# Time-course of tophus resolution on Dual-energy CT and ultrasound after 24 months of a treat-to-target strategy: Results from GOUT-DECTUS study

Tristan Pascart, Pascal Richette, Valérie Bousson, Sébastien Ottaviani, Hang-Korng Ea, Frédéric Lioté, Augustin Latourte, Thomas Bardin, Jérémy Ora, Aurore Pacaud, et al.

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## To cite this version:

Tristan Pascart, Pascal Richette, Valérie Bousson, Sébastien Ottaviani, Hang-Korng Ea, et al. Time-course of tophus resolution on Dual-energy CT and ultrasound after 24 months of a treat-to-target strategy: Results from GOUT-DECTUS study. Joint Bone Spine, 2025, 92 (4), pp.105892. 10.1016/j.jbspin.2025.105892. hal-05105707

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Original article

# Time-course of tophus resolution on Dual-energy CT and ultrasound after 24 months of a treat-to-target strategy: Results from GOUT-DECTUS study

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Tristan Pascart<sup>a,*</sup>, Pascal Richette<sup>b</sup>, Valérie Bousson<sup>c</sup>, Sébastien Ottaviani<sup>d</sup>, Hang-Korng Ea<sup>b</sup>, Frédéric Lioté<sup>b, e</sup>, Augustin Latourte<sup>b</sup>, Thomas Bardin<sup>b, f</sup>, Jérémy Ora<sup>b</sup>, Aurore Pacaud<sup>a</sup>, Marie Vandecandelaere<sup>a</sup>, Hélène Luraschi<sup>a</sup>, Charlotte Jauffret<sup>a</sup>, Victor Laurent<sup>a</sup>, Mathilde Boissel<sup>g</sup>, Laurène Norberciak<sup>g</sup>, Julie Legrand<sup>h</sup>, Guillaume Lefevre<sup>h</sup>, Vincent Ducoulombier<sup>a</sup>, Jean-François Budzik<sup>h</sup>

## ARTICLE INFO

**Article history:**
Accepted 20 March 2025
Available online 24 March 2025

**Keywords:**
Gout
Ultrasound
Dual-energy computed tomography
Monosodium urate

## ABSTRACT

**Objectives:** The main objective of the study was to evaluate the kinetics of tophus volume measured with dual-energy CT (DECT) and ultrasound (US) in patients with gout during their first 24 months of treat-to-target (T2T) urate-lowering therapy.

**Methods:** This was a prospective, multicenter, 24-month longitudinal pilot study including ULT-naïve patients with gout and US tophi. Clinical visits, and DECT and US scans of the knees and feet were performed at baseline, 6, 12 and 24 months. The largest tophus identified by US was chosen as the index tophus. The primary outcome was the change in the absolute volume and relative change from baseline of the tophus index volume measured with US and with DECT at all timepoints, with their correlation assessed by the Spearman correlation coefficient (ρ).

**Results:** A total of 55 patients (63.1 (12.3) years old, predominantly male (47/55 [85.5%]), with baseline serum urate levels of 8.73 mg/dL [7.93; 9.52] were included. Index tophus volume measured with US changed from median [inter-quartile range] 0.61 cm³ [0.30; 1.20] at baseline to 0.07 cm³ [0; 0.50] at month 24, and with DECT from 0.1 cm³ [0; 0.63] at baseline to 0 cm³ [0; 0] at month 24. Relative changes in index tophus volume measured with US and DECT were respectively -56% [-90; 0] and -96% [-100; -34] at M6, -84% [-100; -13] and -100% [-100; -89] at M12, and -96% [-100; -72] and -100% [-100; -100] at M24. The correlation for relative tophus volume change was weak at month 6 (ρ = 0.39 [0.01; 0.74]) and moderate at months 12 (ρ = 0.43 [-0.14; 0.82]) and 24 (ρ = 0.42 [-0.01; 0.73]).

**Conclusion:** Complete tophus resolution is obtained at 24 months of T2T in DECT but not in US, which provided a greater variability of volumetric assessments throughout follow-up.

© 2025 The Author(s). Published by Elsevier Masson SAS on behalf of Sociótó Franóaise de Rhumatologie. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)).

