Imaging tools to measure treatment response in gout

Imaging tools to measure treatment response in gout Abstract 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. gout, imaging, radiology, ultrasound, dual energy computed tomography Rheumatology key messages Imaging tests can assess three key domains in gout: urate deposition, inflammation and structural damage. Scoring systems have been developed that allow assessment of imaging features in response to treatment of gout. The role of imaging to assess treatment response in gout, in addition to clinical assessment, is currently uncertain. Introduction Gout is a chronic disease of MSU crystal deposition [1]. The disease usually presents as recurrent flares of severe acute inflammatory arthritis, typically affecting the lower limb joints. In some patients with persistent hyperuricaemia, tophi may also develop; these lesions consist of collections of MSU crystals surrounded by a chronic granulomatous inflammatory tissue response [2] and are associated with chronic joint inflammation and structural joint damage [3]. Gout flares are typically treated with anti-inflammatory medications such as NSAIDs, colchicine or prednisone [4]. Anti-IL-1 agents such as canakinumab and anakinra also have efficacy for the treatment of acute flares [5, 6]. Long-term effective gout management requires urate-lowering therapy (ULT) to reduce serum urate concentrations to subsaturation concentrations; this approach leads to dissolution of deposited MSU crystals, prevention of flares and regression of tophi [7, 8]. A number of different imaging modalities are in clinical use for the diagnosis of gout, assessment of disease severity and as a marker of treatment responses in patients with gout (reviewed in Dalbeth and Doyle [9]). These techniques include conventional radiography (CR), ultrasonography (US), MRI, conventional CT and dual-energy CT (DECT). US and DECT have particular utility in non-invasive identification of MSU crystals and these imaging tools are being increasingly used for the diagnosis of gout [10–12]. For patients with confirmed disease, assessment of treatment response occurs in two main situations: in clinical practice and in research settings including clinical trials, and applications may differ substantially in these two situations. The focus of this article is to describe progress and provide perspective about the role of imaging for measuring treatment response in patients with gout. A framework for imaging assessment of gout The OMERACT group has assessed various imaging methods as instruments for clinical studies and provides an important framework for imaging assessment of gout. This work has identified three key domains: urate deposition (including tophus burden), joint inflammation and structural joint damage [13]. Various imaging modalities have differing properties for assessment of these key domains. For example, DECT allows excellent detection of urate deposition and bone damage [14, 15] (Fig. 1) but images inflammation poorly. In contrast, MRI provides detailed information regarding structural joint damage and inflammation [16] but less detailed information about urate deposition (except in the context of tophus assessment [17]). US allows assessment of all three domains [18] but can be limited by obscuration of parts of the joints examined by overlying bone and by calcified tophi themselves. Furthermore, for each method there may be variation in the sensitivity and specificity of the test, artefact issues, reliability and sensitivity to change in response to therapy. All of these issues, as well as cost and availability, need to be considered when choosing a test and interpreting the test results. Fig. 1 View largeDownload slide DECT image of right first MTP joint from cadaveric donor with crystal-proven tophaceous gout Urate deposition (colour coded as green) is frequently observed at sites of bone erosion in gout. Note also urate deposits surrounded by soft tissue densities within the tophus. DECT: Dual energy CT. Fig. 1 View largeDownload slide DECT image of right first MTP joint from cadaveric donor with crystal-proven tophaceous gout Urate deposition (colour coded as green) is frequently observed at sites of bone erosion in gout. Note also urate deposits surrounded by soft tissue densities within the tophus. DECT: Dual energy CT. When assessing treatment response, accurate and consistent measurement is important. A number of scoring systems have been described and are shown in Table 1. Currently these systems are primarily for use in gout clinical research. However, some measurement systems, such as DECT urate volume measurement and US assessment of double contour sign or index tophus diameter, are used in clinical practice. Table 1 Scoring systems used for imaging assessment of gout Imaging modality  Domain assessed  Gout-specific scoring method  References describing method  Conventional radiography  Urate deposition  Tophi score  Suh et al. [19]  Inflammation  Not applicable  –  Damage  Sharp–van der Heijde system modified for gout (erosion and joint space narrowing scored)  Dalbeth et al. [20]  Simplified radiographic gout scoring system (erosion and joint space narrowing scored)  Son et al. [21]  Ultrasound  Urate deposition  Double contour sign (present/absent)  Grassi et al. [22]  Index tophus diameter  Perez-Ruiz et al. [23]  US scoring system including double contour sign, tophus, aggregates currently under development by OMERACT US Task Force  Terslev et al. [24]  Inflammation  Power Doppler score  Peiteado et al. [25]  Damage  US scoring system including erosion currently under development by OMERACT US Task Force  Terslev et al. [24]  MRI  Urate deposition  Index tophus volumetric measurement  Schumacher et al. [26]  Tophus diameter  McQueen et al. [16]  Inflammation  RAMRIS modified for gout (synovitis and bone oedema)  McQueen et al. [16]  Damage  RAMRIS modified for gout (erosion)  McQueen et al. [16]  Cartilage damage GOMRICS  Popovich et al. [27]  Conventional CT  Urate deposition  Index tophus volumetric measurement  Dalbeth et al. [28]  Tophus diameter  Dalbeth et al. [3]  Inflammation  Not applicable  –  Damage  CT bone erosion scoring system  Dalbeth et al. [29]  DECT  Urate deposition  DECT urate volume assessment  Choi et al. [14]  DECT semi-quantitative urate scoring system  Bayat et al. [30]  Inflammation  Not applicable  –  Damage  As per conventional CT  As per conventional CT  Imaging modality  Domain assessed  Gout-specific scoring method  References describing method  Conventional radiography  Urate deposition  Tophi score  Suh et al. [19]  Inflammation  Not applicable  –  Damage  Sharp–van der Heijde system modified for gout (erosion and joint space narrowing scored)  Dalbeth et al. [20]  Simplified radiographic gout scoring system (erosion and joint space narrowing scored)  Son et al. [21]  Ultrasound  Urate deposition  Double contour sign (present/absent)  Grassi et al. [22]  Index tophus diameter  Perez-Ruiz et al. [23]  US scoring system including double contour sign, tophus, aggregates currently under development by OMERACT US Task Force  Terslev et al. [24]  Inflammation  Power Doppler score  Peiteado et al. [25]  Damage  US scoring system including erosion currently under development by OMERACT US Task Force  