Performance of classification criteria for gout in early and established disease.

OBJECTIVES: To compare the sensitivity and specificity of different classification criteria for gout in early and established disease. METHODS: This was a cross-sectional study of consecutive rheumatology clinic patients with joint swelling in which gout was defined by presence or absence of monosodium urate crystals as observed by a certified examiner at presentation. Early disease was defined as patient-reported onset of symptoms of 2 years or less. RESULTS: Data from 983 patients were collected and gout was present in 509 (52%). Early disease was present in 144 gout cases and 228 non-cases. Sensitivity across criteria was better in established disease (95.3% vs 84.1%, p<0.001) and specificity was better in early disease (79.9% vs 52.5%, p<0.001). The overall best performing clinical criteria were the Rome criteria with sensitivity/specificity in early and established disease of 60.3%/84.4% and 86.4%/63.6%. Criteria not requiring synovial fluid analysis had sensitivity and specificity of less than 80% in early and established disease. CONCLUSIONS: Existing classification criteria for gout have sensitivity of over 80% in early and established disease but currently available criteria that do not require synovial fluid analysis have inadequate specificity especially later in the disease. Classification criteria for gout with better specificity are required, although the findings should be cautiously applied to non-rheumatology clinic populations.

Flare Rate Thresholds for Patient Assessment of Disease Activity States in Gout.

OBJECTIVE: To determine the relationship between gout flare rate and self-categorization into remission, low disease activity (LDA), and patient acceptable symptom state (PASS). METHODS: Patients with gout self-categorized as remission, LDA, and PASS, and reported number of flares over the preceding 6 and 12 months. Multinomial logistic regression was used to determine the association between being in each disease state (LDA and PASS were combined) and flare count, and self-reported current flare. A distribution-based approach and extended Youden index identified possible flare count thresholds for each state. RESULTS: Investigators from 17 countries recruited 512 participants. Remission was associated with a median recalled flare count of zero over both 6 and 12 months. Each recalled flare reduced the likelihood of self-perceived remission compared with being in higher disease activity than LDA/PASS, by 52% for 6 months and 23% for 12 months, and the likelihood of self-perceived LDA/PASS by 15% and 5% for 6 and 12 months, respectively. A threshold of 0 flares in preceding 6 and 12 months was associated with correct classification of self-perceived remission in 58% and 56% of cases, respectively. CONCLUSION: Flares are significantly associated with perceptions of disease activity in gout, and no flares over the prior 6 or 12 months is necessary for most people to self-categorize as being in remission. However, recalled flare counts alone do not correctly classify all patients into self-categorized disease activity states, suggesting that other factors may also contribute to self-perceived gout disease activity.

Inorganic Pyrophosphatase-Nanodiamond Conjugates Hydrolyze Pyrophosphate in Human Synovial Fluid.

The present work is focused on testing enzyme-based agents for the partial dissolution of calcium pyrophosphate (CaPPi) deposits in the cartilages and synovial fluid of patients with pyrophosphate arthropathy (CPPD disease). Previously, we suggested that inorganic pyrophosphatases (PPases) immobilized on nanodiamonds of detonation synthesis (NDs) could be appropriate for this purpose. We synthesized and characterized conjugates of NDs and PPases from Escherichia coli and Mycobacterium tuberculosis. The conjugates showed high enzymatic activity and resistance to inhibition by calcium and fluoride. Here, we tested the effectiveness of pyrophosphate (PPi) hydrolysis by the conjugates in an in vitro model system simulating the ionic composition of the synovial fluid and in the samples of synovial fluid of patients with CPPD via NMR spectroscopy. The conjugates of both PPases efficiently hydrolyzed triclinic crystalline calcium pyrophosphate (t-CPPD) in the model system. We evaluated the number of phosphorus-containing compounds in the synovial fluid, showed the possibility of PPi detection in it, and estimated the hydrolytic activity of the PPase conjugates. The soluble and immobilized PPases were able to hydrolyze a significant amount of PPi (1 mM) in the synovial fluid in short periods of time (24 h). The maximum activity was demonstrated for Mt-PPase immobilized on ND-NH-(CH2)6-NH2 (2.24 U mg-1).

