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Ultrasonographic measurement of tophi as an outcome measure for chronic gout
Abstract
To validate the usefulness of measuring tophi with ultrasonography (US) as an outcome measure for chronic tophaceous gout.
Patients with crystal-proven gout were included. To evaluate validity, intraarticular and articular deep tophi were evaluated with both magnetic resonance imaging (MRI) and US. Tophi were punctured with US guidance to evaluate face validity. Interobserver and intraobserver measurement studies were done to evaluate reliability, and to estimate the smallest detectable difference. Sensitivity to change was evaluated with a 12-month followup observational study of urate-lowering therapy.
US detected at least one tophus in all joints where MRI found nodules considered to be tophi. There was a good correlation, but just fair agreement between measurements with US and MRI. Puncture of nodules suspected of being tophi recovered urate crystals in 83% of the procedures. Intraobserver intraclass correlation was > 0.90 for diameters and volume, while it was 0.71 to 0.83 in the interobserver study. US was found to be sensitive to change, and there was an inverse correlation between serum urate concentrations and change from baseline measurement of tophi.
US measurement of tophi fulfilled the OMERACT filter for an outcome measure, although it should be tested further in randomized clinical trials.
... 8 These included double contour sign (deposits of crystals on the surface of cartilage), tophus (larger hyperechoic collection of crystals), RMD Open RMD Open RMD Open aggregates (small hyperechoic crystal deposits) and erosion (cortical damage), 8 and the visualisation of double contour sign (DC) in joints has been included in the newest gout classification criteria. 9 A few small studies have evaluated the sensitivity to change of ultrasound visualised urate deposits before validated definitions of lesions existed [10][11][12] and two recent studies have evaluated decreases in DC and tophus-as defined by the OMERACT group-during urate-lowering therapy (ULT). 13 14 However, a systematic follow-up evaluating the sensitivity to change for all four structural lesions has not yet been performed in patients receiving ULT. ...
... The disappearance of tophi and DC as a response to ULT as seen in our study is in line with previous studies. Small cohort studies [10][11][12][13] and one recent larger cohort study 14 showed disappearance of DC 10 11 13 14 and decrease in tophus size visualised by ultrasound [12][13][14] in response to ULT. Also in line with our study, an improvement in clinical parameters and synovial Doppler signal was seen in parallel with dissolution of urate deposits. ...
... The disappearance of tophi and DC as a response to ULT as seen in our study is in line with previous studies. Small cohort studies [10][11][12][13] and one recent larger cohort study 14 showed disappearance of DC 10 11 13 14 and decrease in tophus size visualised by ultrasound [12][13][14] in response to ULT. Also in line with our study, an improvement in clinical parameters and synovial Doppler signal was seen in parallel with dissolution of urate deposits. ...
Objectives
To evaluate the sensitivity to change of ultrasound structural gout lesions, as defined by the Outcome Measures in Rheumatology (OMERACT) ultrasound group, in patients with gout during urate-lowering therapy (ULT).
Methods
Ultrasound (28 joints, 26 tendons) was performed in patients with microscopically verified gout initiating or increasing ULT and repeated after 3 and 6 months. Joints and tendons were evaluated by ultrasound for presence of the OMERACT structural gout lesions—double contour sign (DC), tophus, aggregates and erosion—scored binarily. A sum score was calculated at patient and lesion level. Changes at 3 and 6 months in patient sum scores and lesion scores at different locations were evaluated.
Results
50 patients (48 men), mean age 68.9 (range, 30–88) years, were included. Ultrasound showed a statistically significant decrease in DC and tophus sum scores from 0 months (3.16 and 2.68, respectively) to 3 months (2.33 and 2.43) and 6 months (1.34 and 1.83) (all p<0.002). The aggregate sum score only decreased significantly from 3 to 6 months (6.02 to 5.02, p=0.002), whereas erosion sum score remained almost unchanged. All four structural lesions were most commonly found in metatarsophalangeal (MTP) 1 joints (>1 lesions bilaterally), and furthermore MTP2–4 and knee joints were common sites especially for DC. Likewise, these regions were the locations with most pronounced changes in scores.
Conclusion
Ultrasound assessment of the OMERACT structural gout lesions scored binarily seems to be a useful tool for monitoring urate depositions during ULT. Particularly DC and tophus showed sensitivity to change after only 3 months of treatment.
... Benzbromarone is a uricosuric drug, which reduces the level of uric acid through its increased excretion (2/3 via intestinal and 1/3 via renal). The objective in uric acid reduction therapy is to dissolve the monosodium urate crystals (MSU) crystals when a concentration lower than serum urate saturation is reached (2,3). The subsaturated serum urate has been associated with the reduction, and ultimately the dissappearance, of tophi. ...
... The subsaturated serum urate has been associated with the reduction, and ultimately the dissappearance, of tophi. The inversely proportional correlation between the uric acid and the pace of reduction of the tophi has been documented (2,4). Ultrasonographic evaluation is an important and non-invasive tool able to help in several aspects of gout, such as differential diagnosis, identification of MSU crystal deposit and monitoring therapeutic response. ...
... Some findings, such as double contour sign, inhomogeneous material surrounded by a small anechoic rim related to the presence of tophy, and erosions, may be identified by ultrasonography (5)(6)(7). There are few studies in the literature, which use ultrasound follow-up in the evaluation of tophi (2). Ultrasound, which is an easily performed process, is clearly an important tool in the evaluation of tophi during the course of drug therapy for the reduction of gouty tophi. ...
The objective was to determine the reduction of tophi in patients undergoing drug therapy in correlation with urate serum levels through ultrasound examination. A total of 31 male patients, between the ages of 33 to 77 years, with tophaceous gout were evaluated between 2005 and 2009, 11 of which were selected. Ultrasound examinations of visible tophi and evaluations of serum uric acids levels were performed annually on each patient. There was a statistically significant difference between measurements 1, 2, 3 and measurement 4 and between measurements 4 and 5. A strong significant positive association was seen between variation of tophus size and the reduction of serum uric acid levels.
... However, in clinical practice, screening a large number of locations is time-consuming. Some studies assessed the knees and MTP1s for the DC sign and measured the larger tophus as the index tophus, thus avoiding time-consuming US evaluation [35][36][37]. The Naredo et al. study used US analysis of 26 joints, 6 bursae, 8 tendons and 4 ligaments in patients with gout and controls [38]. ...
... Table 1 summarizes the main results of studies on this subject. Perez-Ruiz et al. first demonstrated that measuring tophus size by US was possible and fulfilled the OMERACT filter [37]. Other studies suggested that under efficient ULT, the DC sign could disappear [36,44] and the number of US-detected tophi might decrease [40]. ...
Imaging modalities such as ultrasonography (US) and dual-energy computed tomography (DECT) have been recognized for their abilities to detect monosodium urate (MSU) crystals. The main described features of gout detected by DECT (tophus) or US (tophus, double contour [DC] sign and aggregates) are very specific for the diagnosis of gout, but the impact of imaging on the follow-up of MSU deposits is not well known. US and DECT allow for visualization of the disappearance of MSU crystals under adequate urate-lowering therapy (ULT). An OMERACT US score and a DECT urate score have been described. The dissolution of the DC sign is detectable on US after 3 months, whereas a decreased size or volume in tophus can be observed on US or DECT after 6 months of ULT. Serum urate level decrease is associated with a reduction in MSU crystal deposition. Finally, the risk of gout flare is associated with the baseline MSU burden and with the degree of dissolution of crystal deposition. All these data confirm that imaging could be useful in managing gout, even if its exact place in routine practice remains unclear.
... ‡ A false-positive double-contour sign (artifact) may appear at the cartilage surface, but it should disappear with a change in probe insonation angle. § Images should be acquired using a dual-energy computed tomography (DECT) scanner, with data acquired at 80 kV and 140 kV and analyzed using gout-specific software with a 2-material decomposition algorithm that color-codes urate (33). A positive scan result is defined as the presence of color-coded urate at articular or periarticular sites. ...
... The gout working group at the OMERACT in 2014 reported that measuring whole-body urate deposition levels is not a feasible option. By contrast, it is possible to quantify tophi within a representative area (e.g., bilateral 1st MTP joints) or a predetermined set of joints 33 . Ultrasound and DECT are the methods best suited to measuring urate deposition 9 ; however, DECT exposes patients to unacceptable levels of radiation and is available in few research centers. ...
Gout is a common metabolic disorder characterized by deposits of monosodium urate monohydrate crystals (tophi) in soft tissue, triggering intense and acute arthritis with intolerable pain as well as articular and periarticular inflammation. Tophi can also promote chronic inflammatory and erosive arthritis. 2015 ACR/EULAR Gout Classification criteria include clinical, laboratory, and imaging findings, where cases of gout are indicated by a threshold score of ≥ 8. Some imaging-related findings, such as a double contour sign in ultrasound, urate in dual-energy computed tomography, or radiographic gout-related erosion, generate a score of up to 4. Clearly, the diagnosis of gout is largely assisted by imaging findings; however, dual-energy computed tomography is expensive and exposes the patient to high levels of radiation. Although musculoskeletal ultrasound is non-invasive and inexpensive, the reliability of the results depends on expert experience. In the current study, we applied transfer learning to train a convolutional neural network for the identification of tophi in ultrasound images. The accuracy of predictions varied with the convolutional neural network model, as follows: InceptionV3 (0.871 ± 0.020), ResNet101 (0.913 ± 0.015), and VGG19 (0.918 ± 0.020). The sensitivity was as follows: InceptionV3 (0.507 ± 0.060), ResNet101 (0.680 ± 0.056), and VGG19 (0.747 ± 0.056). The precision was as follows: InceptionV3 (0.767 ± 0.091), ResNet101 (0.863 ± 0.098), and VGG19 (0.825 ± 0.062). Our results demonstrate that it is possible to retrain deep convolutional neural networks to identify the patterns of tophi in ultrasound images with a high degree of accuracy.
