Objective
To investigate the efficacy and safety of lesinurad in combination with febuxostat in a 12‐month phase III trial in patients with tophaceous gout.
Methods
Patients with serum urate (UA) ...≥8.0 mg/dl (≥6.0 mg/dl with urate‐lowering therapy) and ≥1 measurable target tophus were given febuxostat 80 mg/day for 3 weeks before randomization to receive lesinurad (200 or 400 mg daily) or placebo in addition to the febuxostat. The primary end point was the proportion of patients achieving a serum UA level of <5.0 mg/dl (month 6). The key secondary end point was the proportion of patients with complete resolution of ≥1 target tophus (month 12). Other end points included the percentage change in total target tophi area. Safety assessments included adverse events and laboratory data.
Results
Patients (n = 324) were predominantly male, with a mean age of 54.1 years. Significantly more patients achieved the serum UA target by month 6 with the addition of lesinurad 400 mg (76.1%; P < 0.0001), but not 200 mg (56.6%; P = 0.13), to the febuxostat therapy as compared with febuxostat alone (46.8%). At all other time points, significantly more patients in the lesinurad 200 mg group achieved the serum UA target. The number of patients with complete tophus resolution was not different between groups. Treatment with lesinurad (200 mg and 400 mg) plus febuxostat reduced the total target tophi area as compared with febuxostat alone (50.1% and 52.9% versus 28.3%, respectively; P < 0.05). Safety was generally comparable with that of febuxostat alone, except for higher rates of predominantly reversible elevations in the serum creatinine level, particularly with lesinurad 400 mg.
Conclusion
Treatment with lesinurad in combination with febuxostat demonstrated superior lowering of serum UA levels as compared with febuxostat alone, with clinically relevant added effects on tophi and an acceptable safety profile with lesinurad 200 mg in patients with tophaceous gout warranting additional therapy.
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.
Objective
Existing criteria for the classification of gout have suboptimal sensitivity and/or specificity, and were developed at a time when advanced imaging was not available. The current effort was ...undertaken to develop new classification criteria for gout.
Methods
An international group of investigators, supported by the American College of Rheumatology and the European League Against Rheumatism, conducted a systematic review of the literature on advanced imaging of gout, a diagnostic study in which the presence of monosodium urate monohydrate (MSU) crystals in synovial fluid or tophus was the gold standard, a ranking exercise of paper patient cases, and a multicriterion decision analysis exercise. These data formed the basis for developing the classification criteria, which were tested in an independent data set.
Results
The entry criterion for the new classification criteria requires the occurrence of at least 1 episode of peripheral joint or bursal swelling, pain, or tenderness. The presence of MSU crystals in a symptomatic joint/bursa (i.e., synovial fluid) or in a tophus is a sufficient criterion for classification of the subject as having gout, and does not require further scoring. The domains of the new classification criteria include clinical (pattern of joint/bursa involvement, characteristics and time course of symptomatic episodes), laboratory (serum urate, MSU‐negative synovial fluid aspirate), and imaging (double‐contour sign on ultrasound or urate on dual‐energy computed tomography, radiographic gout‐related erosion). The sensitivity and specificity of the criteria are high (92% and 89%, respectively).
Conclusion
The new classification criteria, developed using a data‐driven and decision analytic approach, have excellent performance characteristics and incorporate current state‐of‐the‐art evidence regarding gout.
There has been increased interest in gout in both academic and clinical practice settings. Several reasons may explain this. The prevalence of both hyperuricemia and gout has risen in the last ...decades in developed countries and therefore the burden of gout has increased. The association of hyperuricemia and gout with cardiovascular outcomes and the opportunity of further benefits of intervention on hyperuricemia have been recently highlighted in the literature. Imaging techniques have proven to be useful for detection of urate deposition, even prior to the first clinical symptoms, enabling the evaluation of the extent of deposition and providing objective measurement of crystal depletion during urate-lowering treatment. Treating to target is increasingly used as the approach to treatment of diverse diseases. Therefore, different targets have been recommended for different stages of the burden of disease and for different stages of treatment. The final strategic target, to which any effort should be taken into consideration, is to completely dissolve urate crystals in tissues and therefore avoid further symptoms and structural damage of involved musculoskeletal structures. In summary, evidence suggest that an early approach to the treatment of gout and associated comorbidities is advisable, that new imaging techniques may help to evaluate both the burden of deposition and response to urate-lowering treatment in selected patients, and finally that the final strategic objective of healthcare for patients with gout is to completely resolve urate crystal deposits.
