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DETAILED DESCRIPTION OF TOPHUS MEASUREMENT TECHNIQUES
Counting the total number of subcutaneous tophi
Using this method, all palpable subcutaneous tophi over the entire body are counted by a
single observer (Figure 1A). This assessment can be undertaken by a clinical research
assistant who has had a short training session in this method. Ideally, this assessor should be
independent of all other aspects of the clinical trial and should perform the tophus counting at
each study visit. The total number of tophi is recorded in the case report form (CRF).
Change in tophus burden has been reported as percentage reduction in the number of
tophi.[1-3]
Tape measurement of subcutaneous tophus size
This method allows assessment of tophus area using a tape measure. Studies to date have
reported measurement of a single index tophus.[1, 3] Criteria for selection of the index
tophus are: >10mm in length and width, as nearly round as possible, location at the foot/ankle
or hand/wrist.[4] Reliability of tophus measurement at the elbow is poor and this site should
be avoided.[4] Draining or acutely inflamed tophi should also be avoided. A standard tape
measure is used to determine the distance between two pen marks that have been drawn on a
pre-defined length and width axis (perpendicular to one another) (Figure 1B). A ballpoint
pen is gently pressed to the skin in the first axis from both sides of the subcutaneous tophus
until movement is obstructed by the nodule. The distance between the two pen marks is then
measured over the top of the tophus to the nearest millimetre using the tape measure. This is
then repeated along the skin at a 90°angle along the second axis. Thus there are two numeric
measurements per tophus. The tophus area is then calculated by multiplying these two
measurements.[4, 5] This assessment can be undertaken by a clinical research assistant who
has had a short training session in this method. Ideally, this assessor should be independent
of all other aspects of the clinical trial and should perform the tophus measurement at each
study visit. The location of the index tophus is recorded in detail by both written anatomic
description and diagram at baseline, for reference at subsequent assessments. The site and
area of the index tophus is recorded in the CRF. Change in tophus size has been reported as
percentage change in index tophus area.[1, 3]
Vernier calipers for measurement of subcutaneous tophus size
This method involves measurement of the longest diameter of an index tophus. Serial
measurement of a single index tophus has been reported.[6] The largest tophus at baseline is
selected as the index tophus. Tophi affecting the elbow, draining tophi and actively inflamed
tophi should not be selected as the index tophus for assessment. The longest axis of the
tophus is identified by inspection. The borders of the tophus in this axis are then marked
using a ballpoint pen. The longest diameter is measured using 150 mm Vernier calipers
(Figure 1C).[6, 7] This assessment can be undertaken by a clinical research assistant who has
had a short training session in this method. Ideally, this assessor should be independent of all
other aspects of the clinical trial and should perform the tophus measurement at each study
visit. The location of the index tophus is recorded in detail by both written anatomic
description and diagram at baseline, for reference at subsequent assessments. The site and
longest diameter of the index tophus is recorded in the CRF. Change in tophus size can be
reported as change in tophus diameter, or velocity of tophus reduction.[6]
Digital photography for measurement of subcutaneous tophus size
The CAPER (Computer Assisted Photographic Evaluation in Rheumatology) method of
assessment has been developed to provide categorical and standardised scoring of
subcutaneous tophus response recorded by photographic imaging (Figure 2).[8] Specialised
software is required to standardise equipment, images and quality. Photographs are taken
using a calibrated camera and standardised template, which includes calibration rulers. The
following equipment is required: camera (calibrated and pre-set) and media card, light stand
and lights, pre-printed templates for placing hands and feet and pre-printed ruler labels. A
training manual and video for image acquisition is available.
At the baseline visit, photographs are taken of the hands and feet for all patients, regardless of
the presence of tophi, and up to two other anatomic locations with tophi. These are repeated
using the same views at all subsequent assessments. The study coordinator ensures that the
feet/hand are centered, that the ruler is present, and that the site/subject/exam date are visible.
Two to three photographs of each anatomical region are taken. Hard copy printouts of each
photograph are maintained by the investigational sites for consistency of positioning in
subsequent photographs.
Image analysis is done by a blinded central reader (rheumatologist). Tophi that are assessed
are categorized as “measured” and “unmeasured” based on the central reader’s assessment of
presence of distinguishable borders in the photographs. Criteria for measurable tophus
selection are: tophus ≥5mm in the longest dimensions and the presence of distinguishable
borders considered to be measurable. At baseline, up to five measureable tophi in the
photographs are chosen by the central reader for measurement over the course of the clinical
trial and up to two tophi that cannot be accurately measured (e.g., due to location, shape, or
other factors) can also be followed during the study as “unmeasured” tophi.
