Imaging Modalities For The Classification Of Gout: Systematic Literature Review And Meta-

Analysis

When it comes to conducting a literature review and meta-analysis on the classification of gout
through imaging modalities, the task can be quite challenging. Gout, a form of arthritis caused by the
buildup of uric acid crystals in the joints, has been studied extensively, leading to a plethora of
literature on the subject. However, navigating through this vast body of research to extract relevant
data and draw meaningful conclusions requires a keen understanding of the topic and rigorous
methodology.

One of the primary difficulties in writing a literature review on imaging modalities for gout
classification is the sheer volume of studies available. Researchers have utilized various imaging
techniques such as ultrasound, dual-energy computed tomography (DECT), magnetic resonance
imaging (MRI), and conventional radiography to diagnose and classify gout. Each modality has its
advantages and limitations, and synthesizing findings from numerous studies to compare their
effectiveness can be a daunting task.

Furthermore, the quality and reliability of the studies must be carefully assessed to ensure the
validity of the conclusions drawn. Factors such as sample size, study design, patient demographics,
and outcome measures can significantly impact the results of the meta-analysis. Therefore,
meticulous attention to detail is required throughout the review process to minimize bias and ensure
the robustness of the findings.

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Many of the commonly used PROMs in this field are currently not yet well supported and more
studies on their measurement properties are needed among both acute and chronic gout populations.
Between-group discrimination has not been demonstrated. For assessing health-related quality of life,
the current evidence suggests the SF-36v2 may be used as an alternative. Results Four hundred and
seventeen articles met inclusion criteria and were included in the review. The majority of clinical
trials identified in the literature search were equivalence and safety NSAID studies, typically with
indomethacin as the active comparator. Crystal-Proven Gout and Characteristic Gout Severity
Factors Are Associated With Cardiovascular Disease. Currently, there were many studies on the
relationship between gout and coronary heart disease. Araujo EG, Bayat S, Petsch C, Englbrecht M,
Faustini F, Kleyer A, et al. Comparators included placebo, urate-lowering medications (uricases,
uricosuric agents, xanthine oxidase inhibitors) or other nonpharmacological interventions including
lifestyle interventions used in treating gout. In 2015, the classification criteria recommended by the
European League Against Rheumatism (EULAR) and the American College of Rheumatology
(ACR) endorsed the US and DECT as a new and effective diagnostic tool for gout ( 12 ). This is
particularly relevant to acute gout, which frequently presents as a monoarthritis 17. The result
showed that both the lifestyle and ULTs were useful in dissolving MSU deposits after 18 months.
These comorbidities and comedications in many patients pose challenges to the management of gout.
JAS’ work was supported by the NIH (grants from the National Institute of Arthritis and
Musculoskeletal and Skin Diseases, the National Institute on Aging, and the National Cancer
Institute) and the Agency for Healthcare Research and Quality (Center for Education and Research
on Therapeutics programme). The electron microscopy appearances were not described (Table 1 ).
Schlesinger N. Treatment of Chronic Gouty Arthritis: It is Not Just About Urate-Lowering Therapy.
Health resource use was collected using a self-report questionnaire that was cross-checked with the
electronic patient file. The Website of the US Food and Drug Administration and European
Medicines Agency were also searched. Modjinou DV, Krasnokutsky S, Gyftopoulos S, Pike VC,
Karis E, Keenan RT, et al. AbbVie did not review the content or have influence on this report.
Febuxostat, rasburicase, benzbromarone, and the combination of allopurinol and benzbromarone all
seem to be effective in gout patients with impairment of renal function. We contacted the trial
authors to obtain pertinent unpublished data and sought clarification of results, respectively, when
there was incomplete or unclear reporting of trial data. OpenUrl CrossRef PubMed 2. ? Choi HK,
Atkinson K, Karlson EW, Willett W, Curhan G. Unlike with allopurinol, there currently is no
recommendation for dose reduction in mild to moderate renal impairment. 7. The analysis of DECT
evaluation displayed that for every 1-cm 3 increase in urate deposition volume in feet, the risk of
gout attacks increased 2.03-fold during the first 6 months compared to the baseline. Mechanisms of
Bone Erosion in Gout: A Quantitative Analysis Using Plain Radiography and Computed
Tomography. Progress in measurement instruments for acute and chronic gout studies. Use of oral
prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence
trial. Correction notice This paper has been amended since it was published Online First. It has been
hypothesized that the decrease in serum uric acid leads to the instability and dissolution of urate,
exposing it to the autoimmune system and producing a strong immune response that leads to an
outbreak of gout ( 23 ).