... Of note, the double contour sign should be differentiated from cartilage appearance in CPPD where the hyperechoic calcified band of deposits are in the middle of the cartilage, not marginally situated [28]. Studies have shown that tophi quantification by US are sensitive to change in response to urate-lowering therapy [29,30]. The double contour sign is attributed to elevated serum uric acid levels, therefore in response to urate-lowering therapy, the sign may disappear when serum uric acid levels are 6 mgÁdL À1 for at least 7 months [31]. ...
... The double contour sign is attributed to elevated serum uric acid levels, therefore in response to urate-lowering therapy, the sign may disappear when serum uric acid levels are 6 mgÁdL À1 for at least 7 months [31]. Perez-Ruiz and colleagues studied patients with crystal-proven gout using US and monitoring the changes in index tophus volume and maximal diameter in response to uratelowering therapy [30]. Sensitivity to change was evaluated with a 12month follow-up observational study of urate-lowering therapy. ...
Gout is a common inflammatory arthritis that manifests as an aggregate of variably symptomatic monosodium urate crystals (MSU) in the joints and surrounding tissues in addition to multisystem involvement such as genitourinary and cardiovascular systems. In recent decades, there has been a documented increase in the prevalence and incidence of gout. Risk factors for gout include obesity, dietary influences, hypertension, renal impairment, and diuretic use. A prompt diagnosis followed by uric acid lowering treatment prior to the onset of bone destruction is the goal in any suspected case of gout. Advanced imaging modalities, such as dual energy computed tomography (DECT) and ultrasonography (US), employed for the diagnosis of gout are each accompanied by advantages and disadvantages. Conventional radiography (CR), although useful in visualizing joint erosions and mineralization, is limited in its ability to diagnose gout flare. Although synovial fluid aspiration remains the gold standard for MSU crystal visualization, less-invasive imaging modalities are preferred to avoid potential complications. DECT and US in particular are useful in the diagnosis of gout. In this review, we will discuss the current state and role of imaging in the detection of gout.
... [52][53][54][55] Studies have also looked at using US in the assessment of treatment response to serum uratelowering therapy in patients with gout. 56,57 These studies have noted an improvement in the double contour sign, hyperechoic spots, cloudy areas in the synovial fluid, and tophus diameter and size in those patients who achieved a treat-to-target with a serum uric acid level ≤ 6 mg/dL. Patients who did not reach this target had no changes in the gout US features. ...
... Patients who did not reach this target had no changes in the gout US features. [56][57] Larger cohort studies are needed to confirm these findings. An active inflammatory process can be determined by using a PD signal in the acute gout setting with increased vascularization; however, an increased PD signal can also be seen in septic arthritis or tenosynovitis, which sometimes can coexist with crystal-induced arthritis. ...
A growing body of clinical and research studies have demonstrated the utility of ultrasound for providing better diagnostic and treatment decisions in patients with rheumatic diseases.
... We also found a correlation between final SU level and clearance of US features of gout. These data are in line with a previous study showing an association between a decrease in SU level and decrease in US tophus size [17] or DC sign disappearance [23]. Of note, DC sign disappearance seemed to appear early during ULT. ...
... Finally, measurement of US tophi, using the largest diameter, might represent an approximation of exact MSU crystal load. Nevertheless, the reliability of US for measuring tophus was almost perfect, and this modality of measure was also used in previous studies with similar results [16,17]. Measurement of the volume of tophus might be an alternative, but according to the form and location of the tophus, could be difficult. ...
Objectives:
We aimed to determine the ability of ultrasonography (US) to show disappearance of urate deposits in gouty patients requiring urate-lowering therapy (ULT).
Methods:
We performed a 6-month multicentre prospective study including patients with: proven gout; presence of US features of gout (tophus and/or double contour sign) at the knee and/or first metatarsophalangeal joints; and no current ULT. US evaluations were performed at baseline and at months 3 and 6 (M3, M6) after starting ULT. Outcomes were: the change in US features of gout at M6 according to final (M6) serum urate (SU) level (high, > 360 μmol/l, i.e. > 6 mg/dl; low, 300-360 μmol/l, i.e. 5-6 mg/dl; very low, < 300 μmol/l, i.e. < 5 mg/dl); and correlation between changed US features and final SU level.
Results:
We included 79 gouty patients (mean ± s.d., age 61.8 (14) years, 91% males, disease duration 6.3 (6.1) years). Baseline SU level was 530 ± 97 µmol/l (i.e. 8.9 mg/dl ± 1.6mg/dl). At least one US tophus and double contour sign was observed in 74 (94%) and 68 (86%) patients, respectively. Among the 67 completers at M6, 18 and 39 achieved a very low and low SU level, respectively. We found a significant decrease in US features of gout among patients with the lowest SU level (P < 0.001). Final M6 SU level was positively correlated with decreased size of tophus (r = 0.54 [95% CI: 0.34, 0.70], P < 0.0001), and inversely correlated with proportion of double contour sign disappearance (r=-0.59 [-0.74, -0.40]).
Conclusion:
US can show decreased urate deposition after ULT, which is correlated with decreased SU level. The responsiveness of US in gout is demonstrated and can be useful for gout follow-up and adherence to ULT.
... An open, prospective 10-year follow-up study showed that despite most patients being compliant on ULT, 50% of them showing subcutaneous tophi at baseline increased the size of their tophi while showing mean sUA 8.2 mg/dl (0.48 mmol/l) [43,44]. In contrast, those patients who experienced a reduction in the size of their tophi had a mean sUA 6.2 mg/dl (0.37 mmol/l), while the only patient who cleared their tophi completely had a sUA < 4 mg/dl (0.24 mmol/l) [45]. ...
... In contrast, those patients who experienced a reduction in the size of their tophi had a mean sUA 6.2 mg/dl (0.37 mmol/l), while the only patient who cleared their tophi completely had a sUA < 4 mg/dl (0.24 mmol/l) [45]. This study highlights the accepted review of the evidence, namely that long-term-to target control of sUA has been shown to be associated with reduction and disappearance of subcutaneous and articular tophi [43,44], although unfortunately for scientific purity this has only been shown in open, non-comparative clinical studies. ...
The treat-to-target (T2T) approach has been successfully implemented in a number of diseases. T2T has been proposed for rheumatic diseases such as RA, spondyloarthritis, lupus, and recently for gout. The level of evidence for such approaches differs from one condition to the other (moderate to high for hyperlipidaemia, for example). Practice is based on the best available evidence at any time, and in absence of good evidence for T2T in gout, some suggest a conservative only-treat-symptoms approach. Evidence suggests that not treating gout to target in the long term is overall associated with worsening outcomes, such as flares, tophi and structural damage, which is associated to loss of quality of life and mortality. Different targets have been proposed for hyperuricaemia in gout; lower than 6 mg/dl (0.36 mmol/l) for all patients, at least <5 mg/dl (0.30 mmol/l) for patients with severe-polyarticular or tophaceous-gout.
... For measurement of index tophus diameter, interreader intraclass correlation coefficients have been reported as 0.710.83 [23]. Some features of urate deposition on US appear to be responsive to ULT over time. ...
... Some features of urate deposition on US appear to be responsive to ULT over time. In a prospective study of patients starting ULT, index tophus volume and maximal diameter measured by US changed over a 12 month period, with a strong relationship between urate concentrations and change in measured size [23]. Several other recent longitudinal studies have shown that US signs of double contour sign, aggregates and tophi can disappear in patients treated with ULT to subsaturation urate concentrations [3538]. ...
Imaging tests are in clinical use for diagnosis, assessment of disease severity and as a marker of treatment response in people with gout. Various imaging tests have differing properties for assessing the three key disease domains in gout: urate deposition (including tophus burden), joint inflammation and structural joint damage. Dual-energy CT allows measurement of urate deposition and bone damage, and ultrasonography allows assessment of all three domains. Scoring systems have been described that allow radiological quantification of disease severity and these scoring systems may play a role in assessing the response to treatment in gout. This article reviews the properties of imaging tests, describes the available scoring systems for quantification of disease severity and discusses the challenges and controversies regarding the use of imaging tools to measure treatment response in gout.
... Several US methods of tophus measurement were described. In 2007, Perez-Ruiz et al. [50] attempted to measure both tophus volume and its maximal diameter in a prospective US study, reporting the smallest detectable difference of 1.27 mm 3 for volume and of 5.5 mm (23.0% of the average measures) for maximal diameter. On the other hand, in 2019, Ebstein et al. [43] evaluated the largest diameter of the tophus, considering a significant difference greater than 20% of the baseline measure. ...