Terslev et al. [24]  MRI  Urate deposition  Index tophus volumetric measurement  Schumacher et al. [26]  Tophus diameter  McQueen et al. [16]  Inflammation  RAMRIS modified for gout (synovitis and bone oedema)  McQueen et al. [16]  Damage  RAMRIS modified for gout (erosion)  McQueen et al. [16]  Cartilage damage GOMRICS  Popovich et al. [27]  Conventional CT  Urate deposition  Index tophus volumetric measurement  Dalbeth et al. [28]  Tophus diameter  Dalbeth et al. [3]  Inflammation  Not applicable  –  Damage  CT bone erosion scoring system  Dalbeth et al. [29]  DECT  Urate deposition  DECT urate volume assessment  Choi et al. [14]  DECT semi-quantitative urate scoring system  Bayat et al. [30]  Inflammation  Not applicable  –  Damage  As per conventional CT  As per conventional CT  DECT: Dual energy computed tomograpgy; RAMRIS: rheumatoid arthritis magnetic resonance imaging score. Measurement of urate deposition Methods to measure urate deposition have been described for all major imaging modalities. A CR tophi score has been described recently [19]; this is a semi-quantitative method of assessing soft tissue swelling on conventional radiographs. Interreader κ scores for this method of measurement were high (0.8). In a retrospective study of 60 patients with paired pre- and post-ULT, CR tophus scores reduced following ULT (mean duration of treatment >9 years) [19]. While this scoring system has been described as a tophus score, the findings of soft tissue swelling on CR are not specific for any pathological feature of gout and may represent urate deposition, the tissue response to urate crystals within a tophus, chronic synovitis or acute synovitis in the context of a gout flare. It is currently unknown whether the soft tissue swelling visualized on CR reflects only tophus or indeed only urate crystal deposition. MRI and conventional CT are able to measure tophus size (diameter or volume) with high interreader reproducibility [3, 26, 28]. However, measurement methods are complex, expensive and labour intensive. A comparison of CT measurement with Vernier calliper measurement of index tophi showed high concordance between measurements and equivalent interreader reliability [28]. These findings suggest that for most clinically apparent tophi, measurement using advanced imaging methods such as CT or MRI has little advantage over less expensive, safer and faster methods of physical measurement. To date, no studies have reported the sensitivity to change of tophus size measured by MRI or conventional CT in response to ULT. Urate deposition has several different appearances in US, including the double contour sign (defined by the OMERACT US Gout Task Force as ‘abnormal hyperechoic band over the superficial margin of the articular hyaline cartilage, independent of the angle of insonation and which may be either irregular or regular, continuous or intermittent and can be distinguished from the cartilage interface sign’ [31]) and is thought to represent MSU crystals overlying the articular cartilage surface, aggregates of MSU crystals (defined by the OMERACT US Gout Task Force as ‘heterogeneous hyperechoic foci that maintain their high degree of reflectivity even when the gain setting is minimized or the insonation angle is changed and which occasionally may generate posterior acoustic shadow’) [31] and tophus (defined by the OMERACT US Gout Task Force as ‘a circumscribed, inhomogeneous, hyperechoic and/or hypoechoic aggregation (which may or may not generate posterior acoustic shadow) which may be surrounded by a small anechoic rim’) [31]. Both double contour sign and aggregates can be reproduced in an in vivo model of MSU crystal deposition in the joint [32]. Some [33], but not all [10], studies have reported that the double contour sign is not specific for gout and that the double contour sign may also be present in patients presenting with acute calcium pyrophosphate crystal arthritis. A recent reliability exercise by the OMERACT US Gout Task Force has shown variable interreader κ values for assessing the presence or absence of these elementary lesions; with quite poor agreement for aggregates (κ = 0.21) and double contour sign (κ = 0.47), but better agreement for tophus (κ = 0.69) [34]. For measurement of index tophus diameter, interreader intraclass correlation coefficients have been reported as 0.71–0.83 [23]. 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 [35–38]. At present, different groups report different sites for US assessment of urate deposition; work is progressing in identifying the optimal joints for scanning. One group has suggested that bilateral scanning of one joint (radiocarpal joint) for aggregates, two tendons (patellar tendon and triceps tendon) for aggregates and three articular cartilages (first metatarsal, talar and second metacarpal/femoral) for double contour sign is sufficient for accurate detection of urate crystal deposition [39]. Another group has reported that a four-joint scan (both knees and the first MTP joints) for aggregates and double contour sign is sufficient [25]. DECT is a CT technique that provides colour-coded information about the composition of certain materials, including urate. In addition to visualization of urate deposition, automated volume assessment tools are available that allow highly reliable measurement of urate depositions within a field of interest [14]. Some studies have reported that DECT has slightly lower sensitivity for urate crystals than US [40, 41]. Artefacts may also arise from nail beds, thickened skin, movement and beam hardening, leading to false-positive results and volume assessment that does not change over time, even with effective therapy [42]. Several studies have compared anatomical pathology appearances with DECT; although there is generally high concordance between DECT and anatomical pathology [43], some lower-density deposits may not be detected by DECT [44]. A further important point to emphasize is that the material colour-coding application of DECT detects the urate content of tophi only and the surrounding inflammatory tissue response within the tophus is not measured [45]. For this is reason, there is not high concordance between physical or conventional CT measurements of tophus size and DECT urate volume [46]. There are emerging data that DECT urate volume measurements change over time in response to changes in serum urate levels. In a 12 month prospective study of patients with tophaceous gout on stable doses of ULT, DECT volumes were stable over the follow-up period, but those who had an increase in DECT urate volumes had higher mean serum urate levels [47]. A reduction in DECT urate volumes has been reported in a small series of patients with very low serum urate concentrations following treatment with pegloticase [48] and in patients commencing oral ULT within 6 months of starting therapy [49]. Although DECT urate volume measurement represents a major advance in the quantification of urate burden in patients with gout, there are some methodological issues. First, volume assessment is still rather time-consuming, as it requires manual outlining of the area of interest with exclusion of artefact sites [30]. A single volume does not provide anatomical detail about sites of deposition, which may vary in their response to