<footnote><sup>a</sup> Department of Rheumatology, Lille Catholic University, Saint-Philibert Hospital, ETHICS laboratory, EA 7446, Lille, France</footnote>

<footnote><sup>b</sup> Department of Rheumatology, Centre Viggo Petersen, Lariboisière Hospital AP-HP.Nord, Inserm, UMR 1132 Bioscar, Inserm, Université Paris Cité, Paris, France</footnote>

<footnote><sup>c</sup> Department of Musculoskeletal Radiology, Lariboisière Hospital, UMR 7052 CNRS, Université Paris Cité, Paris, France</footnote>

<footnote><sup>d</sup> Department of Rheumatology, Bichat-Claude Bernard Hospital, AP-HP, Université Paris Cité, Paris, France</footnote>

<footnote><sup>e</sup> Department of Rheumatology, Institut Arthur Vernes, Paris, France</footnote>

<footnote><sup>f</sup> Institut Mutualiste Montsouris, Paris, France</footnote>

<footnote><sup>g</sup> Department of Research Methodology and Biostatistics, Lille Catholic University, Saint-Philibert Hospital, Lille, France</footnote>

<footnote><sup>h</sup> Department of Medical Imaging, Lille Catholic University, Saint-Philibert Hospital, ETHICS laboratory, EA 7446, Lille, France</footnote>

<footnote>* Corresponding author. Service de Rhumatologie, Hôpital Saint-Philibert, rue du Grand But, 59160 Lomme, France.
E-mail address: pascart.tristan@ghicl.net (T. Pascart).</footnote>
# 1. Introduction

Gout is caused by the deposition of monosodium urate (MSU) crystals after prolonged hyperuricemia, and is the most common cause of inflammatory arthritis worldwide [1]. Gout flares, chronic arthritis, tophus formation and eventually erosive gout, are caused by the inflammatory response to these MSU crystal deposits [2]. The aim of gout management is to obtain complete dissolution of MSU crystals using urate-lowering therapy (ULT), which will allow for flare-free gout remission [3-8]. MSU crystal dissolution is achieved chemically by decreasing serum urate (SU) levels below the saturation point of urate (i.e. at least below 6.0 mg/dL as per all international or national guidelines [3,9-11]) with treat-to-target (T2T) urate-lowering therapy (ULT) [1,12]. As remaining MSU deposits, and not SU levels themselves, are the drivers of the risk of flares, their monitoring is key in the management of gout [5,13,14]. With this in mind, imaging holds a central role as it can identify and quantify MSU deposits inside joints and surrounding tissues, which cannot be done by clinical examination alone [13].

Ultrasound (US) is increasingly considered by rheumatologists as an extension of their clinical examination, and has proven able to detect MSU deposits on the cartilage surface (known as the double-contour (DC) sign) and tophi [15]. Dual-energy computed tomography (DECT) is a useful tool for the discrimination of urate, bone and soft-tissue, and provides direct measurement of significant MSU crystal deposits [16]. The technique is fully recognized in a diagnostic setting as it can identify and quantify MSU crystal deposits, whether or not organized as tophi, in tissues around the joints [13,17,18].

Cross-sectional comparisons of the diagnostic performances of US and DECT have been explored, and suggested that the techniques have a different sensitivity and specificity for identifying elementary gout lesions, which differ from one technique to the other [16,19]. The only elementary lesion they have in common is tophus. However, the two techniques provide different assessments of tophi: while DECT identifies only its crystal components, US observes the tophus as a whole including both its crystal core and the surrounding granulomatous-like crown of macrophages [16,20]. US elementary lesion scores are commonly used to provide semi-quantitative assessments of MSU crystal burden, and when assessed, tophus size is usually appreciated in two dimensions by the largest diameter of the usually ellipsoid tophaceous lesions [6,21,22]. DECT, on the contrary, provides a direct volumetric measurement of tophus volume. A preliminary cross-sectional study showed that the techniques did not provide the same measurement of tophus volume, with DECT providing smaller volumes of individual tophi than US [23]. Both US and DECT have been studied separately for the monitoring of MSU crystal deposit dissolution and elementary gout lesion resolution, and their potential clinical implications, particularly for the risk of flares, the pace of crystal dissolution according to SU levels and structural changes [6,7,21,22,24-29]. Yet the kinetics of the change in individual tophi volume, the hallmark elementary lesion in gout, with US and DECT has never been studied and compared, and it is not known how individual tophus volume measured with the two techniques changes during T2T.

The main objective of the study was to examine the kinetics of tophus volume measured with DECT and US in patients with gout during their first 24 months of T2T ULT.