Treatment of chronic gout in patients with renal function impairment: An open, randomized, actively
controlled study. The joint architecture has been lost, with tophus and significant bone erosion
present. Additionally, the existing published criteria were developed at a time when advanced
imaging modalities, such as ultrasonography or dual-energy CT (DECT), had not been studied; their
utility for gout classification in the context of other clinical and laboratory parameters is not known.
Properties for these 2 instruments are shown in Table 5. Canakinumab for the treatment of acute
flares in difficult-to-treat gouty arthritis: Results of a multicenter, phase II, dose-ranging study.
Cadaveric samples were transferred to 70% ethanol immediately after collection and all samples
were demineralised at room temperature in 10% formic acid and embedded in paraffin. Pascart T,
Capon B, Grandjean A, Legrand J, Namane N, Ducoulombier V, et al. Observations on spontaneous
improvement in patients with podagra: implications for therapeutic trials of non-steroidal anti-
inflammatory drugs. Particularly in this disease where the balance between the need for effective
drugs on the one hand and the cautiousness about potential adverse events of drug treatment on the
other might be more delicate than in other diseases. The expert panel aimed to define relevant clinical
and imaging parameters to be as specific as possible for gout. OpenUrl PubMed 5. ? Primatesta P,
Plana E, Rothenbacher D. All instruments measuring physical function (HAQ-DI, Health Assessment
Questionnaire-II (HAQ-II), SF-36v2 physical functioning subscale) received favorable ratings for
reliability, as did the RA-WIS and a couple of the Gout Assessment Questionnaire 2.0 (GAQ2.0)
subscales and total scale. The management and monitoring of gout complications are an important
part of gout treatment; by using modern and advanced imaging methods, we can clearly know MSU
depositions so as to better understand disease development and dynamic manifestations. FIGURE 1.
One aspect of the complexity is that patients with gout often experience high rates of comorbidities,
raising many challenges 2, 3. These inconsistencies among guidance documents may result from
ethnical and social differences, however, can also be consequences of non-standard developing
processes. Gout is an increasingly prevalent condition worldwide and creates a heavy economic
burden. Applying more strict definitions for a gout case rendered a prevalence of 1.36 % (95 % CI
1.34 to 1.38) and 0.5 (95 % CI 0.49 to 0.51) per 100,000 person-years, respectively. The use of
expert opinion as a reference standard incorporates an unquestionable risk of circularity, especially
when clinical features or operator-dependent features are considered. Preliminary criteria for the
classification of the acute arthritis of primary gout. We contacted the trial authors to obtain pertinent
unpublished data and sought clarification of results, respectively, when there was incomplete or
unclear reporting of trial data. The intervention was defined as gout-specific drugs (colchicine, IL-1
inhibitor, allopurinol, benzbromarone, probenecid, febuxostat, rasburicase, pegloticase, and
sulfinpyrazone). The consistency between MSU crystals and US gouty features (DCs and
hyperechoic areas) in asymptomatic hyperuricemia patients was first reported in 2012, validating the
role of US in the early diagnosis and detection of structural damage in AH patients ( 18 ). This was
done so as proposed by the International Classification of Functioning, disability and health linking
rules 2016. (DOCX 21 kb) Additional file 3: Content of the multi- and unidimensional scales used in
gout outcome studies according to the International Classification of Functioning (ICF) framework,
given as the number, N, and percentage (%) of total health concepts measured. Immunoglobulin in
tophi and on the surface of monosodium urate crystals. The readability of each questionnaire was
assessed using the Flesh-Kincaid Grade level-test. We evaluated instruments for these domains
according to the OMERACT filter: truth, feasibility, and discrimination. The study revealed that the
presence and volume of urate deposits in feet measured by DECT were significantly associated with
flares, rather than the number of joints bearing DCs assessed by US. But perhaps the most
remarkable difference is the separation of studies by reference standards. Since 2002, the Outcome
Measures in Rheumatology (OMERACT) Gout Special Interest Group has worked toward defining
outcome measures for studies in gout 2, 3, 4, 5, 6, 7, 8, 9, 10. Of the 19 instruments, 10 were
variations of the 5-point PGART instrument, using different descriptors, ranges, and methods of data
collection.
Funding Supported jointly by the American College of Rheumatology and the European League
Against Rheumatism. The study includes 104 symptomatic joints with acute or subacute mono or
oligoarthritis that have undergone US and joint aspiration with crystal analysis in a single center’s
rheumatology clinics. The titles and abstracts of the retrieved articles were screened independently
by two reviewers (MOV and CJ) on relatedness to gout and development or evaluation of a PROM.