Brief Report: Validation of a Definition of Flare in Patients With Established Gout.

OBJECTIVE: To perform external validation of a provisional definition of disease flare in patients with gout. METHODS: Five hundred nine patients with gout were enrolled in a cross-sectional study during a routine clinical care visit at 17 international sites. Data were collected to classify patients as experiencing or not experiencing a gout flare, according to a provisional definition. A local expert rheumatologist performed the final independent adjudication of gout flare status. Sensitivity, specificity, predictive values, and receiver operating characteristic (ROC) curves were used to determine the diagnostic performance of gout flare definitions. RESULTS: The mean ± SD age of the patients was 57.5 ± 13.9 years, and 89% were male. The definition requiring fulfillment of at least 3 of 4 criteria (patient-defined gout flare, pain at rest score of >3 on a 0-10-point numerical rating scale, presence of at least 1 swollen joint, and presence of at least 1 warm joint) was 85% sensitive and 95% specific in confirming the presence of a gout flare, with an accuracy of 92%. The ROC area under the curve was 0.97. The definition based on a classification and regression tree algorithm (entry point, pain at rest score >3, followed by patient-defined flare "yes") was 73% sensitive and 96% specific. CONCLUSION: The definition of gout flare that requires fulfillment of at least 3 of 4 patient-reported criteria is now validated to be sensitive, specific, and accurate for gout flares, as demonstrated using an independent large international patient sample. The availability of a validated gout flare definition will improve the ascertainment of an important clinical outcome in studies of gout.

Performance of Ultrasound in the Diagnosis of Gout in a Multicenter Study: Comparison With Monosodium Urate Monohydrate Crystal Analysis as the Gold Standard.

OBJECTIVE: To examine the performance of ultrasound (US) for the diagnosis of gout using the presence of monosodium urate monohydrate (MSU) crystals as the gold standard. METHODS: We analyzed data from the Study for Updated Gout Classification Criteria (SUGAR), a large, multicenter observational cross-sectional study of consecutive subjects with at least 1 swollen joint who conceivably may have gout. All subjects underwent arthrocentesis; cases were subjects with confirmed MSU crystals. Rheumatologists or radiologists who were blinded with regard to the results of the MSU crystal analysis performed US on 1 or more clinically affected joints. US findings of interest were double contour sign, tophus, and snowstorm appearance. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Multivariable logistic regression models were used to examine factors associated with positive US results among subjects with gout. RESULTS: US was performed in 824 subjects (416 cases and 408 controls). The sensitivity, specificity, PPV, and NPV for the presence of any 1 of the features were 76.9%, 84.3%, 83.3%, and 78.2%, respectively. Sensitivity was higher among subjects with a disease duration of ≥2 years and among subjects with subcutaneous nodules on examination (suspected tophus). Associations with a positive US finding included suspected clinical tophus (odds ratio [OR] 4.77 [95% confidence interval (95% CI) 2.23-10.21]), any abnormality on plain radiography (OR 4.68 [95% CI 2.68-8.17]), and serum urate level (OR 1.31 [95% CI 1.06-1.62]). CONCLUSION: US features of MSU crystal deposition had high specificity and high PPV but more limited sensitivity for early gout. The specificity remained high in subjects with early disease and without clinical signs of tophi.

Survey Definitions of Gout for Epidemiologic Studies: Comparison With Crystal Identification as the Gold Standard.