ULT; for example, it appears that urate deposition within tendons may not respond as rapidly to ULT compared with deposition in intra-articular or subcutaneous sites [48]. Finally, a key challenge when using DECT urate volume as an outcome measure is the wide range of baseline volumes; for example, in patients with clinically apparent tophi, the range of total urate volume was from 0.63 to 249.13 cm3 [14]. Aggregating data and reporting change can be complex in samples with such wide variation; for example, a reduction of 0.50 cm3 represents a large percentage reduction for those with the smallest baseline urate volumes but is of no clinical or statistical relevance for patients with large urate volumes. A semi-quantitative scoring method for DECT urate assessment in the feet has been described that may address some of these methodological problems [30]. This system includes scores from different joint and soft tissue sites in the feet, with a score range from 0 to 12. Compared with DECT urate volume measurement, the semi-quantitative scoring system correlated highly with DECT urate volume values and had similar interreader reliability and discrimination for gout disease states. The semi-quantitative scoring system allowed faster scoring and had better ability to discriminate between responders and non-responders to pegloticase treatment (Fig. 2). While this semi-quantitative method requires further testing and validation in larger groups of patients initiating oral ULT, it represents a promising option for measurement of urate burden using DECT. Fig. 2 View largeDownload slide Sensitivity to change of DECT urate assessment methods Box-and-whisker plots showing changes in values in patients treated with pegloticase (n = 8). (A) DECT semi-quantitative urate scores. (B) Urate volumes using automated volume assessment; pegloticase responders achieved a serum urate concentration <6 mg/dl during treatment and non-responders did not achieve a serum urate concentration <6 mg/dl during treatment. Reproduced from Bayat S, Aati O, Rech J et al. Development of a dual-energy computed tomography scoring system for measurement of urate deposition in gout. Arthritis Care Res 2016;68:769–75. Copyright 2016 with permission from John Wiley & Sons. DECT: Dual energy computed tomograpgy. Fig. 2 View largeDownload slide Sensitivity to change of DECT urate assessment methods Box-and-whisker plots showing changes in values in patients treated with pegloticase (n = 8). (A) DECT semi-quantitative urate scores. (B) Urate volumes using automated volume assessment; pegloticase responders achieved a serum urate concentration <6 mg/dl during treatment and non-responders did not achieve a serum urate concentration <6 mg/dl during treatment. Reproduced from Bayat S, Aati O, Rech J et al. Development of a dual-energy computed tomography scoring system for measurement of urate deposition in gout. Arthritis Care Res 2016;68:769–75. Copyright 2016 with permission from John Wiley & Sons. DECT: Dual energy computed tomograpgy. Measurement of inflammation MRI and US are the key imaging modalities for assessment of inflammation in gout. In patients with flares of acute inflammatory gouty arthritis, MRI synovitis is universal, with a higher-grade RA MRI score (RAMRIS) synovitis than patients with active RA [50]. MRI also demonstrates synovitis to be common in patients even in the absence of clinically apparent flare [16, 51] (i.e. during the intercritical period). There are few published studies that report whether MRI synovitis is responsive to change in response to therapy. A recently published clinical trial of people with very early gout (two or fewer flares ever), [52], reported that MRI synovitis in a previously inflamed joint was common even in the absence of clinically apparent flare and that ULT reduced the severity of MRI synovitis over 2 years of treatment. In contrast to other forms of erosive inflammatory arthritis, high-grade bone marrow oedema is rare in gout and, when present, should raise suspicion for concomitant bone infection [53]. Tenosynovitis detected by MRI has been reported in < 20% of patients with gout [53]. There are variable reports of the prevalence of US synovial hypertrophy and synovitis in gout [18, 54]; a recent analysis of the first MTP joints reported US synovitis in 44% of people with gout without clinical apparent flare at the time of scanning [55]. A longitudinal study reported power Doppler signal in 52% of scanned first MTP joints, 21% of patellar tendons and 76% of knee joints at baseline. and over 24 months of ULT there were significant reductions in the percentage of joints with power Doppler signal and the power Doppler scores at all sites [56]. Measurement of structural damage All major imaging methods have been used to measure structural joint damage in gout. Conventional radiographs are most widely used, due to their low cost and widespread availability. Several CR damage scoring systems have been described for assessment of erosion and joint space narrowing [20, 21]. Most widely used is the gout-modified Sharp–van der Heijde method, which has high interreader reliability and is able to discriminate between different disease states [20]. The gout-modified Sharp–van der Heijde method has been used in several studies assessing changes in radiographic scores over time. In a placebo-controlled clinical trial of zoledronate for treatment of bone erosion in gout, the gout-modified Sharp–van der Heijde damage scores did not significantly change in either group over the 2 year study period [57]. In a small study of patients treated with pegloticase using the gout-modified Sharp–van der Heijde method, very intensive ULT was associated with improvements of erosion scores over 1 year of follow-up, with no significant improvement in joint space narrowing scores [58]. A recent longitudinal study using the gout-modified Sharp–van der Heijde method showed that radiographic appearances are stable over a 3 year period in the majority of patients with gout of disease duration <10 years (Fig. 3) [59]. Baseline damage scores and changes in subcutaneous tophus count were the key predictors of progressive radiographic damage [59]. These observations highlight the challenges of using plain radiographs for monitoring structural damage in gout, noting the generally slow rate of change and association with other features of disease such as subcutaneous tophus count that can be measured easily in the clinic with minimal expense. Fig. 3 View largeDownload slide Changes in gout-modified Sharp–van der Heijde radiographic damage scores over a 3 year period These graphs show that the majority of patients with gout for <10 years do not have changes in radiographic scores over a 3 year period. Reproduced from Eason A, House ME, Vincent Z et al. Factors associated with change in radiographic damage scores in gout: a prospective observational study. Ann Rheum Dis 2016;75:2075–9. Copyright 2016, with permission from BMJ Publishing Group. Fig. 3 View largeDownload slide Changes in gout-modified Sharp–van der Heijde radiographic damage scores over a 3 year period These graphs show that the majority of patients with gout for <10 years do not have changes in radiographic scores over a 3 year period. Reproduced from Eason A, House ME, Vincent Z et