Uric acid-lowering therapy is advised when there are recurrent attacks, tophaceous disease, or
polyarticular disease. Information regarding the pathological features of gout was extracted from
each article in a standardized form, along with information about the organ or tissue examined,
fixative for microscopy, and specific features described for the following categories: macroscopic
appearances, light microscopic appearances, immunohistochemistry, and electron microscopy. Bayat
S, Aati O, Rech J, Sapsford M, Cavallaro A, Lell M, et al. Gutierrez M, Schmidt WA, Thiele RG,
Keen HI, Kaeley GS, Naredo E, et al. Patients with uncontrolled gout had higher presenteeism,
overall work impairment, activity impairment, and number of emergency department visits than those
with controlled gout or controls. For the synovial fluid domain, the fluid must be aspirated from a
symptomatic (ever) joint or bursa, and assessed by a trained observer. Twenty different instruments
were used in these studies to assess the pain of acute gout. The risk of bias of each study was rated
as “Yes” (low risk of bias), “No” (high risk of bias), or “Unclear” (either lack of information or
uncertainty over the potential for bias). Cochrane handbook for systematic reviews of interventions,
version 5.1.0 (updated March 2011). Slides with 4??m tissue sections were prepared and then stained
with haematoxylin and eosin or toluidine blue, and examined using polarising light microscopy.
Between-group discrimination has not been demonstrated. As with most diseases, there is a gradient
of probability of truly having the disease based on signs and symptoms. The threshold chosen for
this classification criteria set yielded the best combination of sensitivity and specificity. These
inconsistencies among guidance documents may result from ethnical and social differences, however,
can also be consequences of non-standard developing processes. Additionally, classification criteria
should be applied only to the intended population—those who meet the entry criteria. To enhance
their position in gout research, we recommend that more evidence on the validity and reliability of
PROMs used in gout becomes available. Relation between adverse events associated with allopurinol
and renal function in patients with gout. Ostergaard M, Peterfy C, Conaghan P, McQueen F, Bird P,
Ejbjerg B, et al. This review mainly focuses on the role of US, DECT, and MRI in the management
of gout. Health-related quality of life in gout: a systematic review. The draft search strategy for
EMBASE using the OVID interface is provided as table 1. These findings confirmed that gout
treatment was a long-term battle. Two trials compared 2 different medications in patients with renal
impairment 15, 20. Dalbeth N, House ME, Aati O, Tan P, Franklin C, Horne A, et al. Light
microscopic appearances were reported in 37 articles. Some US and DECT findings show better
performance than most clinical features. Noteworthy efforts were undertaken in the largest study to
confirm the validity of not finding MSU crystals initially (1-year followup and repeat SF analysis if a
new bout of arthritis appeared in all patients with arthritis of unknown origin), thereby reducing the
risk of false-negative findings on the first SF test. Comparative study on treatment of acute gouty
arthritis by electroacupuncture with different frequency.
The most commonly used comedications are antihypertensive drugs, statins, and nonsteroidal
antiinflammatory drugs (NSAID) 2. Outcome domains for studies of acute and chronic gout.
Treatment of acute gouty arthritis with proquazone and indomethacin. Sensitivity to change over
time has been reported in many studies, although data were not available to allow calculation of
effect sizes. Mast cells were also identified in fibrovascular zones. The immunohistochemistry
findings and electron microscopy appearances were not described (Table 1 ). This classification
criteria set will enable a standardised approach to identifying a relatively homogeneous group of
individuals who have the clinical entity of gout for enrolment into studies. The role of lifestyle
interventions as an adjunct to medications for treating acute gout attacks is less well established,
with theoretical concerns that applying lifestyle interventions that affect urate-lowering during the
acute setting may cause harm. However, the ACR guideline 14 suggested that pharmacological ULT
could be started during an acute gout attack as long as anti-inflammatory management was effective.