# 2. Methods

## 2.1. Study design and participants

The GOUT-DECTUS study was a prospective, interventional, 24-month longitudinal pilot study including ULT-naïve patients with

gout carried out in three French centers. Clinical visits, and DECT and US scans of the knees and feet (within 21 days maximum), were planned at baseline, 6, 12 and 24 months. Demographic data, gout history including number of flares during the past 6 months, ongoing treatments, and SU levels were collected at each visit.

The inclusion criteria were ages 18-80 years, a diagnosis of gout based on the 2015 ACR/EULAR criteria [30], SU level ≥ 6.0 mg/dL (360 µmol/L), no use of ULT over the past year, the need for ULT initiation according to the 2012 ACR or 2016 EULAR recommendations with a treat-to-target objective of obtaining an SU level below 6.0 mg/dL [9,31], and at least one tophus in the knees or feet detected with US.

The protocol was approved by the French IRB (Comité de Protection des Personnes Nord-Ouest IV number 17/38) and registered as 2017-A00802-51 (IDRCB number). All participants provided informed written consent. The study complied with the MR001 reference methodology of the French Data Protection Authority (CNIL).

## 2.2. Ultrasound acquisition and scanning protocol

Examinations were performed by trained musculoskeletal radiologists (n=3) or rheumatologists (n=2) (with 5-20 years of experience) on an Applio 400 US machine (Toshiba Medical Systems, Tochigi, Japan). High frequency probes were used: 12 Mhz probe for knee examinations and 18 MHz probe for ankle and foot examinations. US examination for the DC sign and tophi as defined by the OMERACT was performed on the patellofemoral joints, talocrural joints and 1st metatarsophalangeal joints [32]. The largest tophus was chosen as the index tophus. Volume was calculated with the integrated software in the US machine using the maximal longitudinal diameter of the tophus and 2 perpendicular transversal (coronal and sagittal) diameters [33], using the formulae applied to ellipsoid shapes: $4/3 \times \pi \times A \times B \times C$, where A, B, and C are the semi-axis lengths. The DC sign score was defined as the number of joints with a positive DC sign out of the 6 joints scanned.

## 2.3. DECT acquisition and image analysis

All scans were performed using single-source CTs, Somatom Definition Edge; Siemens, Erlangen, Germany in Lille, and Aquilion Prime, Canon Medical Systems in Paris [34,35]. Knees and feet were scanned axially in two separate acquisitions performed consecutively on the same day. All scans were performed with the same image protocol, acquiring two scans with tube potentials of 80 kV and 140 kV (Siemens), or 80 and 135 kV (Canon) for each body part.

Dedicated software (syngo.via VB10B, syngo Dual Energy Gout; Siemens and Dual-Energy Image View, Canon Medical Systems) was used for DECT post-processing, using “gout” default settings. Post-processing images were analyzed by an MSK radiologist (JFB) and a rheumatologist (TP), both experienced in DECT readings on the Siemens machine, and by an experienced MSK radiologist on the Canon machines (VB). A double reading was performed to ascertain the good reproducibility of the analysis already demonstrated (data not shown) [23]. Firstly, volume-rendered 3D images in which urate crystal deposits coded in green (Siemens) or red (Canon) of the knees and feet were measured. Secondly, the index tophus identified on US was manually encompassed on 3D images, by excluding all surrounding tissues, thereby automatically providing the volume of the crystal component of the tophus.
<figure><img src="image_6.png" /><figcaption>**Fig. 1.** Study flow chart. DECT: dual-energy computed tomography.</figcaption></figure>

## 2.4. Outcomes

The primary outcome was the change in the absolute volume and the relative change from baseline in the index of tophus volume measured with US and with DECT throughout month 24.

Secondary outcomes throughout month 24 included the number of flares over the previous 6 months, the SU level, the number of scanned joints (6) with the US DC sign, the change in volume of the index tophus measured with US and with DECT, the overall volume of MSU deposits measured with DECT in the knees and feet and its relative change.

## 2.5. Statistical analysis

Data exploration and statistical analysis were conducted using the R programming language (R version 4.3.0).

The analyzed population is comprised of individuals for whom the presence of ultrasound tophus was observed at the inclusion visit and who do not have outliers between relative changes in US and DECT volumes (outliers defined by their ratio > 100).

Descriptive analysis provided means and standard deviations for normally distributed quantitative variables, and medians and interquartile ranges [Q1; Q3] for non-normally distributed quantitative variables. The normality of the data was verified using the Shapiro-Wilk test. Counts and frequencies are presented for qualitative variables. Longitudinal descriptions of the clinical and biological secondary outcomes were provided for each visit (0, 6, 12, and 24 months), where applicable.

