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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. REFERENCES [1] Becker MA, Schumacher HR, Jr., Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353(23):2450-61. [2] Schumacher HR, Jr., Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum. 2008;59(11):1540-8. [3] Becker MA, Schumacher HR, MacDonald PA, et al. Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout. J Rheumatol. 2009;36(6):1273-82. [4] Schumacher HR, Jr., Becker MA, Palo WA, et al. Tophaceous gout: quantitative evaluation by direct physical measurement. J Rheumatol. 2005;32(12):2368-72. [5] German DC. Practice tips: a simple measurement to monitor the size of gouty tophi and rheumatoid nodules. J Clin Rheumatol. 1997;3(1):45-6. [6] Perez-Ruiz F, Calabozo M, Pijoan JI, et al. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Rheum. 2002;47(4):356-60. [7] Dalbeth N, Clark B, Gregory K, et al. Computed tomography measurement of tophus volume: comparison with physical measurement. Arthritis Rheum. 2007;57(3):461-5. [8] Maroli AN, Waltrip R, Alton M, et al. First Application of Computer-Assisted Analysis of Digital Photographs for Assessing Tophus Response: Phase 3 Studies of Pegloticase in Treatment Failure Gout. Arthritis Rheum. 2009;60(10):S416. [9] Thiele RG, Schlesinger N. Diagnosis of gout by ultrasound. Rheumatology (Oxford). 2007;46(7):1116-21. [10] Perez-Ruiz F, Martin I, Canteli B. Ultrasonographic measurement of tophi as an outcome measure for chronic gout. J Rheumatol. 2007;34(9):1888-93. [11] Popp JD, Bidgood WD, Jr., Edwards NL. Magnetic resonance imaging of tophaceous gout in the hands and wrists. Semin Arthritis Rheum. 1996;25(4):282-9. [12] Yu JS, Chung C, Recht M, et al. MR imaging of tophaceous gout. AJR Am J Roentgenol. 1997;168(2):523-7. [13] Schumacher HR J, Becker MA, Edwards NL, et al. Magnetic resonance imaging in the quantitative assessment of gouty tophi. J Clin Pract. 2006;60(4):408-14. [14] Gerster JC, Landry M, Dufresne L, et al. Imaging of tophaceous gout: computed tomography provides specific images compared with magnetic resonance imaging and ultrasonography. Ann Rheum Dis. 2002;61(1):52-4. [15] Gerster JC, Landry M, Duvoisin B, et al. Computed tomography of the knee joint as an indicator of intraarticular tophi in gout. Arthritis Rheum. 1996;39(8):1406-9. [16] Gerster JC, Landry M, Rivier G. Computed tomographic imaging of subcutaneous gouty tophi. Clin Rheumatol. 1998;17(1):62-4. [17] Johnson TR, Weckbach S, Kellner H, et al. Clinical image: Dual-energy computed tomographic molecular imaging of gout. Arthritis Rheum. 2007;56(8):2809. [18] Choi HK, Al-Arfaj AM, Eftekhari A, et al. Dual energy computed tomography in tophaceous gout. Ann Rheum Dis. 2009;68(10):1609-12. [19] Artmann A, Ratzenbock M, Noszian I, et al. Dual Energy CT - a New Perspective in the Diagnosis of Gout. Rofo. 2009.