A study led by conventional CT, DECT, and XR techniques showed that urate crystals and soft tissue
composition of tophi were directly associated with bone destruction scores, a significant reduction in
soft tissue inflammation was associated with improved bone destruction after ULTs ( 51 ). Names of
regions to be searched are: the United States, Australia, Canada, China, Europe, Hong Kong, India,
Japan, Singapore, South Africa and the United Kingdom. Performance of gout impact scale in a
longitudinal observational study of patients with gout. A large cross-sectional study also confirmed
the role of US in detecting the changes in the kidney induced by gout. A web-based calculator can
be accessed at, as well as through the ACR and EULAR websites. Evidence-based medicine: How
to practice and teach EBM. Both searches were updated prior to publication of the 2 Cochrane
reviews 6, 7 on April 5, 2013. MSU crystals from tophi or joint synovial fluid aspiration by
microscopic detection are negatively birefringent and needle-shaped ( 9 ), which is still the gold
standard in gout diagnosis, while with the rapid development of imaging techniques, particularly US,
DECT, and MRI, which provide non-invasive and clear identification of MSU crystal deposition,
they are considered to be a promising tool for gout diagnosis ( 10, 11 ). In fact, the lack of
prevention and the scarce adherence to monitoring increase the number and costs of hospitalisation.
Ostergaard M, Peterfy C, Conaghan P, McQueen F, Bird P, Ejbjerg B, et al. A systematic review of
the literature concerning all aspects of gout diagnosis was performed. This method has high face
validity as it captures the degree of swelling in the affected joint, which is particularly relevant to
acute gout, which frequently presents as a mono-arthritis 17. For the latter study, hypotheses were
not confirmed for some correlations with the subscales of the SF-36v2 (including emotional health,
emotional role limitation, social), but also for correlations with outcomes such as the number of gout
flares in the past month, Visual Analogue Scale (VAS) for pain, swollen joint count and physician
global assessment. Assessments of test-retest reliability in acute gout are complicated by the often
rapid improvement that occurs, even without treatment, in the clinical status of patients. AbbVie did
not review the content or have influence on this manuscript. An example of the full search strategy
listed is shown in the Additional file 1. Bibliographical references of individual publications were
also checked. Matrix fibres appeared disordered with different sizes and orientations. The second
trial (120 participants), at moderate risk of bias, compared enriched skim milk powder
(glycomacropeptide and G600 milk fat extract) to non-enriched skim milk and lactose powders for
treating chronic gout. While lifestyle and dietary modifications are likely to be beneficial in the
management of comorbid cardiovascular disease and metabolic syndrome in patients with gout, their
role in treating acute gouty arthritis or preventing gout flares in established disease remains
unproven, due to the lack of evidence from high-quality trials. The study includes 104 symptomatic
joints with acute or subacute mono or oligoarthritis that have undergone US and joint aspiration with
crystal analysis in a single center’s rheumatology clinics.
Along these lines, it would be interesting to explore the effect of allopurinol in a dose higher than
100 mg compared to febuxostat, as current studies in the population of patients with impairment of
renal function have concluded that febuxostat is more effective than allopurinol 13, 14. The majority
of the PROMs were rated positively for content validity. Although gout is “curable” through ULTs,
this disease is poorly managed worldwide, because of poor adherence in gout patients to the
medications (e.g., febuxostat or allopurinol) of ULTs. Light microscopic appearances were reported
in 34 articles. Interpretation of crystals in electron micrographs. Evaluation of measurement
properties of such measures in gout seems very relevant. Methods This protocol is developed based
on the Preferred Reporting Items for Systematic Reviews and Meta Analyses for Protocols
(PRISMA-P) 31 32 and is registered with PROSPERO (registration number: CRD42016046104).
Part I: Diagnosis. Report of a task force of the Standing Committee for International Clinical Studies
Including Therapeutics (ESCISIT). Four-point Likert scales assessing index joint swelling and
tenderness have been used in numerous acute gout studies; these instruments are feasible, with high
face and content validity, and show within- and between-group discrimination. Their usage may
enhance the feasibility of studies by, for example, creating less measurement error, leading to a
smaller required sample size. Spontaneous rupture of the Achilles tendon in a patient with gout.
Accurate classification of gout without crystal documentation for recruitment into studies is also
needed, since the majority of cases of gout are managed in primary or acute care settings, 17, 18
where synovial fluid aspiration and polarising microscopy are not commonly performed. However,
there have been recurrent efforts to find alternative, noninvasive methods to establish diagnosis with
sufficient accuracy. Impact of Sonography in Gouty Arthritis: Comparison With Conventional
Radiography, Clinical Examination, and Laboratory Findings. When these differences in response
behavior were controlled for in the model, the authors found that the mean disability scores for the
different disease groups were changed slightly. Limited validity of the criteria of the American
College of Rheumatology criteria for classifying patients with gout in primary care. A further 30
articles were identified in the updated search in March 2018. Hence, we will conduct this systematic
review to identify the quality and consistency of guidelines and consensus, and provide a summary
of guideline recommendations. Ketoprofen versus indomethacin in patients with acute gouty
arthritis: a multicenter, double blind comparative study. OpenUrl CrossRef PubMed 12. ? Wells GA,
Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. No articles reported internal validity,
feasibility, or test-retest reproducibility. The properties of the 3 methods used most frequently have
been shown. This analysis emphasizes the central role of MSU crystal deposition as the pathogenic
lesion in gout, the typical patterns of involvement on anatomical pathology assessment that mirror the
clinical presentation of disease, and the characteristic tissue response to deposited crystals. The most
common comorbidities are hypertension, lipid disorders, and diabetes mellitus 2, 5. The readability of
each questionnaire was assessed using the Flesh-Kincaid Grade level-test. However, the SF-36
physical functioning subscale is the only PROM that currently meets all the quality criteria we
imposed for this review. All 3 methods were considered feasible, with high face and content validity.