For measured tophi, analysis requires identification of the tophus margins and measurement
of the longest diameter and the longest perpendicular diameter using electronic calipers at the
tophus edges. Area is then calculated electronically. Change has been defined as: Complete
Response (100% decrease in tophus area from baseline), Marked Response (at least a 75%
decrease in tophus area from baseline), Partial Response (at least a 50% decrease in tophus
area from baseline), Stable Disease (neither a 50% decrease nor a 25% increase in tophus
area can be demonstrated) and Progressive Disease (25% or more increase in tophus area
from baseline).
Criteria for unmeasured tophus selection are: ≥ 10 mm at baseline in order for the reader to
reliably assess changes in size. Unmeasured tophi are semi-quantitatively assessed by the
central reader and defined as: Complete Response: disappearance of the tophus; Improved:
~50% or greater reduction from baseline; Stable Disease: neither improvement nor
progression from baseline; Progressive Disease: ~50% or more increase in the area of the
tophus.
Each subject is given a categorical “Overall Tophus Response” based on the best response
reported among all target tophi (measureable and unmeasured) for the subject, in absence of
progressive disease of any individual tophus or development of a new tophus. Overall Tophus
Response categories include: Complete Response, Partial Response (including Marked
Response and Improved), Stable Disease and Progressive Disease.
Ultrasonography (US) for measurement of tophus size
Tophi are identified on US as hypoechoic to hyperechoic inhomogeneous material
surrounded by a small anechoic rim.[9] A protocol for tophus diameter and volume
quantification in the knee and ankle has been described using a linear multifrequency probe
(5.5-12.5MHz).[10] This protocol involves measuring an index tophus in the longitudinal
and transverse axes of the joint in B-mode gray-scale using 7.5MHz frequency.
The large joints of the lower limb are optimal for tophus size assessment by US. Criteria for
selection of an index tophus are: longest diameter >5 mm, non-calcified and non-bursal. The
tophus margins are identified by the outer anechoic rim. The longest diameter and total
volume are measured (Figure 3).[10] Tophus volume is calculated by integrated software
using the maximal tophus diameters measured in the longitudinal and transverse axes (Figure
3).[10] Both subcutaneous and intra-articular tophi can be assessed using this method. A
radiologist or rheumatologist trained in musculoskeletal US is required for this method. This
assessor should be independent of all other aspects of the clinical trial and ideally, the same
assessor should perform tophus measurement at each study visit. The site, longest diameter
and volume for the index tophus are recorded in the CRF. Change in tophus size has been
reported as absolute change in tophus diameter and volume.[10]
Magnetic resonance imaging for measurement of tophus size
On MRI, tophi are identified as structures with an intermediate signal intensity appearance on
T1, but more variability on T2 weighted images.[11, 12] Gadolinium enhances the tophus at
its border. Although gadolinium enhancement improves detection of tophi, contrast is often
associated with artefact and is not necessary for quantification of tophus volume.[13] The
following protocol has been described for MRI quantification of tophus volume of the
hand/wrist, foot/ankle or elbow on a 1.5 Tesla MRI scanner employing commercially
available surface coils.[13]
Although pulse sequence parameters are standardised in all subjects, coil selection is tailored
to each subject depending on which site is examined. Dedicated extremity coils should be
used when possible. Imaging planes are standardised according to the orientation and location
of the tophus and are determined by the supervising radiologist. MRI sequences include the
following: two dimensional (2D) T1-weighted (TR/TE = 600/≤20) spin-echo, 2D T2weighted (TR/TE≥3000/>80) fast spin-echo with frequency-selective fat suppression and 3D
gradient-recalled acquisition in the steady state with radiofrequency spoiling (SPGR) (TR/TE
= 15–20/<10 with flip angle of 60 degrees). The 2D images are orientated in the long axis of
the extremity (i.e. coronal or sagittal), and the 3D images are orientated in the short axis (i.e.
axial). Slice thickness is 3 mm for 2D images and 1–1.5 mm for 3D images. The imaging
planes and slice thickness are documented at the first visit and repeated subsequently. An
MRI radiographer and a radiologist are required for this method.
A total volume measurement using MRI is obtained on unenhanced consecutive spin-echo
images by manually tracing the margins of the tophus using consecutive images (Figure
4).[13] Volume is then calculated using automated software. Measurement of longest tophus
diameter in the knee and ankle has also been reported using MRI.[10] Both subcutaneous
and intra-articular tophi can be assessed using MRI. The assessor should be blinded to all
other aspects of the clinical trial, and should complete the tophus measurements for each
study visit. The site and volume and/or longest tophus diameter of the index tophus are
recorded in the CRF. Change in tophus size can be reported as change in tophus diameter
and volume.