The use of ultrasonography (US) has considerable potential for the diagnosis and monitoring of gout due to its capacity to detect monosodium urate deposits. In the last decade, a critical amount of scientific data has become available. Consensus-based definitions for ultrasonographic elementary lesions in gout have been developed, tested, and validated, as well as a semiquantitative scoring system for their quantification. Many scanning protocols have been proposed in different clinical scenarios. In this review, we formulate a set of practical suggestions for the use of the US in daily practice. We discuss the current knowledge to indicate which joints and structures are to be scanned and which elementary findings are to be evaluated according to the clinical scenario. While for some clinical settings, a quite definite scanning protocol can be indicated, others still need to be further investigated, and how to obtain the best out of the US is still entrusted to the individual experience.
... The current gold standard for the diagnosis of GA is the microscopic identification of MSU crystals in synovial fluid or tophi. 14,15 However, the examination is invasive, complex, and requires microscopic analysis techniques, making it difficult to be widely implemented as a routine diagnostic tool. In addition, the gout classification criteria published by American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) in 2015 16 diagnose GA by summing up the scores based on clinical symptoms, laboratory tests, and imaging. ...
Objectives: The study aimed to investigate the diagnostic values of different musculoskeletal ultrasound (MSUS) signs, serum uric acid (SUA), and their combined detection for gouty arthritis (GA).
Patients and methods: In this retrospective study, 70 patients (62 males, 8 females; mean age: 46.1±14.1 years; range, 25 to 86 years) diagnosed with GA (the GA group) between August 2022 and March 2023 and 70 patients (54 females, 16 males; mean age: 49.0±14.1 years; range, 21 to 75 years) diagnosed with rheumatoid arthritis and osteoarthritis during the same period (the non-GA group) were included. The positive rate of MSUS signs and SUA in both groups was recorded to compare the differences. The correlations of MSUS signs and SUA with GA were analyzed using Spearman’s rank correlation analysis. The diagnostic values of different MSUS signs, SUA, and their combined detection for GA were analyzed using a receiver operating characteristic, the area under the curve (AUC), sensitivity, specificity, and the Youden index.
Results: The positive rate of the double contour (DC) sign (chi-squared [χ ² ]=102.935, p<0.001), hyperechoic spots (χ ² =56.395, p<0.001), bone erosions (χ ² =10.080, p<0.001), and SUA (χ ² =41.117, p<0.001) were higher in the GA group than in the non-GA group. The positive rate of the DC sign (rs=0.829, p=0.001), hyperechoic spots (rs=0.631, p<0.001), bone erosion (rs=0.268, p=0.001), and SUA (rs=0.542, p<0.001) were positively correlated with GA. Among the single-indicator measures, the DC sign exhibited the highest diagnostic value (AUC=0.907, sensitivity=81.4%, specificity=100%, p<0.001). Among the combined-indicator measures, the DC sign combined with SUA exhibited the highest diagnostic value (AUC=0.929, sensitivity=91.4%, specificity=94.3%, p<0.001), higher than DC sign detection alone.
Conclusion: The DC sign combined with SUA yielded a high diagnostic value and can thus provide a reliable basis for effectively and efficiently diagnosing GA.
... 14 Ultrasonography (US) is sensitive in detecting and measuring the size of intra-articular tophi as well as subcutaneous tophi not identified by physical examination. 15 However, US has not been widely utilized in clinical trials of long-term gout therapy due to the limited availability of qualified sonographers and sonography machines. ...
... Un monitoring échographique des patients goutteux permet de visualiser la dissolution des dépôts uratiques. En effet, il a été suggéré depuis 2007 que le tophus pouvait être mesuré en échographie [28]. Par la suite, il a observé dans deux petites études que le double contour disparaît rapidement sous traitement efficace [29,30]. ...
La goutte est une arthrite fréquente causée par la précipitation de cristaux d’urate de sodium dans les articulations. Le diagnostic de certitude repose sur la visualisation des cristaux dans le liquide articulaire. Le diagnostic positif est parfois difficile dans les formes précoces et atypiques, et les radiographies standard souvent prises en défaut. Le scanner àdouble énergie peut aider au diagnostic mais sa disponibilité limite son utilisation en pratique courante. Un autre examen d’imagerie, l’échographie, peut permettre la visualisation des dépôts. Dans la goutte, l’échographie peut aider au diagnostic positif en visualisant les tophus infra-cliniques mais aussi le spécifique signe du double contour. Des études récentes ont démontré son intérêt dans le suivi des dépôts uratiques.
... Studies have shown that US correlates well with MRI in the detection of tophi (28) . Erosions are more easily detected on US than on radiography (29) . ...
Rheumatologic diseases are a widespread group of disorders affecting the joints, bones, and connective tissue, and leading to significant disability. Imaging is an indispensable component in diagnosing, assess- ing, monitoring, and managing these disorders, providing information about the structural and functional alterations occurring within the affected joints and tissues. This review article aims to compare the utility, specific clinical applications, advantages, and limitations of high-resolution ultrasound and magnetic reso- nance imaging in the context of rheumatologic diseases. It also provides insights into the imaging features of various types of inflammatory arthritis with clinical relevance and a focus on high-resolution ultrasound and magnetic resonance imaging. By understanding the comparative aspects of high-resolution ultrasound and magnetic resonance imaging, it is easier for the treating physicians to make informed decisions when selecting the optimal imaging modality for specific diagnostic purposes, effective treatment planning, and improve patient outcomes. The patterns of soft tissue and joint involvement; bony erosion and synovitis help in differentiating between various type of arthritis. Involvement of various small joints of the hands also gives an insight into the type of arthritis. We also briefly discuss the potential applications of emerging techniques, such as ultrasound elastography, contrast-enhanced ultrasound, and dual-energy CT, in the field of rheumatology.
... The dimensions of the gouty tophi assume importance in the evaluation of the response to treatment, therefore, to be useful in practice, the method used for this purpose must have good reproducibility. Perez-Ruiz et al. showed that US is able to detect all periarticular tophi identified by MRI [10,28] . Omeract, after these studies, considers US as a possible useful method in the measurement of gouty tophi, but clinical trials need to be con-ducted to validate the method. ...
Gout is an arthritis characterized by the deposition of sodium monoacid crystals in the synovial membrane, articular cartilage, and periarticular tissues that leads to an inflamatory process. In most cases, the diagnosis is established by clinical criteria and analysis of the synovial fluid for MSU crystals. However, gout may manifest in atypical ways and make diagnosis difficult. In these situations, imaging studies play a fundamental role in helping to confirm the diagnosis or even exclude other differential diagnoses. Conventional radiography is still the most commonly used method in the follow-up of these patients, but it is a very insensitive test, because it only detects late changes. In recent years, advances in imaging methods have emerged in relation to gout. Ultrasound has proven to be a highly accurate test in the diagnosis of gout, identifying MSU deposits in articular cartilage and periarticular tissues, and detecting and characterizing tophi, tendinopathies, and tophi enthesopathies. Computed tomography is an excellent exam for the detection of bone erosions and evaluation of spinal involvement. Dual-energy computed tomography, a new method that provides information on the chemical composition of tissues, allows identification of MSU deposits with high accuracy. MRI can be useful in the evaluation of deep tissues not accessible by ultrasound. In addition to diagnosis, with the emergence of drugs that aim to reduce the tophaceous burden, imaging examinations become a useful tool in the follow-up treatment of gout patients.
... 160 Serial scanning with DECT or ultrasound can also allow visualization of changes in MSU crystal deposition, further reinforcing the benefits of treatment. 69,70,161,162 While exposure to radiation limits frequent DECT assessments in clinical practice, point of care ultrasound allows serial assessments over time as part of the clinical visit. ...
Gout is characterized by monosodium urate (MSU) crystal deposits in and within joints. These deposits result from persistent hyperuricaemia and most typically lead to recurrent acute inflammatory episodes (gout flares). Even though some aspects of gout are well characterized, uncertainties remain; this upcoming decade should provide further insights into many of these uncertainties. Synovial fluid analysis allows for the identification of MSU crystals and unequivocal diagnosis. Non-invasive methods for diagnosis are being explored, such as Raman spectroscopy and imaging modalities. Both ultrasound and dual-energy computed tomography (DECT) allow the detection of MSU crystals; this not only provides a mean of diagnosis, but also has furthered gout knowledge defining the presence of a preclinical deposition in asymptomatic hyperuricaemia. Scientific consensus establishes the beginning of gout as the beginning of symptoms (usually the first flare), but the concept is currently under review. For effective long-term gout management, the main goal is to promote crystal dissolution treatment by reducing serum urate below 6 mg/dL (or 5 mg/dL if faster crystal dissolution is required). Current urate-lowering therapies’ (ULTs) options are limited, with allopurinol and febuxostat being widely available, and probenecid, benzbromarone, and pegloticase available in some regions. New xanthine oxidase inhibitors and, especially, uricosurics inhibiting urate transporter URAT1 are under development; it is probable that the new decade will see a welcomed increase in the gout therapeutic armamentarium. Cardiovascular and renal comorbidities are common in gout patients. Studies determining whether optimal treatment of gout will positively impact these comorbidities are currently lacking, but will hopefully be forthcoming. Overall, the single change that will most impact gout management is greater uptake of international rheumatology society recommendations. Innovative strategies, such as nurse-led interventions based on these recommendations have recently demonstrated treatment success for people with gout.