The research question was which instruments assessing the core domains in acute gout met the
OMERACT filter. In addition, MSU can be deposited in some unusual areas such as the ribs, spine,
wrists, and lower extremity enthesopathy, causing pain to the patient. Articles that did not fulfill all
inclusion criteria or had insufficient data for analysis were excluded.
References of included studies and systematic reviews of PROMs found in the search were screened
initially by title, and if relevant, abstracts were assessed for potentially relevant papers. Gutierrez M,
Schmidt WA, Thiele RG, Keen HI, Kaeley GS, Naredo E, et al. Cellular Characterization of the
Gouty Tophus: A Quantitative Analysis. For the renal manifestations of gout, both US and DECT
can detect MSU deposition in the renal medulla of patients with severe gout ( 69 ). Patient-reported
outcomes in chronic gout: a report from OMERACT 10. Based on these key features, initial
formulation of potential criteria was developed, with consideration of entry, sufficient, and exclusion
criteria and more precise definition of domains and their categories. The incidence and prevalence of
gout are increasing worldwide, with recent data estimating that the prevalence of gout ranges from
roughly 1, 2 ). Preliminary criteria for the classification of the acute arthritis of primary gout.
Immunohistochemistry and electron microscopy appearances were reported in one and three articles,
respectively (Table 1 ). References are represented as numerals in parentheses. Prior to the in-person
expert panel meeting, panel members were given the data from Phase 1 to review, and they were
asked to rank-order the 30 paper patient cases from lowest to highest probability of having gout. In
the discrete-choice experiments, the lack of imaging data was weighted the same as for studies
performed with negative results, supporting the validity of using the scoring system in the absence of
imaging data. Both scoring systems were found to be sensitive to changes during treatment. The
health assessment questionnaire disability index is a valid measure of physical function in gout. In
addition, MSU can be deposited in some unusual areas such as the ribs, spine, wrists, and lower
extremity enthesopathy, causing pain to the patient. A third reviewer (PtK) was consulted if
disagreements remained unresolved. Primary care providers’ knowledge, beliefs and treatment
practices for gout: results of a physician questionnaire. Multivariate analysis found that hyperechoic
patterns in the medulla were associated with gout arthritis, DC thickness, disease duration, and
reduced glomerular filtration rate. Within-group and between-group discrimination has been reported
using this instrument ( Table 2 ). These results suggested that hyperuricemia patients who have
sustaining foot pain and positive US features may be the alternative gouty presentation and
responsive to the ULTs, which may also be included in the gout classification criteria to identify and
treat gout at an earlier stage, increasing diagnostic sensitivity and treatment effectiveness. OpenUrl
PubMed 55. Murphy JE. Piroxicam in the treatment of acute gout: a multicentre open study in
general practice. The results suggest that PROMs are available to assess the majority of the
recommended OMERACT core outcome domains for use in clinical research for acute and chronic
gout. No date restrictions were used; the earliest database search date was 1872. Sensitivity to
change over time has been reported in many studies, with effect size calculated as 2.5 following 3
days of high-dose piroxicam 23. However, guidance documents issued by different organisations for
hyperuricaemia and gout are highly inconsistent, which impairs the application of and compliance to
these documents. Dual Energy Computed Tomography in Tophaceous Gout. Caruso I, Fumagalli M,
Marcolongo R, Sacchetti G. OpenUrl CrossRef PubMed 4. ? Sivera F, Andres M, Carmona L, Kydd
AS, Moi J, Seth R, et al. High-resolution ultrasonography of the first metatarsal phalangeal joint in
gout: A controlled study. Summarizing the data in a metaanalysis using a random effects model was
planned if the included studies were sufficiently homogeneous that it was clinically meaningful to
combine them 17.