Conventional CT for measurement of tophus size
Conventional CT can be used to detect the presence of tophi in patients with gout.[14-16]
The mean (2 SD) Hounsfield units of tophi are typically 170 (30) by CT, with the density of
tophi ex vivo in the same range.[15] A protocol for CT assessment of tophus volume in the
hands/wrists and feet/ankles has been reported.[7] For scanning of the hands/wrists, the
scanning range is from the fingertips to 2 cm proximal to the radiocarpal joints in an axial
plane. The left and right hands are both imaged during the same acquisition. Patients are
positioned prone, shoulders in forward flexion, with the forearm and wrists forward of the
body in a neutral position. The palms are opposed and separated by a foam pad. For
scanning of the feet/ankles, the patients are positioned supine with the knees bent to 90
degrees and the feet dorsiflexed 45 degrees. Both feet are scanned together with the CT
gantry vertical. The range covered is from 5cm above the ankle joints to the ends of the toes.
The protocol for tophus volume assessment has been described using a 16-slice scanner;
acquisition at 16 x 0.75mm, reconstructed on a bone algorithm, 768 matrix, to 0.8mm slices
with a 0.4mm increment (kVp 140, 120 mAs/ slice). Additional reconstructions are done on
a soft tissue algorithm, 512 matrix, also to a 0.8mm slice with a 0.4mm increment. The
images are viewed as 0.8mm slices on a CT workstation and reconstructed to 3mm slices for
viewing on Picture Archiving Communication System (PACS). A CT radiographer and a
radiologist are required for this method.
CT tophus volume is assessed using the Surface Shaded Display 3D function on the CT
workstation (Figure 5). This function allows quantitative assessment of predefined tissues.
The central reader identifies up to three index tophi that are best visualised on the baseline
CT scan. The site of each index tophus is recorded in detail, and the same sites are assessed
at each subsequent scan. By drawing freehand around each region of interest (the tophus) on
the multiple two-dimensional slices, a three-dimensional tophus model with an estimated
volume is generated (Figure 5). Both subcutaneous and intra-articular tophi can be assessed
using this method. The assessor should be blinded to all other aspects of the clinical trial, and
should complete the tophus measurements for each study visit. Sites and tophus volume for
each index tophus are recorded in the CRF. Change in tophus size can be reported as change
in tophus volume.
Dual energy computed tomography for measurement of tophus volume
Tophus volume can be calculated by DECT, using a specific display algorithm that assigns
different colours to materials of different chemical composition (Figure 6).[17, 18] A
protocol has been described that colour codes urate as red based on its typical spectral dual
energy properties;[18] all peripheral joints (i.e. elbows, wrists, hands, knees, ankles and feet)
are imaged using a DECT scan. The following scanning parameters are used: tube A, 140
kV/55 mA; tube B, 80 kV/243 mA; and collimation 0.6 mm reconstructed to 0.75 mm thick
slices. The visualisation algorithm is further optimised (by changing values in the advanced
parameter definition table within the dual energy viewer) as needed. The scanning range for
the hands/wrists is from the fingertips to 5 cm proximal to the wrist joint in an axial plane.
The left and right hands should both be imaged during the same acquisition. The patient
should be positioned head-first in a prone position. The forearms and wrists are to be
positioned in front of the patient's head, with the hands in a neutral position on a radiolucent
sponge for support of the palms and digits. Palms should be placed with the dorsum facing
up, in a relaxed dorsiflexion position. The patient's head should be positioned on a pillow to
alleviate strain on the neck position. When scanning the feet/ankles, patients should be
positioned feet-first in a supine position, with the knees bent in approximately a 90 degree
position, with the feet in a firm plantarflexion position. A knee bolster is recommended to
support the position of the knees. The scan is acquired in a craniocaudal direction, starting
proximally 5 cm from the ankle joint to the toe tips. Both ankles and feet should be scanned
axially in one acquisition. A CT radiographer and radiologist are required for this method.
Using dedicated automated volume assessment software, volumes of tophus deposition can
be measured in the hands, wrists, elbows, feet, ankles and knees. These volumes are then
summed to obtain a total uric acid volume load. It has been reported that DECT of peripheral
regions shows excellent image quality, with poorer image quality noted in the trunk.[19] All
subcutaneous and intra-articular tophi within the scanned area can be assessed using this
method. The assessor should be blinded to all other aspects of the clinical trial, and should
complete the tophus measurements for each study visit. Total uric acid volume load is
recorded in the CRF. Change in tophus burden can be reported as change in total uric acid
volume load.
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