... Among them, the DCs could be an early marker with an obvious change after 3 months of treatment, while tophi changed more significantly after 6 months of treatment. In line with other studies (54,55), the reduction in urate deposition was associated with low sUA levels and was more pronounced in the group with lower serum sUA (<5 mg/dl), suggesting that lower levels of sUA were one of the effective therapeutic targets and consistent with last EULAR recommendations (7). Similarly, several other research also showed that the DCs, tophi, and aggregates decreased obviously measured by US under ULTs (55)(56)(57). ...
Gout is a common form of inflammatory arthritis where urate crystals deposit in joints and surrounding tissues. With the high prevalence of gout, the standardized and effective treatment of gout is very important, but the long-term treatment effect of gout is not satisfied because of the poor adherence in patients to the medicines. Recently, advanced imaging modalities, including ultrasonography (US), dual-energy computed tomography (DECT), and magnetic resonance imaging (MRI), attracted more and more attention for their role on gout as intuitive and non-invasive tools for early gout diagnosis and evaluation of therapeutic effect. This review summarized the role of US, DECT, and MRI in the management of gout from four perspectives: hyperuricemia, gout attacks, chronic gout, and gout complications described the scoring systems currently used to quantify disease severity and discussed the challenges and limitations of using these imaging tools to assess response to the gout treatment.
... US may be used to monitor therapy. With successful therapy, the double-contour cartilage sign can resolve, and tophi can reduce in size [7,9,20,26,27,31,32,67,118,121,122]. ...
Gout, a crystalline arthropathy caused by the deposition of monosodium urate crystals in the articular and periarticular soft tissues, is a frequent cause of painful arthropathy. Imaging has an important role in the initial evaluation as well as the treatment and follow up of gouty arthropathy. The imaging findings of gouty arthropathy on radiography, ultrasonography, computed tomography, dual energy computed tomography, and magnetic resonance imaging are described to include findings of the early, acute and chronic phases of gout. These findings include early monosodium urate deposits, osseous erosions, and tophi, which may involve periarticular tissues, tendons, and bursae. Treatment of gout includes non-steroidal anti-inflammatories, colchicine, glucocorticoids, interleukin-1 inhibitors, xanthine oxidase inhibitors, uricosuric drugs, and recombinant uricase. Imaging is critical in monitoring response to therapy; clinical management can be modulated based on imaging findings. This review article describes the current standard of care in imaging and treatment of gouty arthropathy.
... This serum urate target was also endorsed in the 2017 British Society for Rheumatology guideline for the management of gout (13). Achievement of this serum urate target leads to gradual reduction in MSU crystal deposition (14,15). The aim of this study was to determine whether intensive oral urate-lowering therapy to maintain serum urate concentrations of <0.20 mmoles/liter results in improved bone erosion scores in erosive gout, compared to the serum urate target of <0.30 mmoles/liter. ...
Objective
To determine whether a therapeutic approach of intensive serum urate lowering results in improved bone erosion scores in patients with erosive gout.
Methods
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.
Results
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.
Conclusion
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.
... Our data suggest that patients who are prospectively followed up show high adherence rates and close to 90% patients reach sUA therapeutic target. Poor adherence for ULT is associated with poorer clinical outcomes as sUA levels are a surrogate for gout outcomes [16,17]. ...
IntroductionGout is commonly associated with low adherence rates, thus limiting the effectiveness of treatment. Nevertheless, informed and empowered patients may be more likely to achieve high adherence. We intend to demonstrate that adherence in clinical practice may reach that achieved in clinical trials.Methods
This was a transversal study within an inception cohort of patients with gout prospectively followed up. Patients were informed at entrance in the cohort of outcomes, targets, and means to implement for successful treatment. Adherence was evaluated through electronic medication possession ratio (MPR) for urate-lowering medication and oral medications for hypertension, diabetes, and hyperlipidemia for comparison. Factors associated with nonadherence, and the relation between nonadherence and serum urate levels while on treatment were analyzed.ResultsData were retrieved from 336 patients, who showed a mean MPR of 87.5%, with 82.1% of patients showing MPR ≥ 0.8. Rates of adherence for hypertension, hyperlipidemia, and diabetes were quite similar (88%, 87%, and 83%, respectively), although MPR > 0.8 was significantly lower for oral medications for diabetes. Adherence was lower, but nevertheless quite fair, during the first year of follow-up, and increasing over time. Active follow-up and comorbidity were associated with good adherence, and adherence and long-term follow-up were associated with higher rates of achieving serum urate within therapeutic target.Conclusion
Patients with gout show high rates of adherence if empowered. Active follow-up and comorbidity are associated with high rates of adherence. Adherence is strongly associated with higher rates of achievement of therapeutic serum urate target.
... Aspiration of nodules suspected as tophi found MSU crystals in 83%. The study revealed a good correlation, but only fair agreement, between US and MRI [45] Table 2. ...
... Based on an US pilot study in daily clinical practice, Slot et al. has demonstrated that the double-contour sign is a consistent finding in MTP joints in gout patients [20]. Despite of that, as a deposit of UA crystals, tophi is an outcome measure for chronic gout [21]. The development of gouty tophi can limit joint function and cause bone destruction, leading to noticeable disabilities, especially when gout cannot successfully be treated [22]. ...
Background:
This study aimed to confirm the diagnostic accuracy of ultrasound (US) on gout and explore the potential risk factors for double-contour sign and tophi formation in gout patients.
Methods:
The US analyses were performed on all knee, ankle, and first metatarsophalangeal (MTP 1) joints to reveal the type and location of lesions. While a questionnaire and blood biochemical index were used to explore the potential risk factors for double-contour sign and tophi in gout, the SPSS17.0 software was used for statistical analysis in the present study.
Results:
Totally, 117 gout patients with 702 joints (38 lesions in knee joint, 93 lesions in ankle joint, and 112 lesions in MTP 1 joint) were enrolled in current analyses. Double-contour sign and joint effusion were the two most outstanding lesion manifestations in knee joints and ankle joints. Tophi and double-contour sign were the two most outstanding lesion manifestations in TMP 1 joints. Moreover, factors including uric acid (UA) level and the highest blood UA were potential risk factors of the double-contour sign, while age and history of US were potential risk factors for tophi.
Conclusion:
US was effective on the joints of gout patients. There was US sensitivity for tophi and double-contour sign in MTP 1 joints. The double-contour sign was a potential specific manifestation in knee joints and ankle joints. Furthermore, UA and highest blood UA level were potential risk factors for double-contour sign, while age and US history were potential risk factors for tophi.
... Furthermore, it does not provide an estimate of the burden of MSU deposits. Therefore, techniques have been developed that allow visualization of MSU deposits in a noninvasive manner (7)(8)(9)(10). ...
Objective:
Few studies have systematically and quantitatively addressed the impact of urate-lowering therapy on monosodium urate (MSU) deposition. Herein, we analyzed the effect of lifestyle measures and conventional uric acid lowering therapy on MSU deposits in gout patients.
Methods:
In this prospective study, subjects with a diagnosis of gout according to ACR/EULAR classification criteria and presence of MSU deposits in dual energy computed tomography (DECT) scans received either lifestyle intervention or conventional urate-lowering therapy for a mean period of 18 months before follow-up DECT scan. Detected MSU deposits were quantified by volumetric measurement, validated by semi-quantitative scoring and compared between baseline and follow-up measurements.
Results:
Baseline and follow-up DECT examination were available from all 83 subjects. 6 subjects discontinued treatment, 77 subjects (lifestyle intervention: n=24, allopurinol: n=29, febuxostat: n=22, benzbromarone n=2) continued treatment over the entire observation period. Serum uric acid (SUA) level decreased from 7,2 to 5,8 mg/dl in the overall population. In patients discontinuing treatment, no change in MSU deposits or SUA levels was observed. MSU deposits burden significantly decreased in patients undergoing lifestyle intervention (MSU volume: p=0.007; MSU score: p=0.001) or treatment with allopurinol (MSU volume/score: p<0.001) or febuxostat (MSU volume: p<0.001; MSU score: p=0.001). No significant decline of MSU deposits was noted in patients discontinuing treatment.
Conclusion:
These data show that lifestyle intervention and xanthine oxidase inhibitors significantly decrease MSU deposit burden. Hence, conventional gout therapy not only lowers SUA levels but also pathologic MSU depositions. This article is protected by copyright. All rights reserved.
... Previous clinical and ultrasound observational studies have demonstrated that long-term urate-lowering therapy to a target serum urate (SU) level of <0.36 mmoles/liter (6 mg/dl) can lead to the dissolution of deposited MSU crystals (14)(15)(16)(17). The effects of urate-lowering therapy on structural joint damage and on MSU crystal deposition, detected using DECT, have not been previously tested in a randomized clinical trial setting. ...
Objective
To examine whether allopurinol dose escalation to achieve serum urate (SU) target can influence bone erosion or monosodium urate (MSU) crystal deposition, as measured by dual‐energy computed tomography (DECT) in patients with gout.
Methods
We conducted an imaging study of a 2‐year randomized clinical trial that compared immediate allopurinol dose escalation to SU target with conventional dosing for 1 year followed by dose escalation to target, in gout patients who were receiving allopurinol and who had an SU level of ≥0.36 mmoles/liter. DECT scans of feet and radiographs of hands and feet were obtained at baseline, year 1, and year 2 visits. DECT scans were scored for bone erosion and urate volume.
