facial weakness over years, and an opaque, irregular-appearing tympanic membrane anterior to the malleus found to have CPPD on surgical pathology, with immediate postoperative improvement of facial function. The second was a 75-year-old gentleman with progressive conductive loss and similar appearing tympanic membrane as case 1, previously diagnosed with tympanosclerosis, found to have gout on surgical pathology. In both cases, the CT showed a heterogenous, bony-appearing lesion in the middle ear, and both tophaceous lesions were a of gritty, chalky consistency intraoperatively. CONCLUSION: Tophaceous lesions of the middle ear are rare but have similar findings. Notably, the tympanic membrane can appear opaque and irregular, and the CT demonstrates a radiopaque, heterogeneous appearance. Facial weakness is an unusual finding. Specimens of suspected tophi must be sent to pathology without formalin for accurate diagnosis.

Assessing the causal relationships of gut microbial genera with hyperuricemia and gout using two-sample Mendelian randomization.

BACKGROUND AND AIMS: The causal relationship between gut microbiota and gout and hyperuricemia (HUA) has not been clarified. The objective of this research was to evaluate the potential causal effects of gut microbiota on HUA and gout using a two-sample Mendelian randomization (MR) approach. METHODS AND RESULTS: Genetic instruments were selected using summary statistics from genome-wide association studies (GWASs) comprising a substantial number of individuals, including 18,473 participants for gut microbiome, 288,649 for serum urate (SU), and 763,813 for gout. Two-sample MR analyses were performed to determine the possible causal associations of gut microbial genera with the risk of HUA and gout using the inverse-variance weighted (IVW) method, and robustness of the results was confirmed by several sensitivity analyses. A reverse MR analysis was conducted on the bacterial taxa that were identified in forward MR analysis. Based on the results of MR analyses, Escherichia-Shigella (OR = 1.05; 95% CI, 1.01-1.08; P = 0.009) exhibited a positive association with SU levels, while Lachnospiraceae NC2004 group (OR = 0.95; 95% CI, 0.92-0.98; P = 0.001) and Family XIII AD3011 group (OR = 0.94; 95% CI, 0.90-0.99; P = 0.015) were associated with a reduced HUA risk. Moreover, Coprococcus 3 (OR = 1.17, 95% CI: 1.01-1.34, P = 0.031) was causally associated with a higher gout risk. In reverse MR analysis, no causal relationships were identified between these bacterial genera and HUA or gout. CONCLUSION: This study provides evidence for a causal association between gut microbial genera and HUA or gout, and further investigations of the underlying mechanism are warranted.

Clinical characteristics of adolescent-onset gout in Chinese: A hospital-based cross-sectional study.

OBJECTIVE: Adolescent-onset gout has a greater impact on the lives and health of patients than adult-onset gout. However, there is a relative lack of clinical information on adolescent-onset gout. Hence, we analyzed a Chinese cohort. METHODS: We studied clinical features of 9,003 Chinese patients. Gout onset age of 12 - 19 years is defined as adolescent-onset group (AG), 20 - 40 years as early-onset group (EG), and 41 - 64 years as late-onset group (LG). Multivariable regression analysis evaluated factors associated with recurrent flares, serum urate (SU) levels, and underexcretion type in AG. RESULTS: Compared with EG and LG, the AG had higher SU levels [AG: 9.5 (2.2) mg/dL, EG: 8.6 (2.1) mg/dL, LG: 7.73 (2.0) mg/dL, P < 0.001], higher percentage of positive family history of gout (AG: 41.8 %, EG: 29.6 %, LG: 24.6 %, P < 0.001), underexcretion type (AG: 62.4 %, EG: 62.5 %, LG: 58.8 %, P = 0.04), recurrent flares (AG: 78.1 %, EG: 70.3 %, LG: 68.9 %, P = 0.01). Urate-lowering therapy (ULT) initiated [OR 6.58 (95 % CI 1.35 - 32.00)] and hypercholesterolemia [OR 4.16 (95 % CI 1.28 - 13.53)] were associated with recurrent flares. eGFR was identified to be a significant variable of increasing SU levels [beta -0.24 (95 % CI -0.04 to -0.01)]. Hypertriglyceridemia [OR 0.35 (95 % CI 0.17 - 0.71)] was related to underexcretion type. CONCLUSION: Adolescent-onset gout patients had clinically distinctive features with higher SU levels, BMI, positive gout family history, underexcretion type and recurrent flares. These specific populations were less likely to achieve ULT target, requiring more clinical attention.

Wearable intelligent sweat platform for SERS-AI diagnosis of gout.