al. Factors associated with change in radiographic damage scores in gout: a prospective observational study. Ann Rheum Dis 2016;75:2075–9. Copyright 2016, with permission from BMJ Publishing Group. US has high interreader agreement for assessment of bone erosion [24], although it detects substantially fewer erosions in gout than MRI [54]. For MRI, the RAMRIS method has high interreader reliability for erosion [16]. A scoring method for MRI cartilage damage in gout has also been described [Gout MRI Cartilage Score (GOMRICS)] with high interreader reliability [27]. To date, no published studies have reported changes in US or MRI damage scores in longitudinal studies or clinical trials. Conventional CT allows excellent visualization for bone erosion and has been used widely to analyse mechanisms of bone damage in gout [3, 15, 60]. DECT also allows for assessment of bone erosion using the conventional CT images acquired at the time of scanning. A semi-quantitative CT damage score has been developed using CT scans of both feet, based on the RAMRIS method [29]. This scoring system has very high interreader agreement. In the placebo-controlled clinical trial of zoledronate for treatment of bone erosion in gout, CT damage scores did not significantly change in either group over the 2 year study period [57]. To date, this method has not been used for assessment of bone damage in studies of ULT. Challenges and uncertainties The work to date examining the role of imaging for assessment of treatment responses has identified several exciting techniques to measure urate crystal deposition, joint inflammation and structural damage. However, a number of challenges and core questions remain about the application of these methods to assess treatment response. Further standardization of lesions, definitions and sites for scanning and consistent assessment over different units and studies is also essential. For example, it is unclear whether a simplified CR score [21] is preferable to the widely used Sharp–van der Heijde score for assessing radiographic damage [20]; whether a four-joint US protocol is sufficient [25] or whether a more extensive scanning protocol is required [39] and whether DECT of the feet is sufficient [61] or whether a more extended field of scanning is needed [62]. The work of the OMERACT US Gout Task Force provides an exemplar of international cooperation to address such key questions of standardization [31, 34, 24]. The relative importance of different disease elements also requires further consideration; urate deposition often coexists with inflammation and structural damage, and it is unclear whether measurement of features other than urate deposition provides additional clinically relevant information. There is increasing evidence that subclinical joint inflammation is common in people with gout [16, 51, 52, 55, 56] and emerging data that ULT can reduce imaging features of inflammation [52, 56]. Research to date has focused almost exclusively on sensitivity to change of imaging tests in response to ULT, with no published data on the role of imaging in the assessment of the response to anti-inflammatory medications. This question requires a separate piece of work to determine whether imaging methods allow more sensitive assessment of joint inflammation to measure treatment response to anti-inflammatory therapies. A fundamental question is whether the use of imaging to assess treatment response provides important information in addition to low-cost clinical assessment. For example, for a patient on long-term ULT who has a well-controlled serum urate level below the treatment target, with suppressed flares and regressing tophi, does imaging assessment of urate burden, joint inflammation or radiographic damage add additional clinical information that allows better prediction of prognosis? Similarly, if a patient has poorly controlled hyperuricaemia and recurrent flares, does the presence of the double contour sign at the first MTP joint or urate deposition viewed on a DECT add additional clinical information? It is currently unclear whether imaging appearances can predict clinically important endpoints such as flares, disability and poor health-related quality of life or whether changes in imaging appearances over the short term predict changes in these clinical outcomes in the long term. At present it is also unknown whether changes in imaging findings are important to patients or reflect the patient’s experience in a clinically meaningful way. These uncertainties are important when considering the potential role of imaging, due to the procedural cost, additional time costs to the patient and physician and potential risks due to exposure to medical radiation or contrast (depending on the test). Furthermore, clinical trials and longitudinal cohort studies have shown that changes in imaging appearances occur slowly and over long periods of time in people with gout. The exception is the effect of pegloticase, an infusional agent that leads to profound urate lowering with rapid tophus regression by physical assessment [63] and also improvements in DECT urate deposition and CR bone erosion [48, 58]. In patients with less intensive ULT, tophus regression by physical assessment and changes in imaging appearances are slower. If changes in imaging occur in parallel with changes in clinical findings, it seems unlikely that imaging assessment of treatment response will be of major additional benefit to clinical assessment. Conclusion There has been rapid progress in the development of imaging techniques to assess domains of disease in gout. The place of imaging in the assessment of treatment response in gout is an evolving issue. Increasing data support the role of imaging for the diagnosis of disease, to assist clinical decision making about the intensity of ULT, to improve patient understanding and adherence to therapies and to dissect the mechanisms of disease. Although reliable scoring systems have been developed, the ultimate place of imaging tools for assessing treatment responses in gout remains uncertain. Understanding the benefits of imaging assessment of treatment response, in addition to comprehensive clinical assessment, will be essential to further establish the role of these methods. Acknowledgements We acknowledge Dr Ashika Chhana and Dr Sue McGlashan for assistance with cadaveric imaging. The collection and use of cadaveric tissue was in accordance with the New Zealand Human Tissue Act 2008. Supplement: This supplement was funded by Grunenthal. Funding: This work is supported by the Health Research Council of New Zealand (15/576). 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Arthritis Care Res  2014; 66: 82– 5. Google Scholar CrossRef Search ADS   59 Eason A, House ME, Vincent Z et al.   Factors associated with change in radiographic damage scores in gout: a prospective observational study. Ann Rheum Dis  2016; 75: 2075– 9. Google Scholar CrossRef Search ADS PubMed  60 Dalbeth N, Milligan A, Doyle AJ, Clark B, McQueen FM. Characterization of new bone formation in gout: a quantitative site-by-site analysis using plain radiography and computed tomography. Arthritis Res Ther  2012; 14: R165. Google Scholar CrossRef Search ADS PubMed  61 Dalbeth N, House ME, Aati O et al.   Urate crystal deposition in asymptomatic hyperuricaemia and symptomatic gout: a dual energy CT study. Ann Rheum Dis  2015; 74: 908– 11. Google Scholar CrossRef Search ADS PubMed  62 Choi HK, Burns LC, Shojania K et al.   Dual energy CT in gout: a prospective validation study. Ann Rheum Dis  2012; 71: 1466– 71. Google Scholar CrossRef Search ADS PubMed  63 Sundy JS, Baraf HS, Yood RA et al.   Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA  2011; 306: 711– 20. Google Scholar CrossRef Search ADS PubMed  © The Author 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Imaging tools to measure treatment response in gout