Results
Paired imaging data were available for 87 patients (42 in the dose‐escalation group and 45 in the control group). At year 2, the progression in the CT erosion score was higher in the control group than in the dose‐escalation group (+7.8% versus +1.4%; P = 0.015). Changes in plain radiography erosion or narrowing scores did not differ between groups. Reductions in DECT urate volume were observed in both groups. At year 2, patients in the control group who had an SU level of <0.36 mmoles/liter and patients in the dose‐escalation group had reduced DECT urate volume (−27.6 to −28.3%), whereas reduction in DECT urate volume was not observed in control group patients with an SU level of ≥0.36 mmoles/liter (+1.5%) (P = 0.023).
Conclusion
These findings provide evidence that long‐term urate‐lowering therapy using a treat‐to‐SU‐target strategy can influence structural damage and reduce urate crystal deposition in gout.
... After many acute mono-or oligo-articular attacks, a proportion of patients may progress into chronic synovitis with joint destructions. With development of the imaging modalities such as magnetic resonance imaging (MRI) [2], computed tomography (CT) [3], and ultrasonography (US) [4,5], we are cur-rently able to visualize MSU crystals without joint aspiration. Dual-energy computed tomography (DECT), which can differentiate chemical components of material using material-specific differences in attenuation on different peak voltages, is a highly sensitive method for detecting MSU crystal deposits [6][7][8][9]. ...
... However, results from most clinical trials indicate only modest decreases in tophi, perhaps owing to their relatively short duration [17,21,22]. Although there appears to be a significant correlation between the magnitude of serum urate reduction and resolution of tophi [26,27], and although oral urate-lowering therapies are capable of decreasing serum urate from baseline by 50-60%, resulting in levels that are between 4 and 6 mg/dl [17,20,22], this may be insufficient for rapid tophus resolution. ...
Background
Pegloticase is a recombinant mammalian uricase conjugated to polyethylene glycol approved in the United States for treatment of chronic refractory gout. It can profoundly decrease serum urate to < 1 mg/dl. In patients receiving pegloticase who did not generate high-titer antidrug antibodies (responders), the serum urate remained low for the duration of therapy, 6 months in the phase III clinical trials plus the open-label extension. The objective of this study was to assess the velocity of tophus resolution in subjects treated with pegloticase.
Methods
Data from two randomized controlled trials of pegloticase in chronic refractory gout were analyzed. Tophi were assessed by computer-assisted measurements of standardized digital photographs. Subjects were designated as responders and nonresponders based on maintenance of serum urate < 6 mg/dl at months 3 and 6 of treatment. The projected time of complete resolution of all tophi was determined by linear regression analysis.
Results
The mean total tophus area at baseline was 585.8 mm² for responders, 661.5 mm² for nonresponders, and 674.4 mm² for placebo-treated patients. Complete resolution at 6 months of at least one tophus was achieved by 69.6% of 23 responders, 27.9% of 43 nonresponders, and 14.3% of 21 patients who received placebo. Complete resolution of all photographed tophi was achieved by 34.8% of biochemical responders, 11.6% of nonresponders, and 0% of placebo-treated patients. The mean velocity of resolution of all tophi was 60.1 mm²/month in responders with a mean projected time of complete resolution of 9.9 months (4.6–32.6 months). There was a significant inverse correlation between serum urate AUC and tophus resolution velocity (r = − 0.40, P = 0.0002), although considerable heterogeneity in the velocity of resolution was noted. The only patient characteristic that correlated with the velocity of tophus resolution was the baseline tophus area.
Conclusions
Pegloticase treatment caused a rapid resolution of tophi in responders that correlated with the serum urate lowering associated with this therapy.
... 6 mg/dl bilden sich die sonographischen Veränderungen einschließlich des Doppelkonturzeichens zurück bzw. verschwinden komplett [26,40]. Während sich Harnsäurekristalle extraartikulär, im Synovium oder auf dem Knorpel ablagern, finden sich Pyrophosphatkristalle bei Chondrokalzinose innerhalb des Knorpels. ...
Die Arthrosonographie ist ein etabliertes und validiertes diagnostisches Verfahren in der Rheumatologie. Durch ihren hohen Weichteilkontrast ist die Sonographie in der Lage, Weichteilveränderungen wie z.B. Synovialisveränderungen zu detektieren. Knorpel- oder Knochenveränderungen im Rahmen einer rheumatoiden Arthritis (RA), einer Spondyloarthritis oder einer Kristallarthritis können teilweise nur sonographisch oder in vielen Fällen zu einem früheren Zeitpunkt als mit der konventionellen Bildgebung erfasst werden. Die Aktivität entzündlicher Veränderungen kann mit Hilfe der Doppler- und Power-Dopplersonographie gut dargestellt werden. In der Früharthritisdiagnostik gewinnt die Sonographie zunehmend an Bedeutung, insbesondere bei undifferenzierter Arthritis und bei unauffälligem Röntgenbefund. Neben der Diagnostik der Früharthritis und dem Therapiemonitoring einer RA erlaubt die Sonographie die Darstellung pathognomonischer Veränderungen bei seronegativen Spondyloarthritiden und Kristallablagerungserkrankungen wie Gicht, Chondrokalzinose und Apatitose. Sonographiegesteuerte diagnostische und therapeutische Interventionen zeichnen sich durch eine extrem hohe Treffsicherheit und Verbesserung der klinischen Wirksamkeit verglichen mit ungesteuerten Verfahren aus. Zusammenfassend nimmt die Sonographie zunehmend einen zentralen Stellenwert ein in der Abklärung und Behandlungssteuerung bei entzündlichen Gelenkerkrankungen
... Data are also emerging concerning the usefulness of US for monitoring treatment efficacy, demonstrating regression of US signs at 6 months of treatment in responders, with an excellent correlation between the resolution of US signs and SUA levels [93,94]. US is therefore being considered as an outcome measure in gout, but needs further standardization [95]. ...
This review article summarizes the relevant English literature on gout from 2010 through April 2017. It emphasizes that the current epidemiology of gout indicates a rising prevalence worldwide, not only in Western countries but also in Southeast Asia, in close relationship with the obesity and metabolic syndrome epidemics. New pathogenic mechanisms of chronic hyperuricaemia focus on the gut (microbiota, ABCG2 expression) after the kidney. Cardiovascular and renal comorbidities are the key points to consider in terms of management. New imaging tools are available, including US with key features and dual-energy CT rendering it able to reveal deposits of urate crystals. These deposits are now included in new diagnostic and classification criteria. Overall, half of the patients with gout are readily treated with allopurinol, the recommended xanthine oxidase inhibitor (XOI), with prophylaxis for flares with low-dose daily colchicine. The main management issues are related to patient adherence, because gout patients have the lowest rate of medication possession ratio at 1 year, but they also include clinical inertia by physicians, meaning XOI dosage is not titrated according to regular serum uric acid level measurements for targeting serum uric acid levels for uncomplicated (6.0 mg/dl) and complicated gout, or the British Society for Rheumatology recommended target (5.0 mg/dl). Difficult-to-treat gout encompasses polyarticular flares, and mostly patients with comorbidities, renal or heart failure, leading to contraindications or side effects of standard-of-care drugs (colchicine, NSAIDs, oral steroids) for flares; and tophaceous and/or destructive arthropathies, leading to switching between XOIs (febuxostat) or to combining XOI and uricosurics.
... While it appears logical to target a serum urate level in the subsaturation range, serum urate levels well below the solubility threshold may be required for more rapid crystal dissolution. Evidence of an inverse relationship between the velocity of crystal dissolution and serum urate concentration has been used to support the application of more intensive serum urate targets, particularly for severe presentations of gout [38,39]. The time required to deplete MSU crystal deposits has also been found to vary with disease duration prior to treatment, implying that the accumulation of crystal load is time-dependent. ...
Purpose of review:
Most current clinical guidelines for gout management advocate a treat-to-target serum urate approach, although notable differences exist. Serum urate is a rational target for gout treatment given the central role of urate in disease causality, its association with key outcomes and its practicality of use in clinical practice. This review analyses the evidence for this strategy in gout.
Recent findings:
Recent studies have confirmed the efficacy of urate-lowering therapy in achieving serum urate targets, both in trials using fixed doses and those applying a treat-to-target strategy. In a limited number of long-term studies (> 12-month duration), interventions that incorporate a treat-to-target serum urate approach have been shown to promote regression of tophi, reduce the frequency of gout flares and improve MRI-detected synovitis. A strong case can be made for a treat-to-target serum urate strategy in gout, supported by existing knowledge of disease pathophysiology, outcomes from urate-lowering therapy studies and emerging results of randomised strategy trials of sufficient duration.
Objective
To summarise current data regarding the use of imaging in crystal-induced arthropathies (CiAs) informing a European Alliance of Associations for Rheumatology task force.
Methods
We performed four systematic searches in Embase, Medline and Central on imaging for diagnosis, monitoring, prediction of disease severity/treatment response, guiding procedures and patient education in gout, calcium pyrophosphate dihydrate deposition (CPPD) and basic calcium phosphate deposition (BCPD). Records were screened, manuscripts reviewed and data of the included studies extracted. The risk of bias was assessed by validated instruments.