In the analysis of the primary endpoint of tophus volume measurement with DECT and US, the absolute changes were calculated at each visit M (for month) as the difference in volume compared to baseline ("M0"). The relative changes were also calculated at each visit M as the division of the current volume by the one at baseline

("M0"). Spearman correlation coefficients (denoted ρ) and their 95% confidence interval (95%CI) were calculated to evaluate the correlation between the changes at 6, 12, and 24 months of treatment for tophus volume measured by US and DECT, in patients having had both assessments. The Spearman method was chosen as the data were not normally distributed. The correlation was considered very good if the absolute value of the coefficient (|ρ|) was strictly greater than 0.8; good if |ρ| was between 0.61 and 0.8; moderate if |ρ| was between 0.41 and 0.6; and weak otherwise. A sensitivity analysis was performed including only participants with index tophi detectable with DECT (i.e. DECT index tophus volume > 0 cm³ at the baseline visit).

The same method was considered to analyze the correlation between the DECT MSU volume and the overall US DC sign count for each visit, because of the discreet nature of the global US DC sign count. The correlation coefficients between the relative changes in these two measures were also calculated with the Spearman method.

# 3. Results

## 3.1. Patients

Between August 2017 and August 2019, *n* = 60 patients were included at the baseline clinical visit, four of whom were excluded in the absence of US tophus at baseline, and one patient was removed as different tophi were assessed during follow-up; *n* = 55 participants composed our analyzed population, with 37, 35 and 29 attending months 6, 12 and 24 clinical visits, respectively (Fig. 1). Both US and DECT scans were performed as planned in 37, 22, 16 and 20 participants, at baseline, month 6, 12 and 24, respectively. Patients were aged (mean [SD]) 63.1 (12.3) years old and were predominantly male (47/55 [85.5%]) (Table 1). Participants
<table><caption>**Table 1**
Participants' characteristics.</caption><thead><tr><th>Characteristics</th><th>Participants (n = 55)</th></tr></thead><tbody><tr><td><strong>Demographics</strong></td><td></td></tr><tr><td>Age, mean (SD) (years)</td><td>63.1 (12.3)</td></tr><tr><td>Men, n (%)</td><td>47 (85.5)</td></tr><tr><td>Body Mass Index, median [IQR] (kg/m²)</td><td>28.1 [25.9; 31.9]</td></tr><tr><td><strong>Gout characteristics</strong></td><td></td></tr><tr><td>Family history of gout, n (%)</td><td>17 (31.5)</td></tr><tr><td>Duration since gout diagnosis, mean (SD) (years)</td><td>7.3 (8.8)</td></tr><tr><td>Crystal-proven gout on SFA, n (%)</td><td>20 (39.2)</td></tr><tr><td>Number of flares over past 6 months, median</td><td>2 [1; 4]</td></tr><tr><td><strong>[IQR]</strong></td><td></td></tr><tr><td>Subcutaneous tophi, n (%)</td><td>32 (58.2)</td></tr><tr><td>Erosive gout, n (%)</td><td>16 (34.8)</td></tr><tr><td>Urate-lowering therapy initiated after baseline</td><td></td></tr><tr><td>Allopurinol</td><td>37 (69.8)</td></tr><tr><td>Febuxostat</td><td>14 (26.9)</td></tr><tr><td>Benzbromarone</td><td>2 (3.8)</td></tr><tr><td><strong>Comorbidities</strong></td><td></td></tr><tr><td>Myocardial infarction, n (%)</td><td>8 (18.6)</td></tr><tr><td>Stroke, n (%)</td><td>2 (4.7)</td></tr><tr><td>Peripheral artery disease, n (%)</td><td>3 (7.0)</td></tr><tr><td>Type 2 diabetes, n (%)</td><td>10 (23.3)</td></tr><tr><td>Dyslipidemia, n (%)</td><td>26 (60.5)</td></tr><tr><td>Hypertension, n (%)</td><td>39 (90.7)</td></tr><tr><td>Urolithiasis, n (%)</td><td>10 (18.1%)</td></tr><tr><td><strong>Biology</strong></td><td></td></tr><tr><td>Serum urate level, median [IQR], mg/dL</td><td>8.73 [7.93; 9.52]</td></tr><tr><td>eGFR, mean (SD) (mL/min/1.73 m²)</td><td>71.07 (22.7)</td></tr><tr><td><strong>Imaging</strong></td><td></td></tr><tr><td>Double contour sign score (/6), median [IQR]</td><td>2 [0.5; 2]</td></tr><tr><td>Presence of US tophi in the feet, n (%)</td><td>44 (86.3)</td></tr><tr><td>Presence of US tophi in the knees, n (%)</td><td>17 (34)</td></tr><tr><td>Ultrasound volume of index tophus, median [IQR] (cm³)</td><td>0.61 [0.3; 1.2]</td></tr><tr><td>DECT volume of index tophus, median [IQR] (cm³)</td><td>0.1 [0; 0.463]</td></tr><tr><td>DECT volume of MSU deposition in the feet, median [IQR]</td><td>0.51 [0.09; 2.13]</td></tr><tr><td>DECT volume of MSU deposition in the knees, median [IQR]</td><td>0.1 [0.04; 1]</td></tr></tbody></table>