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Abstract

Abstract 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. gout, imaging, radiology, ultrasound, dual energy computed tomography Rheumatology key messages Imaging tests can assess three key domains in gout: urate deposition, inflammation and structural damage. Scoring systems have been developed that allow assessment of imaging features in response to treatment of gout. The role of imaging to assess treatment response in gout, in addition to clinical assessment, is currently uncertain. Introduction Gout is a chronic disease of MSU crystal deposition [1]. The disease usually presents as recurrent flares of severe acute inflammatory arthritis, typically affecting the lower limb joints. In some patients with persistent hyperuricaemia, tophi may also develop; these lesions consist of collections of MSU crystals surrounded by a chronic granulomatous inflammatory tissue response [2] and are associated with chronic joint inflammation and structural joint damage [3]. Gout flares are typically treated with anti-inflammatory medications such as NSAIDs, colchicine or prednisone [4]. Anti-IL-1 agents such as canakinumab and anakinra also have efficacy for the treatment of acute flares [5, 6]. Long-term effective gout management requires urate-lowering therapy (ULT) to reduce serum urate concentrations to subsaturation concentrations; this approach leads to dissolution of deposited MSU crystals, prevention of flares and regression of tophi [7, 8]. A number of different imaging modalities are in clinical use for the diagnosis of gout, assessment of disease severity and as a marker of treatment responses in patients with gout (reviewed in Dalbeth and Doyle [9]). These techniques include conventional radiography (CR), ultrasonography (US), MRI, conventional CT and dual-energy CT (DECT). US and DECT have particular utility in non-invasive identification of MSU crystals and these imaging tools are being increasingly used for the diagnosis of gout [10–12]. For patients with confirmed disease, assessment of treatment response occurs in two main situations: in clinical practice and in research settings including clinical trials, and applications may differ substantially in these two situations. The focus of this article is to describe progress and provide perspective about the role of imaging for measuring treatment response in patients with gout. A framework for imaging assessment of gout The OMERACT group has assessed various imaging methods as instruments for clinical studies and provides an important framework for imaging assessment of gout. This work has identified three key domains: urate deposition (including tophus burden), joint inflammation and structural joint damage [13]. Various imaging modalities have differing properties for assessment of these key domains. For example, DECT allows excellent detection of urate deposition and bone damage [14, 15] (Fig. 1) but images inflammation poorly. In contrast, MRI provides detailed information regarding structural joint damage and inflammation [16] but less detailed information about urate deposition (except in the context of tophus assessment [17]). US allows assessment of all three domains [18] but can be limited by obscuration of parts of the joints examined by overlying bone and by calcified tophi themselves. Furthermore, for each method there may be variation in the sensitivity and specificity of the test, artefact issues, reliability and sensitivity to change in response to therapy. All of these issues, as well as cost and availability, need to be considered when choosing a test and interpreting the test results. Fig. 1 View largeDownload slide DECT image of right first MTP joint from cadaveric donor with crystal-proven tophaceous gout Urate deposition (colour coded as green) is frequently observed at sites of bone erosion in gout. Note also urate deposits surrounded by soft tissue densities within the tophus. DECT: Dual energy CT. Fig. 1 View largeDownload slide DECT image of right first MTP joint from cadaveric donor with crystal-proven tophaceous gout Urate deposition (colour coded as green) is frequently observed at sites of bone erosion in gout. Note also urate deposits surrounded by soft tissue densities within the tophus. DECT: Dual energy CT. When assessing treatment response, accurate and consistent measurement is important. A number of scoring systems have been described and are shown in Table 1. Currently these systems are primarily for use in gout clinical research. However, some measurement systems, such as DECT urate volume measurement and US assessment of double contour sign or index tophus diameter, are used in clinical practice. Table 1 Scoring systems used for imaging assessment of gout Imaging modality  Domain assessed  Gout-specific scoring method  References describing method  Conventional radiography  Urate deposition  Tophi score  Suh et al. [19]  Inflammation  Not applicable  –  Damage  Sharp–van der Heijde system modified for gout (erosion and joint space narrowing scored)  Dalbeth et al. [20]  Simplified radiographic gout scoring system (erosion and joint space narrowing scored)  Son et al. [21]  Ultrasound  Urate deposition  Double contour sign (present/absent)  Grassi et al. [22]  Index tophus diameter  Perez-Ruiz et al. [23]  US scoring system including double contour sign, tophus, aggregates currently under development by OMERACT US Task Force  Terslev et al. [24]  Inflammation  Power Doppler score  Peiteado et al. [25]  Damage  US scoring system including erosion currently under development by OMERACT US Task Force  Terslev et al. [24]  MRI  Urate deposition  Index tophus volumetric measurement  Schumacher et al. [26]  Tophus diameter  McQueen et al. [16]  Inflammation  RAMRIS modified for gout (synovitis and bone oedema)  McQueen et al. [16]  Damage  RAMRIS modified for gout (erosion)  McQueen et al. [16]  Cartilage damage GOMRICS  Popovich et al. [27]  Conventional CT  Urate deposition  Index tophus volumetric measurement  Dalbeth et al. [28]  Tophus diameter  Dalbeth et al. [3]  Inflammation  Not applicable  –  Damage  CT bone erosion scoring system  Dalbeth et al. [29]  DECT  Urate deposition  DECT urate volume assessment  Choi et al. [14]  DECT semi-quantitative urate scoring system  Bayat et al. [30]  Inflammation  Not applicable  –  Damage  As per conventional CT  As per conventional CT  Imaging modality  Domain assessed  Gout-specific scoring method  References describing method  Conventional radiography  Urate deposition  Tophi score  Suh et al. [19]  Inflammation  Not applicable  –  Damage  Sharp–van der Heijde system modified for gout (erosion and joint space narrowing scored)  