Results
For gout, 88 studies were included. Diagnostic studies reported good to excellent sensitivity and specificity of dual-energy CT (DECT) and ultrasound (US), high specificity and lower sensitivity for conventional radiographs (CR) and CT. Longitudinal studies demonstrated sensitivity to change with regard to crystal deposition by US and DECT and inflammation by US and structural progression by CR and CT. For CPPD, 50 studies were included. Diagnostic studies on CR and US showed high specificity and variable sensitivity. There was a single study on monitoring, while nine assessed the prediction in CPPD. For BCPD, 56 studies were included. There were two diagnostic studies, while monitoring by CR and US was assessed in 43 studies, showing a reduction in crystal deposition. A total of 12 studies with inconsistent results assessed the prediction of treatment response. The search on patient education retrieved two studies, suggesting a potential role of DECT.
Conclusion
This SLR confirmed a relevant and increasing role of imaging in the field of CiAs.
Objective
This study investigates the efficacy of multidisciplinary fusion therapy based on 3D reconstruction technology for the treatment of gouty stone by comparing the efficacy of multidisciplinary fusion therapy with pharmacologic therapy.
Methods
This study is a cohort study.Patients who underwent gout stone surgery at the Affiliated Hospital of Qingdao University from November 2020 to November 2022 were included in this study, totaling 85 to form the MDT surgery group, and matched among gout stone patients in the outpatient clinic during the same period to form the medication group. Patients in the 2 groups were followed up for 6 months to compare baseline and follow-up data.
Results
Both groups experienced a decrease in uric acid levels and an increase in SF-36 scores during follow-up. After adjusting for confounders, multifactorial logistic regression showed that the uric acid attainment rate of patients in the MDT surgery group was 4.011 times higher than that of the drug group (OR: 4.011, 95% CI: 1.595, 10.086, P = 0.003); the proportion of patients with an increase in SF-36 in the MDT surgery group was 4.976 times higher than that of the drug group (OR: 4.976, 95% CI : 2.243, 11.040, P < 0.001); the proportion of patients treated with high-dose medication in the MDT surgery group was 1.8% of that of patients in the drug group (OR: 0.018, 95% CI: 0.002, 0.148, P < 0.001); and the proportion of patients in the MDT surgery group who developed frequent gout was 2.8% of that in the drug group (OR: 0.028 95% CI: 0.003, 0.2398, P = 0.001). the proportion of patients in the MDT surgery group who developed abnormal liver function was 0.317 times higher than that in the drug group (OR: 0.317, 95% CI: 0.121, 0.831, P = 0.019).
Conclusion
The multidisciplinary integration of 3D reconstructive techniques for gout stone treatment resulted in an increase in uric acid compliance, a decrease in the frequency of gout and the appearance of liver impairment; and a greater benefit in terms of improvement in the quality of life of the patients after treatment.
Objectives
In 2015, the 20-item Tophus Impact Questionnaire (TIQ-20) was developed as a tophus-specific patient reported outcome measure. The aim of this study was to determine whether TIQ-20 scores change during urate-lowering therapy.
Methods
We analysed data from a two-year clinical trial of allopurinol dose escalation using a treat-to-target serum urate approach. For participants with tophaceous gout, the longest diameter of up to three index tophi was measured using Vernier calipers and the TIQ-20 was recorded at study visits. Participants at the one site were invited into a dual energy CT (DECT) sub-study. Participants were included in this analysis if they had tophaceous gout and TIQ-20 scores available at baseline, Year 1, and Year 2 (n = 58, 39 with DECT data). Data were analysed using mixed model approach to repeated measures.
Results
Improvements were observed in all tophus measures over the two-year period. The mean (SD) TIQ-20 scores reduced over two years from 3.59 (1.77)–2.46 (1.73), P< 0.0001, and the mean (95%CI) TIQ-20 change over the two years was -1.13 (-1.54, -0.71). Effect size (Cohen’s d) for the change in the sum of the index tophi diameter over two years was 0.68, for DECT urate volume was 0.50, and for the TIQ-20 was 0.71.
Conclusion
For people with tophaceous gout treated with allopurinol using a treat to target serum urate approach, improvements in TIQ-20 occur, as well as improvements in physical and imaging tophus measures. These findings demonstrate that the TIQ-20 is a responsive patient-reported instrument of tophus impact.
Xanthine oxidase inhibitors such as allopurinol and febuxostat have been the mainstay urate-lowering therapy (ULT) for treating hyperuricaemia in patients with gout. However, not all patients receiving oral ULT achieve the target serum urate level, in part because some patients cannot tolerate, or have actual or misconceived contraindications to, their use, mainly due to comorbidities. ULT dosage is also limited by formularies and clinical inertia. This failure to sufficiently lower serum urate levels can lead to difficult-to-treat or uncontrolled gout, usually due to poorly managed and/or under-treated gout. In species other than humans, uricase (urate oxidase) converts urate to allantoin, which is more soluble in urine than uric acid. Exogenic uricases are an exciting therapeutic option for patients with gout. They can be viewed as enzyme replacement therapy. Uricases are being used to treat uncontrolled gout, and can achieve rapid reduction of hyperuricaemia, dramatic resolution of tophi, decreased chronic joint pain and improved quality of life. Availability, cost and uricase immunogenicity have limited their use. Uricases could become a leading choice in severe and difficult-to-treat gout as induction and/or debulking therapy (that is, for lowering of the urate pool) to be followed by chronic oral ULT. This Review summarizes the evidence regarding available uricases and those in the pipeline, their debulking effect and their outcomes related to gout and beyond.
Gout is a representative inflammatory arthritis with an increasing incidence in recent years. Gout may be accompanied by a chronic course in which sodium urate crystals are continuously deposited to form gout nodules if proper uric acid management is not performed after acute symptom onset. In the past, an invasive method was applied to diagnose gout, but the development of various imaging modalities has prompted attempts to diagnose gout with a non-invasive method. Among these, ultrasound examination is a patient-friendly examination, is relatively convenient to perform in an outpatient setting, and can be used for treatment evaluation. Therefore, in this thesis, the ultrasound findings of gout are investigated and applied to actual treatment.
Gout management involves two broad aspects: treatment of gout flares to provide rapid symptomatic relief and long-term urate-lowering therapy to lower serum urate sufficiently to prevent gout flares from occurring. All of the major rheumatology societies recommend a target serum urate of <5 mg/dl (<0.30 mmol/l) or <6 mg/dl (<0.36 mmol/l), both of which are below the point of saturation for urate and therefore lead to monosodium urate crystal dissolution. In this Review, we describe the rationale for treat-to-target urate approach in the long-term management of gout and the current evidence and controversy around the appropriate serum urate targets.
Crystal-related arthropathies are diseases characterized by crystal deposition at joint and periarticular level. There are three main types of crystals: monosodium urate (MSU) crystals, responsible for the gout; calcium pyrophosphate (CPP) crystals, responsible for calcium pyrophosphate deposition disease (CPPD); and basic calcium phosphate (BCP) crystals.The identification of US patterns defined by the topographic distribution of crystal deposits has been shown to be accurate in distinguishing between different crystal deposits.US findings in crystal arthritis include unspecific signs of soft tissue inflammation and highly specific features due to crystal deposits at joint and periarticular level. Crystal deposits are characterized by a high reflectivity of the US beam, independently of the angle of insonation.The main US findings of MSU deposits are the following: double-contour sign, tophi, and aggregates. CPP crystals appear as hyperechoic dots which may be isolated or aggregated, typically without acoustic shadowing and usually located within the cartilage (fibrocartilage and hyaline cartilage). At tendon level, CPP crystal deposits usually appear as hyperechoic bands without posterior acoustic shadow and distributed along the major axis of the tendon.BCP crystal-related musculoskeletal pathology can be divided into two main conditions, osteoarthritis secondary to intra-articular BCP crystals and calcific periarthritis due to BCP crystal deposition in tendons, bursae, and other soft tissues around joints. Shoulder calcific periarthritis is the main BCP-related condition and BCP crystal deposits appear as hyperechoic dots generating acoustic shadowing.KeywordsGoutTophiMonosodium urateCalcium pyrophosphateBasic calcium phosphate crystal deposits
Background
Background: Gout is one of the most common inflammatory arthritis, where identification of MSU crystals in synovial fluid is a widely used diagnostic measure. Ultrasonography has a great sensitivity in detecting signs of MSU deposits, such as tophi and double contour (DC), as mentioned in the latest gout criteria, allowing early clinical diagnosis and therapy.
Objective
The objective of this study was to evaluate the changes in ultrasound of gout patients’ knee and 1st metatarsophalangeal joint (MTP1) after initiation of urate-lowering therapy (ULT) drugs in the six-month period.
Methods
Forty-three patients, fulfilling the ACR/EULAR 2015 criteria of gout with a score of >8, were enrolled; they were in between attacks and not on ULT for the last 6 months, or SUA concentration (SUA) of >6.0 mg/dL. Full examination, evaluation of joints pain by visual analog scale (VAS), ultrasonography (US) for tophus and DC at the knee, and MTP1 were performed at baseline and at 3 and 6 months (M3, M6) after starting ULT.
Result
After 6 months of treatment, patients reached the target SUA level showed higher disappearance of DC sign (p<0.05) and a decrease in tophus size (p<0.05). The percentage of tophus size at 6th month was 26.4% and 3% for DC sign disappearance, which was more at MTP1.