For the past few years, sweat analysis for health monitoring has attracted increasing attention benefiting from wearable technology. In related research, the sensitive detection of uric acid (UA) in sweat with complex composition based on surface-enhanced Raman spectroscopy (SERS) for the diagnosis of gout is still a significant challenge. Herein, we report a visualized and intelligent wearable sweat platform for SERS detection of UA in sweat. In this wearable platform, the spiral channel consisted of colorimetric paper with Ag nanowires (AgNWs) that could capture sweat for SERS measurement. With the help of photos from a smartphone, the pH value and volume of sweat could be quantified intelligently based on the image recognition technique. To diagnose gout, SERS spectra of human sweat with UA are collected in this wearable intelligent platform and analyzed by artificial intelligence (AI) algorithms. The results indicate that the artificial neural network (ANN) algorithm exhibits good identification of gout with high accuracy at 97%. Our work demonstrates that SERS-AI in a wearable intelligent sweat platform could be a feasible strategy for diagnosis of gout, which expands research on sweat analysis for comfortable and noninvasive health monitoring.

Gout: one year in review 2023.

Gout is a chronic joint disease caused by the deposition of monosodium urate crystals into and around the articular tissues. In the last two years, new insights regarding diagnosis, genetic involvement, pathogenesis, comorbidities, and clinical data, have allowed the identification of new strategies to improve the control of the disease and its flares. In keeping, the discover of new mechanisms concerning crystal-induced inflammation have suggested new ways for the management not only of gout, but also other systemic diseases, mainly including renal and cardiovascular disorders. In this context it is very representative the case of colchicine which, given the surprising results obtained both in laboratory and clinical experiments, has recently received by FDA the approval for the prevention of cardiovascular disorders.

Risk of gout flare after medication: prescription symmetry sequence analysis.

OBJECTIVES: The research aimed to study the following questions: (1) five well-known gout-related medications were selected to test the validity of the prescription symmetry sequence analysis in Taiwan; (2) four exploratory medications were selected to test their relation to gout flares. METHODS: We utilized the 2003-2017 dataset of the Taiwan National Health Insurance Program containing all claims data with 2 million beneficiaries as a data source. In order to explore the temporal association, we designed a scenario of medication-induced gout flares. Nine medications were selected as the index agent, including aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol, pyrazinamide, metformin, pioglitazone, fenofibrate, and losartan. The gout flare was defined as subjects with use of the marker agent for treatment of gout flares. The observation-window period between initiation of the index agent and initiation of the marker agent was 1 year. Subjects who used an index agent and a marker agent on the same day were excluded. The prescription symmetry sequence analysis was carried out to compare the observed number of persons who took an index agent prior to starting a marker agent with the observed number of persons who took a marker agent before starting an index agent. The adjusted sequence ratio (adjusted SR) with 95% confidence interval was applied to estimate the relation between an index agent and the marker agent. RESULTS: Among five medications including aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol, and pyrazinamide, the adjusted sequence ratio ranged from 1.15 to 3.35 and all reached statistical significance. Fenofibrate use and losartan use were associated with a lower probability of gout flares, with reaching statistical significance (adjusted SR = 0.60 for fenofibrate and adjusted SR = 0.92 for losartan). Metformin use was associated with a greater probability of gout flares, with reaching statistical significance (adjusted SR = 1.14). Pioglitazone use did not reach statistical significance. CONCLUSION: Based on the confirmatory analysis including five well-known gout-related medications, this study supports that the prescription symmetry sequence analysis can be used to detect an adverse drug event associated with one potential offending agent. The exposure to fenofibrate or losartan might be a protective factor against gout flares. Metformin use could be associated with a greater probability of gout flares, but this finding should be validated by other studies. KEY POINTS: • What is already known about this subject? 1. The prescription symmetry sequence analysis is a useful method for detecting an adverse drug reaction associated with one potential offending drug. 2. Numerous medications are found to induce gout flares. • What does this study add? 1. The prescription symmetry sequence analysis supports the evidence that aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol and pyrazinamide are associated with a greater probability of gout flares. 2. The exposure to fenofibrate or losartan might be a protective factor against gout flares. 3. Metformin use could be associated with a greater probability of gout flares. • How might this impact on clinical practice or future developments? 1. Clinicians should always consider the possibility of medication-induced gout flares. If gout flares develop, discontinuation of risky medications is the first step. Then prescribing cascades can be eliminated.

Gout in Native Hawaiian Patients in Hawai'i: Clinical Characteristics and Disparities.