Dalbeth et al. [20]  Simplified radiographic gout scoring system (erosion and joint space narrowing scored)  Son et al. [21]  Ultrasound  Urate deposition  Double contour sign (present/absent)  Grassi et al. [22]  Index tophus diameter  Perez-Ruiz et al. [23]  US scoring system including double contour sign, tophus, aggregates currently under development by OMERACT US Task Force  Terslev et al. [24]  Inflammation  Power Doppler score  Peiteado et al. [25]  Damage  US scoring system including erosion currently under development by OMERACT US Task Force  Terslev et al. [24]  MRI  Urate deposition  Index tophus volumetric measurement  Schumacher et al. [26]  Tophus diameter  McQueen et al. [16]  Inflammation  RAMRIS modified for gout (synovitis and bone oedema)  McQueen et al. [16]  Damage  RAMRIS modified for gout (erosion)  McQueen et al. [16]  Cartilage damage GOMRICS  Popovich et al. [27]  Conventional CT  Urate deposition  Index tophus volumetric measurement  Dalbeth et al. [28]  Tophus diameter  Dalbeth et al. [3]  Inflammation  Not applicable  –  Damage  CT bone erosion scoring system  Dalbeth et al. [29]  DECT  Urate deposition  DECT urate volume assessment  Choi et al. [14]  DECT semi-quantitative urate scoring system  Bayat et al. [30]  Inflammation  Not applicable  –  Damage  As per conventional CT  As per conventional CT  DECT: Dual energy computed tomograpgy; RAMRIS: rheumatoid arthritis magnetic resonance imaging score. Measurement of urate deposition Methods to measure urate deposition have been described for all major imaging modalities. A CR tophi score has been described recently [19]; this is a semi-quantitative method of assessing soft tissue swelling on conventional radiographs. Interreader κ scores for this method of measurement were high (0.8). In a retrospective study of 60 patients with paired pre- and post-ULT, CR tophus scores reduced following ULT (mean duration of treatment >9 years) [19]. While this scoring system has been described as a tophus score, the findings of soft tissue swelling on CR are not specific for any pathological feature of gout and may represent urate deposition, the tissue response to urate crystals within a tophus, chronic synovitis or acute synovitis in the context of a gout flare. It is currently unknown whether the soft tissue swelling visualized on CR reflects only tophus or indeed only urate crystal deposition. MRI and conventional CT are able to measure tophus size (diameter or volume) with high interreader reproducibility [3, 26, 28]. However, measurement methods are complex, expensive and labour intensive. A comparison of CT measurement with Vernier calliper measurement of index tophi showed high concordance between measurements and equivalent interreader reliability [28]. These findings suggest that for most clinically apparent tophi, measurement using advanced imaging methods such as CT or MRI has little advantage over less expensive, safer and faster methods of physical measurement. To date, no studies have reported the sensitivity to change of tophus size measured by MRI or conventional CT in response to ULT. Urate deposition has several different appearances in US, including the double contour sign (defined by the OMERACT US Gout Task Force as ‘abnormal hyperechoic band over the superficial margin of the articular hyaline cartilage, independent of the angle of insonation and which may be either irregular or regular, continuous or intermittent and can be distinguished from the cartilage interface sign’ [31]) and is thought to represent MSU crystals overlying the articular cartilage surface, aggregates of MSU crystals (defined by the OMERACT US Gout Task Force as ‘heterogeneous hyperechoic foci that maintain their high degree of reflectivity even when the gain setting is minimized or the insonation angle is changed and which occasionally may generate posterior acoustic shadow’) [31] and tophus (defined by the OMERACT US Gout Task Force as ‘a circumscribed, inhomogeneous, hyperechoic and/or hypoechoic aggregation (which may or may not generate posterior acoustic shadow) which may be surrounded by a small anechoic rim’) [31]. Both double contour sign and aggregates can be reproduced in an in vivo model of MSU crystal deposition in the joint [32]. Some [33], but not all [10], studies have reported that the double contour sign is not specific for gout and that the double contour sign may also be present in patients presenting with acute calcium pyrophosphate crystal arthritis. A recent reliability exercise by the OMERACT US Gout Task Force has shown variable interreader κ values for assessing the presence or absence of these elementary lesions; with quite poor agreement for aggregates (κ = 0.21) and double contour sign (κ = 0.47), but better agreement for tophus (κ = 0.69) [34]. For measurement of index tophus diameter, interreader intraclass correlation coefficients have been reported as 0.71–0.83 [23]. 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 [35–38]. At present, different groups report different sites for US assessment of urate deposition; work is progressing in identifying the optimal joints for scanning. One group has suggested that bilateral scanning of one joint (radiocarpal joint) for aggregates, two tendons (patellar tendon and triceps tendon) for aggregates and three articular cartilages (first metatarsal, talar and second metacarpal/femoral) for double contour sign is sufficient for accurate detection of urate crystal deposition [39]. Another group has reported that a four-joint scan (both knees and the first MTP joints) for aggregates and double contour sign is sufficient [25]. DECT is a CT technique that provides colour-coded information about the composition of certain materials, including urate. In addition to visualization of urate deposition, automated volume assessment tools are available that allow highly reliable measurement of urate depositions within a field of interest [14]. Some studies have reported that DECT has slightly lower sensitivity for urate crystals than US [40, 41]. Artefacts may also arise from nail beds, thickened skin, movement and beam hardening, leading to false-positive results and volume assessment that does not change over time, even with effective therapy [42]. Several studies have compared anatomical pathology appearances with DECT; although there is generally high concordance between DECT and anatomical pathology [43], some lower-density deposits may not be detected by DECT [44]. A further important point to emphasize is that the material colour-coding application of DECT detects the urate content of tophi only and the surrounding inflammatory tissue response within the tophus is not measured [45]. For this is reason, there is not high concordance between physical or conventional CT measurements of tophus size and DECT urate volume [46]. There are emerging data that DECT urate volume measurements change over time in response to changes in serum urate levels. In a 12 month prospective study of patients with tophaceous gout on stable doses of ULT, DECT volumes were stable over the follow-up period, but those who had an increase in DECT urate volumes had higher mean serum urate levels [47]. A reduction in DECT urate volumes has been reported in a small series of patients with very low serum urate