Conclusion
Ultrasound examination in screening for gout tophi or DC sign before starting ULT and during follow-up is important and complements clinical examination.
Objectives:
To evaluate responsiveness of gout-specific ultrasound lesions representing urate deposition in patients receiving treat-to-target urate-lowering therapy using a binary and the OMERACT-defined semi-quantitative scoring systems. Furthermore, to determine the most responsive ultrasound measure for urate deposition and the optimal joint/tendon set for monitoring this.
Methods:
Ultrasound (28 joints, 14 tendons) was performed in microscopically verified gout patients initiating/increasing urate-lowering therapy and repeated after 6 and 12 months. Static images/videos of pathologies were stored and scored binarily and semi-quantitatively for tophus, double contour(DC) and aggregates. Lesion-scores were calculated at patient level as were combined crystal sum scores. Responsiveness of lesions-binarily and semi-quantitatively-were calculated at both patient and joint/tendon level.
Results:
Sixty-three patients underwent longitudinal evaluation. The static images/videos assessed retrospectively showed statistically significant decreases in tophus and DC, when scored binarily and semi-quantitatively, whereas aggregates were almost unchanged during follow-up. The responsiveness of the semi-quantitative tophus and DC sum scores were markedly higher than those of the binary. The most responsive measure for urate deposition was a combined semi-quantitative tophus-DC-sum score. A feasible joint/tendon set for monitoring included knee and 1st-2nd metatarsophalangeal joints and peroneus and distal patella tendons (all bilateral) representing the most prevalent and responsive sites.
Conclusion:
The OMERACT consensus-based semi-quantitative ultrasound gout scoring system showed longitudinal validity with both tophus and DC being highly responsive to treatment when assessed in static images/videos. A responsive ultrasound measure for urate deposition and a feasible joint/tendon set for monitoring were proposed and may prove valuable in future longitudinal studies.
This prospective study was aimed at observing the changes in three ultrasound (US) outcome domains (urate deposition, joint inflammation and bone erosion) in gout patients within the 1 y on urate-lowering therapy. The elementary lesions, including tophus, double-contour (DC) sign, aggregates, synovitis and bone erosion of the bilateral knee, ankle and first metatarsophalangeal joints, were evaluated repeatedly by US before and after 3, 6 and 12 mo of treatment, and the effective rates of clearance of tophus, DC sign and aggregates in different time groups were compared. A Global OMERACT–EULAR Synovitis Score (GLOESS) was calculated for these three paired joints to observe the inflammation. Bone erosion was also scored. The correlation between serum uric acid levels and tophus size changes was analyzed. Our results indicated that the decrease in serum uric acid levels was not completely parallel to the decrease in tophus size. For tophus, there was no significant difference in the clearance rate between different time groups (χ² = 1.76, p = 0.392), while for DC sign and aggregates, there were significant differences (χ² = 21.48, p < 0.001, χ² = 7.75, p = 0.018). Meanwhile, GLOESS was significantly lower after 6 mo of therapy (χ² = 32.316, p < 0.001). Additionally, bone erosion had not improved after 1 y of treatment (Z = –1.633, p = 0.102). Thus, US is crucial for assessing response to urate-lowering therapy in gout.
Crystal-related arthropathies are the result of crystal deposition in joint and periarticular soft tissues. Identification of urate crystals is mandatory to distinguish gout from other crystalline arthropathies, including calcium pyrophosphate dihydrate and basic calcium phosphate crystal deposition diseases. ACR/EULAR classification criteria for gout included dual-energy computed tomography and ultrasound with equal impact to the final score. Different diagnostic strengths of these imaging modalities depend on disease duration and scanned anatomic site. While ultrasound has been indicated as the first-choice imaging technique, especially in the early stages of the disease, dual-energy computed tomography has shown to be highly specific, allowing the detection of crystal deposits in anatomic sites not accessible by ultrasound, such as the spine. At the spinal level, MRI findings are usually nonspecific. Finally, there is preliminary evidence that at the knee, dual-energy computed tomography may discriminate calcium pyrophosphate dihydrate from basic calcium phosphate crystal deposits.
Objectives:
To determine whether changes in ultrasonography (US) features of monosodium urate crystal deposition is associated with the number of gouty flares after stopping gout flare prophylaxis.
Methods:
We performed a 1-year multicentre prospective study including patients with proven gout and US features of gout. The first phase of the study was a 6-month US follow-up after starting urate-lowering therapy (ULT) with gout flare prophylaxis. After 6 months of ULT, gout flare prophylaxis was stopped, followed by a clinical follow-up (M6 to 12) and ULT was maintained. Outcomes were the proportion of relapsing patients between M6 and M12 according to changes of US features of gout and determining a threshold decrease in tophus size according to the probability of relapse.
Results:
We included 79 gouty patients (mean [± SD] age 61.8 ± 14 years, 91% males, median disease duration 4 [IQR 1.5; 10] years). Among the 49 completers at M12, 23 (47%) experienced relapse. Decrease in tophus size ≥ 50% at M6 was more frequent without than with relapse (54% vs 26%, P= 0.049). On ROC curve analysis, a threshold decrease of 50.8% in tophus size had the best sensitivity/specificity ratio to predict relapse (AUC 0.649 [95% confidence interval 0.488 ; 0.809]). Probability of relapse was increased for patients with a decrease in tophus size <50% between M0 and M6 (OR 3.35 [95% confidence interval 0.98; 11.44]).
Conclusion:
A high reduction in US tophus size is associated with lower probability of relapse after stopping gout prophylaxis. US follow-up may be useful for managing ULT and gout flare prophylaxis.
Urate-lowering therapy is indispensable for the treatment of gout, but available drugs do not control serum urate levels tightly enough. Although the uricosurics benzbromarone and probenecid inhibit a urate reabsorption transporter known as renal urate transporter 1 (URAT1) and thus lower serum urate levels, they also inhibit other transporters responsible for secretion of urate into urine, which suggests that inhibiting URAT1 selectively would lower serum urate more effectively. We identified a novel potent and selective URAT1 inhibitor, UR-1102, and compared its efficacy with benzbromarone in vitro and in vivo. In human embryonic kidney (HEK)293 cells overexpressing URAT1, organic anion transporter 1 (OAT1), and OAT3, benzbromarone inhibited all transporters similarly, whereas UR-1102 inhibited URAT1 comparably to benzbromarone but inhibited OAT1 and OAT3 quite modestly. UR-1102 at 3-30 mg/kg or benzbromarone at 3-100 mg/kg was administered orally once a day for 3 consecutive days to tufted capuchin monkeys, whose low uricase activity causes a high plasma urate level. When compared with the same dosage of benzbromarone, UR-1102 showed a better pharmacokinetic profile, increased the fractional excretion of urinary uric acid, and reduced plasma uric acid more effectively. Moreover, the maximum efficacy of UR-1102 was twice that of benzbromarone, suggesting that selective inhibition of URAT1 is effective. Additionally UR-1102 showed lower in vitro potential for mechanisms causing the hepatotoxicity induced by benzbromarone. These results indicate that UR-1102 achieves strong uricosuric effects by selectively inhibiting URAT1 over OAT1 and OAT3 in monkeys, and could be a novel therapeutic option for patients with gout or hyperuricemia.
This thesis discusses and summarizes our recent work about the role of neutrophil extracellular traps and phagocytes in the initiation and resolution of inflammation. First an overview is provided of the immune system, followed by a description of the different types of cell death which occur in our body on a daily basis. This is followed by the role of neutrophils and phagocytes in the clearance of cellular debris and their respective roles for the initiation and resolution of inflammation and autoimmunity. Lastly, the relevance of our findings and the context for the respective scientific community will be discussed in a broader manner. With the discovery of neutrophil extracellular traps (NETs) in 2004 in Zychlinsky’s lab, a new era in neutrophils research ensued (Brinkmann et al., 2004). Originally, this process was discovered for its participation in the defense against infections and immobilization of pathogens. Since then many other functions were discovered, we proceeded to explore the role of NETs in vitro and discovered that NETs trap and degrade inflammatory mediators (Schauer et al., 2014). This was later confirmed in Papillon Lefèvre Syndrome (PLS) patients, which are known to have non-functioning serine proteases, and thus can suffer from non-resolving inflammation, often in the oral cavity (J. Hahn et al., 2018). The importance of immobilizing and trapping of pathogens was further shown in NOX2 knockout mice, which fail to mount an oxidative burst and subsequently failed to trap and immobilize pathogens via NETs causing prolonged and enhance inflammation. We later used nanodiamonds, an inert material, to show the importance of NOX2 in the resolution of sterile inflammation (M. H. Biermann et al., 2016; J. Hahn et al., 2017). We then checked whether neutrophils could differentiate the nanodiamonds by size and thus react differently (Munoz et al., 2016). An overview to the scientific community of our findings was provided in our review (J. Hahn et al., 2016). In addition, we explored the influence of NETs on autoimmunity, focusing on their role in gout and systemic lupus erythematosus (SLE). A pristane lupus model was employed in Ncf1** mice, here we showed exacerbated disease and organ involvement due to no ROS dependent NET formation (Kienhöfer et al., 2017). Further, we observed that neutrophil densities are pivotal for resolving sterile inflammation in gout (J. Hahn et al., 2018). Our findings were then summarized for the scientific community in two reviews (Maueroder et al., 2015; Podolska, Biermann, Maueroder, Hahn, & Herrmann, 2015). We also checked if we can find other mechanistic defects in Ncf1** mice and were able to find an increased clearance of cellular debris into inflammatory phagocytes coupled with a defect in degradation, leading to a change of the extracellular milieu (Hahn et al., unpublished). The importance of the extracellular milieu was also evident in the formation of NETs, where we showed that the ratio of bicarbonate, CO2 and pH influence the formation of NETs; explaining the many controversial and opposing results in similar models (Maueroder et al., 2016). In summary, we could show that NOX2, NET formation and phagocytosis are responsible for the initiation and resolution of inflammation and autoimmunity.