OBJECTIVE: To identify the best-performing survey definition of gout from items commonly available in epidemiologic studies. METHODS: Survey definitions of gout were identified from 34 epidemiologic studies contributing to the Global Urate Genetics Consortium (GUGC) genome-wide association study. Data from the Study for Updated Gout Classification Criteria (SUGAR) were randomly divided into development and test data sets. A data-driven case definition was formed using logistic regression in the development data set. This definition, along with definitions used in GUGC studies and the 2015 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) gout classification criteria were applied to the test data set, using monosodium urate crystal identification as the gold standard. RESULTS: For all tested GUGC definitions, the simple definition of "self-report of gout or urate-lowering therapy use" had the best test performance characteristics (sensitivity 82%, specificity 72%). The simple definition had similar performance to a SUGAR data-driven case definition with 5 weighted items: self-report, self-report of doctor diagnosis, colchicine use, urate-lowering therapy use, and hyperuricemia (sensitivity 87%, specificity 70%). Both of these definitions performed better than the 1977 American Rheumatism Association survey criteria (sensitivity 82%, specificity 67%). Of all tested definitions, the 2015 ACR/EULAR criteria had the best performance (sensitivity 92%, specificity 89%). CONCLUSION: A simple definition of "self-report of gout or urate-lowering therapy use" has the best test performance characteristics of existing definitions that use routinely available data. A more complex combination of features is more sensitive, but still lacks good specificity. If a more accurate case definition is required for a particular study, the 2015 ACR/EULAR gout classification criteria should be considered.

Diagnostic Arthrocentesis for Suspicion of Gout Is Safe and Well Tolerated.

OBJECTIVE: To determine the frequency of adverse events of diagnostic arthrocentesis in patients with possible gout. METHODS: Consecutive patients underwent arthrocentesis and were evaluated at 6 weeks to determine adverse events. The 95% CI were obtained by bootstrapping. RESULTS: Arthrocentesis was performed in 910 patients, and 887 (97.5%) were evaluated for adverse events. Any adverse event was observed in 12 participants (1.4%, 95% CI 0.6-2.1). There was 1 case (0.1%, 95% CI 0-0.34) of septic arthritis. CONCLUSIONS: Diagnostic arthrocentesis is associated with a low frequency of adverse events. Septic arthritis rarely occurs.

Study for Updated Gout Classification Criteria: Identification of Features to Classify Gout.

OBJECTIVE: To determine which clinical, laboratory, and imaging features most accurately distinguished gout from non-gout. METHODS: We performed a cross-sectional study of consecutive rheumatology clinic patients with ≥1 swollen joint or subcutaneous tophus. Gout was defined by synovial fluid or tophus aspirate microscopy by certified examiners in all patients. The sample was randomly divided into a model development (two-thirds) and test sample (one-third). Univariate and multivariate association between clinical features and monosodium urate-defined gout was determined using logistic regression modeling. Shrinkage of regression weights was performed to prevent overfitting of the final model. Latent class analysis was conducted to identify patterns of joint involvement. RESULTS: In total, 983 patients were included. Gout was present in 509 (52%). In the development sample (n = 653), the following features were selected for the final model: joint erythema (multivariate odds ratio [OR] 2.13), difficulty walking (multivariate OR 7.34), time to maximal pain <24 hours (multivariate OR 1.32), resolution by 2 weeks (multivariate OR 3.58), tophus (multivariate OR 7.29), first metatarsophalangeal (MTP1) joint ever involved (multivariate OR 2.30), location of currently tender joints in other foot/ankle (multivariate OR 2.28) or MTP1 joint (multivariate OR 2.82), serum urate level >6 mg/dl (0.36 mmoles/liter; multivariate OR 3.35), ultrasound double contour sign (multivariate OR 7.23), and radiograph erosion or cyst (multivariate OR 2.49). The final model performed adequately in the test set, with no evidence of misfit, high discrimination, and predictive ability. MTP1 joint involvement was the most common joint pattern (39.4%) in gout cases. CONCLUSION: Ten key discriminating features have been identified for further evaluation for new gout classification criteria. Ultrasound findings and degree of uricemia add discriminating value, and will significantly contribute to more accurate classification criteria.