concentrations following treatment with pegloticase [48] and in patients commencing oral ULT within 6 months of starting therapy [49]. Although DECT urate volume measurement represents a major advance in the quantification of urate burden in patients with gout, there are some methodological issues. First, volume assessment is still rather time-consuming, as it requires manual outlining of the area of interest with exclusion of artefact sites [30]. A single volume does not provide anatomical detail about sites of deposition, which may vary in their response to ULT; for example, it appears that urate deposition within tendons may not respond as rapidly to ULT compared with deposition in intra-articular or subcutaneous sites [48]. Finally, a key challenge when using DECT urate volume as an outcome measure is the wide range of baseline volumes; for example, in patients with clinically apparent tophi, the range of total urate volume was from 0.63 to 249.13 cm3 [14]. Aggregating data and reporting change can be complex in samples with such wide variation; for example, a reduction of 0.50 cm3 represents a large percentage reduction for those with the smallest baseline urate volumes but is of no clinical or statistical relevance for patients with large urate volumes. A semi-quantitative scoring method for DECT urate assessment in the feet has been described that may address some of these methodological problems [30]. This system includes scores from different joint and soft tissue sites in the feet, with a score range from 0 to 12. Compared with DECT urate volume measurement, the semi-quantitative scoring system correlated highly with DECT urate volume values and had similar interreader reliability and discrimination for gout disease states. The semi-quantitative scoring system allowed faster scoring and had better ability to discriminate between responders and non-responders to pegloticase treatment (Fig. 2). While this semi-quantitative method requires further testing and validation in larger groups of patients initiating oral ULT, it represents a promising option for measurement of urate burden using DECT. Fig. 2 View largeDownload slide Sensitivity to change of DECT urate assessment methods Box-and-whisker plots showing changes in values in patients treated with pegloticase (n = 8). (A) DECT semi-quantitative urate scores. (B) Urate volumes using automated volume assessment; pegloticase responders achieved a serum urate concentration <6 mg/dl during treatment and non-responders did not achieve a serum urate concentration <6 mg/dl during treatment. Reproduced from Bayat S, Aati O, Rech J et al. Development of a dual-energy computed tomography scoring system for measurement of urate deposition in gout. Arthritis Care Res 2016;68:769–75. Copyright 2016 with permission from John Wiley & Sons. DECT: Dual energy computed tomograpgy. Fig. 2 View largeDownload slide Sensitivity to change of DECT urate assessment methods Box-and-whisker plots showing changes in values in patients treated with pegloticase (n = 8). (A) DECT semi-quantitative urate scores. (B) Urate volumes using automated volume assessment; pegloticase responders achieved a serum urate concentration <6 mg/dl during treatment and non-responders did not achieve a serum urate concentration <6 mg/dl during treatment. Reproduced from Bayat S, Aati O, Rech J et al. Development of a dual-energy computed tomography scoring system for measurement of urate deposition in gout. Arthritis Care Res 2016;68:769–75. Copyright 2016 with permission from John Wiley & Sons. DECT: Dual energy computed tomograpgy. Measurement of inflammation MRI and US are the key imaging modalities for assessment of inflammation in gout. In patients with flares of acute inflammatory gouty arthritis, MRI synovitis is universal, with a higher-grade RA MRI score (RAMRIS) synovitis than patients with active RA [50]. MRI also demonstrates synovitis to be common in patients even in the absence of clinically apparent flare [16, 51] (i.e. during the intercritical period). There are few published studies that report whether MRI synovitis is responsive to change in response to therapy. A recently published clinical trial of people with very early gout (two or fewer flares ever), [52], reported that MRI synovitis in a previously inflamed joint was common even in the absence of clinically apparent flare and that ULT reduced the severity of MRI synovitis over 2 years of treatment. In contrast to other forms of erosive inflammatory arthritis, high-grade bone marrow oedema is rare in gout and, when present, should raise suspicion for concomitant bone infection [53]. Tenosynovitis detected by MRI has been reported in < 20% of patients with gout [53]. There are variable reports of the prevalence of US synovial hypertrophy and synovitis in gout [18, 54]; a recent analysis of the first MTP joints reported US synovitis in 44% of people with gout without clinical apparent flare at the time of scanning [55]. A longitudinal study reported power Doppler signal in 52% of scanned first MTP joints, 21% of patellar tendons and 76% of knee joints at baseline. and over 24 months of ULT there were significant reductions in the percentage of joints with power Doppler signal and the power Doppler scores at all sites [56]. Measurement of structural damage All major imaging methods have been used to measure structural joint damage in gout. Conventional radiographs are most widely used, due to their low cost and widespread availability. Several CR damage scoring systems have been described for assessment of erosion and joint space narrowing [20, 21]. Most widely used is the gout-modified Sharp–van der Heijde method, which has high interreader reliability and is able to discriminate between different disease states [20]. The gout-modified Sharp–van der Heijde method has been used in several studies assessing changes in radiographic scores over time. In a placebo-controlled clinical trial of zoledronate for treatment of bone erosion in gout, the gout-modified Sharp–van der Heijde damage scores did not significantly change in either group over the 2 year study period [57]. In a small study of patients treated with pegloticase using the gout-modified Sharp–van der Heijde method, very intensive ULT was associated with improvements of erosion scores over 1 year of follow-up, with no significant improvement in joint space narrowing scores [58]. A recent longitudinal study using the gout-modified Sharp–van der Heijde method showed that radiographic appearances are stable over a 3 year period in the majority of patients with gout of disease duration <10 years (Fig. 3) [59]. Baseline damage scores and changes in subcutaneous tophus count were the key predictors of progressive radiographic damage [59]. These observations highlight the challenges of using plain radiographs for monitoring structural damage in gout, noting the generally slow rate of change and association with other features of disease such as subcutaneous tophus count that can be measured easily in the clinic with minimal expense. Fig. 3 View largeDownload slide Changes in gout-modified Sharp–van der Heijde radiographic damage scores over a 3 year period These graphs show that the majority of patients with gout for <10 years do not have changes in radiographic scores over a 3 year