SD: standard deviation; [IQR]: Q1–Q3 interquartile range; SFA: synovial fluid analysis; eGFR: estimated glomerular filtration rate (CKD-EPI); US: ultrasound; DECT: dual-energy computed tomography; MSU: monosodium urate.

had baseline SU levels of 8.73 mg/dL [7.93; 9.52] and 32/55 (58.2%) had clinically palpable subcutaneous tophi.

The index tophus was localized at the first MTP joint in 31/54 (57.4%) participants, in knee tendons/ligaments in 11/54 (20.3%), and on the tarsi in 6/54 (11.1%) cases, and localization was not specified in one participant. Overall, 44/51 (86.3%) participants had US tophi in the feet, and 17/50 (34%) in the knees. Index tophi were not detected by DECT in 12/37 (32.4%) participants at baseline. Index tophi not seen on DECT were localized at the MTP1 joint (10/12) and the in knee collateral ligaments (2/12). Their size was slightly smaller than the average volume of US tophi (0.56 cm³ [0.32; 0.71] vs 0.61 cm³ [0.3; 1.2]), and they were associated with a lower prevalence of the DC sign at baseline than the average of the cohort (48% vs 63% of MTP1 joints, 23% vs 28% of talocrural joints, and 9% vs 33% of knees).

## 3.2. Comparison of kinetics of index tophus volume in US and DECT

Median index tophus volume measured with US changed from 0.61 cm³ [0.30; 1.20] at baseline to 0.07 cm³ [0; 0.50] at month 24, and with DECT from 0.1 cm³ [0; 0.46] at baseline to 0 cm³ [0; 0] at month 24. Relative changes in index tophus volume measured with US and DECT were respectively −56% [−90; 0] and −96% [−100; −34] at M6, −84% [−100; −13] and −100% [−100; −89] at M12, and −96% [−100; −72] and −100% [−100; −100] at M24 (Fig. 2).

An example of the changes in an index tophus in US and DECT, and overall MSU deposition observed in DECT in a single patient is presented in Fig. 3.

The correlation of US and DECT in the assessment of the absolute index tophus volume change was weak at all timepoints, with a Spearman correlation coefficient of 0.12 [−0.34; 0.60] at month 6, 0.23 [−0.32; 0.76] at month 12, and 0.33 [−0.22; 0.72] at month 24, respectively (Fig. 4A, B and C). The correlation in the assessment of the relative tophus volume change was weak at month 6 (ρ = 0.39 [0.01; 0.74]) and moderate at months 12 (ρ = 0.43 [−0.14; 0.82]) and 24 (ρ = 0.42 [−0.01; 0.73]) (Fig. 4D, E and F).

When considering participants (n = 24) with an index tophus having a DECT volume of over 0 cm³ at baseline, the baseline volumes of index tophi measured were larger with US than DECT (1.15 cm³ [0.44; 3.76] versus 0.27 cm³ [0.10; 1.30]), and decreased more rapidly with DECT at months 6 and 12 (0.16 cm³ [0.02; 0.29] and 0.02 cm³ [0.005; 0.18]) than US (1.38 cm³ [0.21; 2.30] and 0.42 cm³ [0.10; 1.78]), and by month 24 were undetectable in DECT (0 cm³ [0; 0.01]) while they were still well identified with US (0.22 cm³ [0.07; 1.81]) (Fig. 5). For these 24 patients with detectable index tophi with DECT, the correlation between US and DECT for the assessment of relative tophus volume change was moderate at all timepoints (Fig. 5). Absolute changes in tophus volume were weak at months 6 and 12, and moderate at month 24.