Objective
Classification criteria for calcium pyrophosphate deposition (CPPD) disease will facilitate clinical research on this common crystalline arthritis. Our objective was to report on the first ...2 phases of a 4‐phase process for developing CPPD classification criteria.
Methods
CPPD classification criteria development is overseen by a 12‐member steering committee. Item generation (phase I) included a scoping literature review of 5 literature databases and contributions from a 35‐member combined expert committee and 2 patient research partners. Item reduction and refinement (phase II) involved a combined expert committee meeting, discussions among clinical, imaging, and laboratory advisory groups, and an item‐rating exercise to assess the influence of individual items toward classification. The steering committee reviewed the modal rating score for each item (range –3 strongly pushes away from CPPD to +3 strongly pushes toward CPPD) to determine items to retain for future phases of criteria development.
Results
Item generation yielded 420 items (312 from the literature, 108 from experts/patients). The advisory groups eliminated items that they agreed were unlikely to distinguish between CPPD and other forms of arthritis, yielding 127 items for the item‐rating exercise. Fifty‐six items, most of which had a modal rating of +/– 2 or 3, were retained for future phases. As numerous imaging items were rated +3, the steering committee recommended focusing on imaging of the knee and wrist and 1 additional affected joint for calcification suggestive of CPP crystal deposition.
Conclusion
A data‐ and expert‐driven process is underway to develop CPPD classification criteria. Candidate items comprise clinical, imaging, and laboratory features.
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.
Bacterial pathogens utilize a myriad of mechanisms to invade mammalian hosts, damage tissue sites, and evade the immune system. One essential strategy of Gram-negative bacteria is the secretion of ...virulence factors through both inner and outer membranes to reach a potential target. Most secretion systems are harbored in mobile elements including transposons, plasmids, pathogenicity islands, and phages, and
Escherichia coli
is one of the more versatile bacteria adopting this genetic information by horizontal gene transfer. Additionally,
E. coli
is a bacterial species with members of the commensal intestinal microbiota and pathogens associated with numerous types of infections such as intestinal, urinary, and systemic in humans and other animals. T6SS cluster plasticity suggests evolutionarily divergent systems were acquired horizontally. T6SS is a secretion nanomachine that is extended through the bacterial double membrane; from this apparatus, substrates are conveyed straight from the cytoplasm of the bacterium into a target cell or to the extracellular space. This nanomachine consists of three main complexes: proteins in the inner membrane that are T4SS component-like, the baseplate complex, and the tail complex, which are formed by components evolutionarily related to contractile bacteriophage tails. Advances in the T6SS understanding include the functional and structural characterization of at least 13 subunits (so-called core components), which are thought to comprise the minimal apparatus. So far, the main role of T6SS is on bacterial competition by using it to kill neighboring non-immune bacteria for which antibacterial proteins are secreted directly into the periplasm of the bacterial target after cell–cell contact. Interestingly, a few T6SSs have been associated directly to pathogenesis, e.g., roles in biofilm formation and macrophage survival. Here, we focus on the advances on T6SS from the perspective of
E. coli
pathotypes with emphasis in the secretion apparatus architecture, the mechanisms of pathogenicity of effector proteins, and the events of lateral gene transfer that led to its spread.
Serine proteases exist in eukaryotic and prokaryotic organisms and have emerged during evolution as the most abundant and functionally diverse group. In Gram-negative bacteria, there is a growing ...family of high molecular weight serine proteases secreted to the external milieu by a fascinating and widely employed bacterial secretion mechanism, known as the autotransporter pathway. They were initially found in Neisseria, Shigella, and pathogenic Escherichia coli, but have now also been identified in Citrobacter rodentium, Salmonella, and Edwardsiella species. Here, we focus on proteins belonging to the serine protease autotransporter of Enterobacteriaceae (SPATEs) family. Recent findings regarding the predilection of serine proteases to host intracellular or extracellular protein-substrates involved in numerous biological functions, such as those implicated in cytoskeleton stability, autophagy or innate and adaptive immunity, have helped provide a better understanding of SPATEs’ contributions in pathogenesis. Here, we discuss their classification, substrate specificity, and potential roles in pathogenesis.
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