period. Reproduced from Eason A, House ME, Vincent Z et al. Factors associated with change in radiographic damage scores in gout: a prospective observational study. Ann Rheum Dis 2016;75:2075–9. Copyright 2016, with permission from BMJ Publishing Group. Fig. 3 View largeDownload slide Changes in gout-modified Sharp–van der Heijde radiographic damage scores over a 3 year period These graphs show that the majority of patients with gout for <10 years do not have changes in radiographic scores over a 3 year period. Reproduced from Eason A, House ME, Vincent Z et al. Factors associated with change in radiographic damage scores in gout: a prospective observational study. Ann Rheum Dis 2016;75:2075–9. Copyright 2016, with permission from BMJ Publishing Group. US has high interreader agreement for assessment of bone erosion [24], although it detects substantially fewer erosions in gout than MRI [54]. For MRI, the RAMRIS method has high interreader reliability for erosion [16]. A scoring method for MRI cartilage damage in gout has also been described [Gout MRI Cartilage Score (GOMRICS)] with high interreader reliability [27]. To date, no published studies have reported changes in US or MRI damage scores in longitudinal studies or clinical trials. Conventional CT allows excellent visualization for bone erosion and has been used widely to analyse mechanisms of bone damage in gout [3, 15, 60]. DECT also allows for assessment of bone erosion using the conventional CT images acquired at the time of scanning. A semi-quantitative CT damage score has been developed using CT scans of both feet, based on the RAMRIS method [29]. This scoring system has very high interreader agreement. In the placebo-controlled clinical trial of zoledronate for treatment of bone erosion in gout, CT damage scores did not significantly change in either group over the 2 year study period [57]. To date, this method has not been used for assessment of bone damage in studies of ULT. Challenges and uncertainties The work to date examining the role of imaging for assessment of treatment responses has identified several exciting techniques to measure urate crystal deposition, joint inflammation and structural damage. However, a number of challenges and core questions remain about the application of these methods to assess treatment response. Further standardization of lesions, definitions and sites for scanning and consistent assessment over different units and studies is also essential. For example, it is unclear whether a simplified CR score [21] is preferable to the widely used Sharp–van der Heijde score for assessing radiographic damage [20]; whether a four-joint US protocol is sufficient [25] or whether a more extensive scanning protocol is required [39] and whether DECT of the feet is sufficient [61] or whether a more extended field of scanning is needed [62]. The work of the OMERACT US Gout Task Force provides an exemplar of international cooperation to address such key questions of standardization [31, 34, 24]. The relative importance of different disease elements also requires further consideration; urate deposition often coexists with inflammation and structural damage, and it is unclear whether measurement of features other than urate deposition provides additional clinically relevant information. There is increasing evidence that subclinical joint inflammation is common in people with gout [16, 51, 52, 55, 56] and emerging data that ULT can reduce imaging features of inflammation [52, 56]. Research to date has focused almost exclusively on sensitivity to change of imaging tests in response to ULT, with no published data on the role of imaging in the assessment of the response to anti-inflammatory medications. This question requires a separate piece of work to determine whether imaging methods allow more sensitive assessment of joint inflammation to measure treatment response to anti-inflammatory therapies. A fundamental question is whether the use of imaging to assess treatment response provides important information in addition to low-cost clinical assessment. For example, for a patient on long-term ULT who has a well-controlled serum urate level below the treatment target, with suppressed flares and regressing tophi, does imaging assessment of urate burden, joint inflammation or radiographic damage add additional clinical information that allows better prediction of prognosis? Similarly, if a patient has poorly controlled hyperuricaemia and recurrent flares, does the presence of the double contour sign at the first MTP joint or urate deposition viewed on a DECT add additional clinical information? It is currently unclear whether imaging appearances can predict clinically important endpoints such as flares, disability and poor health-related quality of life or whether changes in imaging appearances over the short term predict changes in these clinical outcomes in the long term. At present it is also unknown whether changes in imaging findings are important to patients or reflect the patient’s experience in a clinically meaningful way. These uncertainties are important when considering the potential role of imaging, due to the procedural cost, additional time costs to the patient and physician and potential risks due to exposure to medical radiation or contrast (depending on the test). Furthermore, clinical trials and longitudinal cohort studies have shown that changes in imaging appearances occur slowly and over long periods of time in people with gout. The exception is the effect of pegloticase, an infusional agent that leads to profound urate lowering with rapid tophus regression by physical assessment [63] and also improvements in DECT urate deposition and CR bone erosion [48, 58]. In patients with less intensive ULT, tophus regression by physical assessment and changes in imaging appearances are slower. If changes in imaging occur in parallel with changes in clinical findings, it seems unlikely that imaging assessment of treatment response will be of major additional benefit to clinical assessment. Conclusion There has been rapid progress in the development of imaging techniques to assess domains of disease in gout. The place of imaging in the assessment of treatment response in gout is an evolving issue. Increasing data support the role of imaging for the diagnosis of disease, to assist clinical decision making about the intensity of ULT, to improve patient understanding and adherence to therapies and to dissect the mechanisms of disease. Although reliable scoring systems have been developed, the ultimate place of imaging tools for assessing treatment responses in gout remains uncertain. Understanding the benefits of imaging assessment of treatment response, in addition to comprehensive clinical assessment, will be essential to further establish the role of these methods. Acknowledgements We acknowledge Dr Ashika Chhana and Dr Sue McGlashan for assistance with cadaveric imaging. The collection and use of cadaveric tissue was in accordance with the New Zealand Human Tissue Act 2008. Supplement: This supplement was funded by Grunenthal. Funding: This work is supported by the Health Research Council of New Zealand (15/576). 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Published: Jan 1, 2018

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