## 3.3. Changes in clinical manifestations, SU levels, and other imaging evidence of MSU deposition during follow-up

At month 24, 16/28 (57.1%) and 12/28 (42.9%) patients were treated with allopurinol (mean dose 341 mg/day) and febuxostat (mean dose 77 mg/day) respectively, all patients had an SU level below the target of <6.0 mg/dL and 25/29 patients (86.2%) had not flared over the past 6 months (Fig. 2).

Volumes of MSU deposition measured with DECT changed from 0.1 cm³ [0.04; 0.1] and 0.51 cm³ [0.085; 2.125] at baseline in the knees and feet respectively to 0.01 cm³ [0; 0.04] and 0.05 cm³ [0.01; 0.085] at month 24. The DC sign was present in 100/306 (32.7%) joints at baseline, mostly in the 1st MTP joints (61/105 (58.1%), and 15/170 (8.82%) at month 24, mostly in the 1st MTP joints (9/58 [15.5%]) (Fig. 2).

## 3.4. Correlation between the US DC sign and DECT volume of MSU deposition and their changes

The correlation between the US DC count and the MSU volume measured with DECT in the knees and feet at each visit (Fig. 2) was moderate at baseline (ρ = 0.47 [0.11; 0.71]), poor at month 6 (ρ = 0.24 [−0.26; 0.69]), moderate at month 12 (ρ = 0.46 [−0.12; 0.87]) and good at month 24 (ρ = 0.64 [0.37; 0.84]).

The correlation between the relative change in the US DC count and the overall DECT volume of MSU deposition was weak at all timepoints: ρ = 0.33 [−0.23; 0.75] at month 6, ρ = 0.18 [−0.44; 0.72] at month 12, and ρ = 0.25 [−0.17; 0.67] at month 24.

# 4. Discussion

The study provides the first parallel assessment of changes in individual tophi volume measured with DECT and US over the first two years of T2T ULT. The study demonstrates that the tophi's crystal core dissolution has, most of the time, occurred by month 12, while the volume of the general tophaceous structure measured with US disappears unevenly and can still be detected by month 24 in 51.7% of cases. The discrepancy in the sensitivity to change in tophus volume between DECT and US was further confirmed by the overall poor to (at best) moderate correlations in tophus volume change throughout follow-up. Assessing relative change in tophus
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**Fig. 2.** Changes in biological (serum urate levels) (A), clinical (number of flares over previous 6 months) (B) and imaging features (absolute index tophus volume in ultrasound (US) (C) and dual-energy computed tomography (DECT) (D), relative change in index tophus volume in US (E) and DECT (F), US double contour score (0–6) (G), global volume measured with DECT of monosodium urate (MSU) crystal deposition in the knees and feet combined [H]) at all timepoints (baseline, months 6, 12 and 24). Values are represented as medians and [Q1; Q3] interquartile ranges.
<figure><img src="image_15.png" /><figcaption>**Fig. 3.** 24-month follow-up of the monosodium urate (MSU) burden assessed with ultrasonography (US) and dual-energy computed tomography (DECT) in a 76 year-old woman with gout initiating treatment with allopurinol. Images of the change in the index tophus volume measured with US (panels A, B, C and D) and DECT (panels E, F, G and H) are shown for each timepoint (baseline, 6, 12 and 24 months). The overall volume of MSU measured with DECT in the feet at each timepoint is shown in panels I, J, K and L.</figcaption></figure>

volume rather than absolute change seemed to slightly improve the correlation between the two techniques but the small sample size available during the follow up (about 20 patients or less depending on the visit) limits the scope of our conclusion. The dissolution of intra-articular MSU deposits according to US (DC sign) and extra-articular MSU deposits according to DECT (absolute overall volume change) observed similar courses at 1 and 2 years. Both techniques demonstrated significant, often total, MSU crystal dissolution during the course of the first two years of treat-to-target ULT, which also paralleled the decrease in occurrence of gout flares, which were absent in the 18–24 month period.