OBJECTIVE: The purpose of this study was to investigate differences in clinical characteristics and health care use of Native Hawaiian and White patients with gout. METHODS: We performed a retrospective chart review of Native Hawaiian and White patients with gout treated from 2011 to 2017 within a large health care system in Hawai'i. We compared demographic characteristics, clinical outcomes, and risk factors for gout. We used multivariable logistic regression to identify predictive factors of emergency department visits. RESULTS: We identified 270 Native Hawaiian patients with gout and 239 White patients with gout. The Native Hawaiian patients were younger on average (54.0 vs 64.0 years; P < 0.0001) and had an earlier onset of disease (50.0 vs 57.0 years; P < 0.0001). Native Hawaiian patients with gout had higher mean (7.58 vs 6.87 mg/dL; P < 0.0001) and maximum (10.30 vs 9.50 mg/dL; P < 0.0001) serum urate levels compared to White patients with gout. Native Hawaiian patients with gout also had a greater number of tophi (median 2.00 vs 1.00; P < 0.0001). Native Hawaiians patients with gout were 2.7 times more likely to have frequent (≥1) emergency department visits than White patients with gout. Native Hawaiian patients with gout were less likely to have a therapeutic serum urate ≤6.0 mg/dL and had lower rates of rheumatology specialty care. CONCLUSION: Native Hawaiian patients have a higher disease burden of gout, with earlier disease onset and more tophi. Native Hawaiian patients with gout are more likely to use emergency services for gout and have lower rates of rheumatology specialty care compared to White patients. Future studies are needed to promote culturally appropriate preventive care and management of gout in Native Hawaiians.

Tophi and carotid atherosclerosis in gout patients: Role of insulin resistance.

BACKGROUND AND AIM: Gout and cardiovascular disease are closely related, but the mechanism linking them is still unknown. Gout may affect the insulin signaling pathway inducing insulin resistance (IR). The study aims to evaluate the association between tophi and carotid atherosclerosis, considering the potential role of IR. METHODS AND RESULTS: A total of 595 patients with gout aged 18 to 80 were enrolled in this study. Carotid intima-media thickness, plaques and tophi were evaluated by B-mode ultrasonography. IR was assessed by the HOMA index (hepatic IR) and Gutt index (peripheral IR). Multivariable logistic regression and interaction analysis were used to examine the association between tophi and IR and its impact on carotid atherosclerosis. Among these participants, the average age was 55.4 (±12.54) years, and 94.6 % were male. Tophi were associated with increased odds of carotid atherosclerosis and burden after adjustment for confounders (P < 0.05). Tophi and IR synergically interacted for inducing carotid atherosclerosis. The interaction between peripheral IR with tophi was more pronounced than hepatic IR with tophi. CONCLUSIONS: Tophi were independently associated with carotid atherosclerosis risk. IR mediated a significant amount of the effect of tophi on the development of carotid atherosclerosis. Peripheral IR probably plays a more important role than hepatic IR does.

The Risk of COVID-19 and Its Outcomes in Korean Patients With Gout: A Multicenter, Retrospective, Observational Study.

This retrospective cohort study aimed to compare coronavirus disease 2019 (COVID-19)-related clinical outcomes between patients with and without gout. Electronic health record-based data from two centers (Seoul National University Hospital [SNUH] and Boramae Medical Center [BMC]), from January 2021 to April 2022, were mapped to a common data model. Patients with and without gout were matched using a large-scale propensity-score algorithm based on population-level estimation methods. At the SNUH, the risk for COVID-19 diagnosis was not significantly different between patients with and without gout (hazard ratio [HR], 1.07; 95% confidence interval [CI], 0.59-1.84). Within 30 days after COVID-19 diagnosis, no significant difference was observed in terms of hospitalization (HR, 0.57; 95% CI, 0.03-3.90), severe outcomes (HR, 2.90; 95% CI, 0.54-13.71), or mortality (HR, 1.35; 95% CI, 0.06-16.24). Similar results were obtained from the BMC database, suggesting that gout does not increase the risk for COVID-19 diagnosis or severe outcomes.

From skin to microscope, case report of a rare manifestation of tophaceous gout: Miliary gout.

Joint symptoms associated with gout, mostly characterized by joint flare-ups, are well known. Tophi represent the main cutaneous manifestation of gout, most often associated with a chronic and inadequately controlled disease. On rare occasions, atypical skin manifestations may occur. We present the case of a miliary form of gout in a 36-year-old man known to have hyperuricemia. Microscopic direct analysis of the skin material revealed the presence of monosodium urate (MSU) crystals. Rash disappeared with corticosteroid therapy in parallel with joint symptoms recovery. Knowledge of this unusual gout-related skin disease is essential to diagnosing uncommon presentations of gout, which sometimes occur before joint symptoms. This case highlights the importance of sampling any skin lesion suspected of being tophus, for MSU crystal identification, and provides a definitive diagnosis.