In this systematic literature review, we update imaging modalities in gout, with a focus on newer technologies, particularly Dual-energy computed tomogra-phy (DECT). Conventional radiography (CR), ultrasonography (US), magnetic resonance imaging (MRI), computed tomography (CT) and dual-energy CT (DECT) have been used to evaluate different stages and clinical manifestations of gout and hyperuricaemia. We compare and contrast these modalities across the spectrum of this disease and of clinical scenarios and objectives (1).
Pour le diagnostic de chondrocalcinose la mise en évidence de cristaux de pyrophosphate de calcium peut être parfois difficile voire impossible pour de multiples raisons techniques. À l’heure actuelle, les radiographies articulaire à la recherche de liseré calcique de chondrocalcinose sont utilisées malgré une bonne spécificité mais une sensibilité médiocre. Le but de cette étude est d’évaluer la performance de l’échographie ostéo-articulaire dans le diagnostic du rhumatisme à pyrophosphate de calcium. MATÉRIEL ET MÉTHODES : Notre étude est prospective transversale de cohorte à but diagnostique bicentrique, chaque patient présentant une arthrite de genou a été inclus et a bénéficié d’une ponction articulaire, de radiographies bilatérales des genoux et d’une échographie ostéo-articulaire. Le diagnostic a été porté sur le résultat de l’analyse du liquide articulaire. RÉSULTATS : 78 patients ont été inclus : 22 chondrocalcinoses, 11 gouttes, 16 rhumatismes inflammatoires chroniques, 14 arthroses et 15 arthrite inclassées. 39 patients ont présentés des signes échographiques de chondrocalcinose dont 21 prouvées à la ponction articulaire. L’échographie ostéo-articulaire a une sensibilité de 95,4%, une spécificité de 65,8%, une VPP de 60% et une VPN de 96,4% pour le diagnostic de chondrocalcinose. Il n’a pas été observé de différence statistiquement significative entre échographie et radiographie concernant les sensibilités (p=0,219). Par ailleurs, l’analyse des ménisques des genoux en échographie est statistiquement le site le plus sensible pour la détection de la chondrocalcinose (p=0,006). CONCLUSION : L’échographie ostéo-articulaire et en particulier l’analyse des ménisques des genoux est un examen au moins aussi performant que la radiographie standard dans le diagnostic de la chondrocalcinose mais présente l’avantage d’être plus facile d’accès pour les rhumatologues, moins couteux et moins irradiant.
Objective:
To compare ultrasound-detected abnormalities, namely double contour sign (DCS) and hyperechoic aggregates (HAGs), at two sites (knee and first metatarsophalangeal [1st MTP] joints) versus six sites (knee joint, 1st MTP joint, radiocarpal joint, talar joint, patellar tendon and triceps tendon) in gout patients.
Methods:
Forty-seven clinically diagnosed gout patients and 50 subjects (serum uric acid < 7 mg/dL) as controls were included. DCS was looked for at three articular cartilage sites (first metatarsal, tibiotalar and femoral condyle), whereas HAGs were looked for at one joint site (radiocarpal joint) and two tendon sites (patellar tendon and triceps tendon). Ultrasound findings of both the groups were compared.
Results:
Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and positive likelihood ratio (LR) of two sites ultrasound findings for gout were 87.2%, 84%, 83.7%, 85.6% and 5.5 respectively. Similar sensitivity, specificity, PPV, NPV and positive LR were observed with six sites ultrasound findings. Among controls, 16% were found to have these abnormal ultrasound findings by both two sites and six sites examinations.
Conclusion:
Screening of two sites (knee and 1st MTP) has similar sensitivity, specificity, PPV, NPV and positive LR as compared to six sites in diagnosing gout.
Several milestones have marked the progress in the treatment of gout in the past quarter of a century. Our aims now are to understand more of the genesis of hyperuricemia, to prevent the development of symptomatic gout, to avoid its possible complications and to treat its associated diseases when present. It is the responsibility of the physician to decide when in the clinical course to intervene with the potent drugs at our disposal. Indiscriminate medication is definitely unwarranted. It is also the responsibility of the physician to educate and guide the patient in understanding the problems associated with this disease, so that both stand on the same front in search for further progress in this noble disease.
To determine the usefulness of computed tomography (CT), magnetic resonance imaging (MRI), and Doppler ultrasonography (US) in providing specific images of gouty tophi.
Four male patients with chronic gout with tophi affecting the knee joints (three cases) or the olecranon processes of the elbows (one case) were assessed. Crystallographic analyses of the synovial fluid or tissue aspirates of the areas of interest were made with polarising light microscopy, alizarin red staining, and x ray diffraction. CT was performed with a GE scanner, MR imaging was obtained with a 1.5 T Magneton (Siemens), and ultrasonography with colour Doppler was carried out by standard technique.
Crystallographic analyses showed monosodium urate (MSU) crystals in the specimens of the four patients; hydroxyapatite and calcium pyrophosphate dihydrate (CPPD) crystals were not found. A diffuse soft tissue thickening was seen on plain radiographs but no calcifications or ossifications of the tophi. CT disclosed lesions containing round and oval opacities, with a mean density of about 160 Hounsfield units (HU). With MRI, lesions were of low to intermediate signal intensity on T(1) and T(2) weighting. After contrast injection in two cases, enhancement of the tophus was seen in one. Colour Doppler US showed the tophi to be hypoechogenic with peripheral increase of the blood flow in three cases.
The MR and colour Doppler US images showed the tophi as masses surrounded by a hypervascular area, which cannot be considered as specific for gout. But on CT images, masses of about 160 HU density were clearly seen, which correspond to MSU crystal deposits.
The optimal serum urate levels necessary for elimination of tissue deposits of monosodium urate in patients with chronic gout is controversial. This observational, prospective study evaluates the relationship between serum urate levels during therapy and the velocity of reduction of tophi in patients with chronic tophaceous gout.
Sixty-three patients with crystal-confirmed tophaceous gout were treated with allopurinol, benzbromarone, or combined therapy to achieve serum uric acid levels less than the threshold for saturation of urate in tissues. The tophi targeted for evaluation during followup were the largest in diameter found during physical examination.
Patients taking benzbromarone alone or combined allopurinol and benzbromarone therapy achieved faster velocity of reduction of tophi than patients taking allopurinol alone. The velocity of tophi reduction was linearly related to the mean serum urate level during therapy. The lower the serum urate levels, the faster the velocity of tophi reduction.
Serum urate levels should be lowered enough to promote dissolution of urate deposits in patients with tophaceous gout. Allopurinol and benzbromarone are equally effective when optimal serum urate levels are achieved during therapy. Combined therapy may be useful in patients who do not show enough reduction in serum urate levels with single-drug therapy.
Tophi deposits are a well-known cause of joint destruction, gouty nephropathy and spinal cord compression. This study reports another major complication of gout, namely tophi deposition causing limited knee joint excursion.
Seven gout patients with limited knee joint excursion owing to tophi deposition were studied to reveal clinical features and magnetic resonance imaging (MRI) findings. None of the patients were able to assume a full squatting posture.
No patients had visible subcutaneous tophi over the knee joints, except for one case in which a pea-sized subcutaneous tophus was noted. Additionally, two patients even lacked visible tophi elsewhere. All knee problems in the study group were initially regarded as being due to degenerative or other internal derangements, but MRI unexpectedly revealed multiple tophaceous depositions within and around the joint.
Intra-articular and periarticular tophi limiting knee joint range of motion are a rare but important cause of walking disability in gout patients. Although most patients do not display visible subcutaneous tophi over the knee on physical examination, the differential diagnosis should consider intra-articular tophi and MRI is valuable in this clinical setting.
The effectiveness of long term uricosuric therapy was evaluated in sixty-four patients with primary gout. Serum uric acid was reduced to normal in half the patients; the majority manifested a urate diuresis. In seventeen of fifty patients with tophi, these lesions decreased in size. Acute gouty attacks were reduced to less than one per year in forty-five, patients; the chronic symptoms present in fifty-one patients improved in forty., Effectiveness of therapy was categorized as good, moderate, and poor, with examples of illustrative cases.
Esseva evalutate le efficacia de therapia uricosuric a longe vista in 64 patientes con gutta primari. Le nivello seral de acido uric esseva reducite al nonna in un medietate del patientes; le majoritate manifestava diurese de urato. In 17 ex 50 patientes con tophos, iste lesiones deveniva plus micre. In 45 patientes, le acute attaccos de gutta diminueva a minus que un per anno. Le symptomas chronic, presente in 51 patientes, se meliorava in 40. Le efficacia del therapia esseva classificate como bon, moderate, e non bon. Casos illustrative es citate.