The inconsistency between the two techniques, and the apparent higher variability of US, is probably explained by the fact that US and DECT measure different lesions, particularly in the case of tophi, and are therefore difficult to compare. Tophi are composed of a central core of MSU crystal aggregation, surrounded by an inflammatory crown of mononuclear cells [20]. In essence, while DECT captures the chemical presence of crystals inside the core of the tophus alone, US observes the whole structure of the tophus, which explains why the US volume is higher than the DECT volume in cross-sectional assessments [23]. Around a third of US index tophi were not detected with DECT, maybe in part because some appearances at the MTP1 joint may trick readers in thinking they are tophi (almost 20% of MTP1 joints had persistent tophi at month 24), but most likely because the crystal load was too low for DECT to detect (lower prevalence of the DC sign). This also certainly explains why we observed a more rapid relative change in tophus volume with DECT than with US, as the chemical dissolution of MSU crystals (disappearance in DECT) is the first step before the granulomatous-like local response disappears (disappearance in US), as was evidenced in a selection of 32 patients from a trial with allopurinol, who exhibited a 70.6% DECT volume reduction in index tophus MSU volume while the soft tissue content of the tophi only decreased by 37.8% (*P* < 0.001) over the same time period [36]. In the NOR-GOUT study including ULT-naïve patients receiving a treat-to-target strategy and with sequential US semi-quantitative assessment of elementary gout lesions including tophi, 92.9% of the 207 patients at baseline had at least one US tophus, while the 187/207 reassessed at month 12 still had detectable US tophi in 80.2% of cases [21]. In the meantime, the same patients underwent DECT scans at baseline, 1

and 2 years, and showed that the mean (SD) score of MSU deposition at baseline of 4.6 (6.4) (out of a maximum of 12), changed to 2.8 (4.7) at 1 year (*P* < 0.01) and 1.5 (3.2) (*P* < 0.001) at 2 years, with the limitation of having used only a semi-quantitative score which did not reflect directly the remaining volume of deposition [24]. The techniques provided more consistent and comparable information when considering the DC sign (which only depicts MSU crystals) and overall DECT MSU deposition.

Measuring individual tophus volume with US and its sensitivity to change may not be reliable. US was less consistent in the assessment of tophus volume throughout follow-up, suggesting that its measurement should not be used. To date, individual tophus measurement has rarely been done, but this inconsistency was also shown in the USEFUL study, which also included ULT-naïve patients, with baseline, month 3 and month 6 US scans. Tophus size was measured in two dimensions, taking the largest axis of the lesion as the reference for follow-up [6,22]. At 6 months, the relative change in tophus size ranged from −87.5% to −36.3% in participants with SU levels below 5.0 mg/dL [22]. Similarly, tophus size in a 12-month follow-up with US and MRI only showed faire agreement in a study including 25 participants [33]. A small monocenter study including 11 patients monitored the volume of index tophi over time, and also had a vast range of relative tophus volume changes, from 50 to 100% at all timepoints. Volume calculation requires the measurement of 3 axes, multiplying exponentially the limitations of reproducibility of the measurements of a single axis [22].

Significant baseline volumes of MSU deposition are required to monitor their dissolution with DECT. The first studies measuring MSU crystal depletion by DECT in patients taking conventional ULT produced disappointing results, with only very partial crystal depletion at 18 and 24 months and over 50% persistence of baseline deposits, even as participants had reached the therapeutic target of SU levels < 6.0 mg/dL [25,26]. However, these studies included patients with very small MSU deposits detected with DECT, as overall volumes were very small (< 0.1 cm³) with a difficult-to-measure sensitivity to change [25]. In groups of patients with more significant deposits at baseline, the change in MSU crystal volume measured with DECT was more substantial in quantitative [36] and semi-quantitative [24] assessments of patients managed with a
<figure><img src="image_16.png" /><figcaption>**Fig. 4.** Correlation of ultrasound (US) and dual-energy computed tomography (DECT) assessment of the absolute (panels A, B and C) (in cm³) and relative (panels D, E and F) (in %) index tophus volume changes throughout the 2-year follow-up after urate-lowering therapy initiation in patients with gout.</figcaption></figure>

treat-to-target ULT approach. In addition, only significant volumes (at least ≥ 0.1 cm³) of MSU deposition measured with DECT have a prognostic value in terms of flare prediction, cardiovascular risk and mortality [34,37–40]. In addition, as pointed out by the 2023 EULAR recommendations on the imaging of crystal-induced arthropathies, “smaller tophi in gout, or crystal aggregates or crystal deposits in cartilage may not necessarily lead to clinical manifestations and are seen as asymptomatic MSU crystal deposition”, which suggest we should not bother measuring them, and even less monitoring them [13]. In our study, taking into account overall MSU deposition in the knees and feet provided more comprehensive information on MSU crystal debulking than using index tophi identified with US which were sometimes barely observed in DECT.