Prevalence and treatment rate of gout by depressive symptom severity: A cross-sectional analysis of NHANES 2007-2018.

BACKGROUND: The co-disease of depression and gout is becoming more common in the modern era. However, the relationship between the severity of depressive symptoms and gout prevalence and treatment rate was still unclear. OBJECTIVE: This study aimed to determine the relationship between the prevalence, treatment rate of gout, and the severity of depression in the United States. METHOD: The cross-sectional analysis of the 2007-2018 National Health and Nutrition Examination Survey (NHANES) for participants with depression was performed. According to their Patient Health Questionnaire-9 (PHQ-9) scores, participants were categorized as none, mild, moderate, moderately severe, and severe. To learn the correlation between the severity of depressive symptoms and the prevalence and treatment rate of gout using multivariate logistic regression to control for confounder interference. RESULTS: A total of 25 022 patients were included in this study. As the severity of the depressive symptoms worsened (Mild, Moderate and Moderately severe), the risk of gout increased in non-adjusted model and model 1,2,3 (p-value for trend =.01 in non-adjusted model, <.0001 in model 1, <.01 in models 2 and 3; prevalence group in Model 1, aOR1.71, 95% CI (1.40, 2.08) in the mild group, aOR1.68, 95% CI (1.19, 2.39) in the moderate group, aOR1.31,95% CI (0.82, 2.11) in the moderately severe group, aOR1.21, 95% CI (0.62, 2.38) in the severe group). However, the lower gout prevalence trend has no statistical significance after adjusting all factors in Model 4(p-value for trend =.98). Compared with patients without depression, only a few patients received treatment, especially patients with severe depression (none, 80.1%; severe, 0.2%). The more severe the depression, the lower the treatment rate (p-value for trend: non-adjusted model, p < .001; model 1, p = .05; model 2, p = .02; model 3, p = .03). CONCLUSION: Compared with patients without depression, the patients with depression had a higher risk of gout. With the aggravation of depression, the prevalence of gout and the rate of treatment both were decreased. Patients with gout and depression need to receive multidisciplinary care after diagnosis. However, currently, treatment cannot meet the needs of the current patients.

Are the cut-offs of the rheumatoid factor and anti-cyclic citrullinated peptide antibody different to distinguish rheumatoid arthritis from their primary differential diagnoses?

OBJECTIVE: Rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP) are commonly used for diagnosis of rheumatoid arthritis (RA), although other rheumatic diseases with arthritis can test positive. This study aimed to determine the cutoff values for RF and anti-CCP with the best diagnostic performance in a sample of patients with RA, compared with other rheumatic diseases. METHODS: This was a descriptive, prospective study. EUROINMMUN enzyme-linked immunosorbent assays for RF isotypes immunoglobulin (Ig) A (IgA), IgG and IgM and third-generation assay IgG for anti-CCP were used in serum samples of patients with RA, other rheumatic diseases and healthy subjects. The cutoff with the best diagnostic performance was determined by the Youden Index and receiver operating characteristic analysis Results: Three hundred and thirty-two serum samples were analysed. The cutoffs proposed in our population were for RF in RA patients versus other rheumatic diseases, and healthy subjects IgM 135 IU/mL, for each disease, compared with RA, were psoriatic arthritis (Psa) IgA 47.2 IU/mL, clinically suspicious arthralgia (CSA) IgA 39.5 IU/mL, primary Sjögren's syndrome (pSS) IgM 180.6 IU/mL, systemic lupus erythematosus (SLE) IgA 42.6 IU/mL, primary fibromyalgia (pFM) IgM 68.6 IU/mL, osteoarthritis (OA) IgM 48 IU/mL, gout IgM 117 IU/mL and healthy IgM 16.3 IU/mL. For anti-CCP, in RA patients versus other rheumatic diseases, and healthy subjects 6.95 IU/mL, for each disease, compared with RA, were Psa 6.8 IU/mL, CSA 9.95 IU/mL, pSS 20.7 IU/mL, SLE 6 IU /mL, pFM 11.8 IU/mL, OA 11.9 IU/mL, gout 5 IU/mL and healthy 5 IU/mL. CONCLUSION: Irrespective of the manufacturer's suggested cutoff, the RA versus differential diagnosis cutoffs must be considered.