We acknowledge study limitations. One of the initial secondary objectives was to determine whether the brand of DECT machines influenced the correlation with US tophus assessment. A defect

in acquisition settings in a center with a Canon machine, and a higher than expected number of lost-to-follow-ups led to an insufficient number of patients for this analysis (95%CI of Spearman correlation coefficient is wide). The number of participants lost-to-follow up and the number of index tophi detected with DECT (DECT baseline index volume ≠ 0) require caution when interpreting the sub-analysis, including participants with DECT volumes of index tophi ≥ 0 cm³ at baseline, performed on an even smaller sample size (between 10 and 14 patients depending on the visit). We did not perform an intra- and inter-reader reliability exercise of tophus volume measurement with US, but using the same measurements the exercise had been done in a prior Spanish study, showing good reliabilities [33]. Finally, the OMERACT experts have agreed on a semi-quantitative scoring system for US gout lesions since our study was designed, which we could not implement in the present study which was half-way through when they were pub-
<figure><img src="image_17.png" /></figure>

<figure><img src="image_18.png" /></figure>

**Fig. 5.** Changes in tophus volume according to ultrasound (US) and dual-energy computed tomography (DECT), in tophi with a baseline DECT volume > 0 cm³. Changes in the absolute volume of the index tophus measured with US and DECT, and of the largest tophus observed in DECT at each timepoint are presented in panel A, and relative volume changes in the index tophi measured with US and DECT are presented in panel B. Values are represented as medians and [Q1; Q3] interquartile ranges. For each timepoint, the Spearman correlation coefficient ρ of the correlation between US and DECT is provided.

lished. We had already shown that inter-reader reliability of the measurement of index tophi with DECT was good using the same methodology in our previous cross-sectional study [23].

This first study of repeated quantitative assessment of gout lesions with both US and DECT shows that the techniques provide different information on tophus resolution and MSU crystal depletion during T2T. They poorly correlate on the change in tophus volume, with DECT demonstrating a more rapid dissolution of its crystal core than US assessing the whole tophaceous structure. The study suggests that monitoring individual tophus volume in US is unreliable, and semi-quantitative assessment of gout lesions may be a more appropriate outcome in US [41]. The correlation between the two techniques is higher when elementary lesions composed exclusively of crystals are compared, i.e. the US DC sign and DECT overall MSU deposition, whose resolution is generally obtained after one year of T2T. Further studies are needed to develop which quantitative thresholds of elementary gout lesions should be considered as treatment responses for US and DECT separately, specifically for each imaging technique.

## Data availability

Summary statistics can be requested by researchers for use in independent scientific research and will be provided following review and approval of the research proposal (including the statistical analysis plan) and completion of a data sharing agreement with the Lille Catholic University Hospitals. Data requests can be made anytime from 9 months after the publication of this study for up to 5 years (extendable). Requests should be sent to the corresponding author.

## Funding/support

The DECTUS study has received funding from Horizon Pharmaceutical and the Lille Catholic Hospitals.

## Author contributions

TP, PR, TB, VB, SO, JFB, LN: study conception and design, development of study protocol. TP, MB, LN, JFB: review of statistical analyses; TP, PR, VB, SO, HKE, FL, TB, AL, AP, MV, HL, VL, CJ, JL, GL, JO, VD, JFB: data collection; TP: writing the first draft of the manuscript; PR, VB, SO, HKE, FL, TB, AL, AP, MV, HL, VL, CJ, JL, JO, GL, VD, MB, LN, JFB: critical revisions and submission of the manuscript, approval of the final manuscript version.

## Disclosure of interest

TP has received research support from Horizon Pharmaceuticals and Novartis; personal speaker and advisory fees from Novartis. PR received consulting fees from Horizon Therapeutics. VB receive funding for an ongoing research project by Canon outside this work. HKE receives funding for an ongoing research project by Canon outside this work. FL has received personal speaker and advisory board fees from SOBI, and unrestricted education funding from Horizon Pharmaceuticals, AMGEN, SOBI, Fresenius-Kabi for annual European Crystal network workshops. AL received funding for an ongoing research project by Fresenius Kabi. TB, SO, AP, MV, HL, CJ, VL, MB, LN, JL, GL, VD, and JFB declare that they have no competing interest.

## Acknowledgements

We thank Horizon Pharmaceuticals (formerly)/AMGEN and Dr. Brian LaMoreaux for their support of this investigator-initiated study. We thank Mrs. Plets for her support in establishing the protocol. We thank Mr. Charles Herman for his technical support with DECT scans.

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