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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., Competing Interests: AO has received consulting fees from Novartis. ND has received consulting fees, speaker fees or grants from the following companies: Takeda, Menarini, Teijin, Pfizer, Crealta, Cymabay, Fonterra, Ardea Biosciences and AstraZeneca, outside the submitted work. WT has received consulting fees from AstraZeneca and Pfizer. FPR has received consulting fees from AstraZeneca, Menarini and Cymabay; speaker fees from AstraZeneca and Menarini; investigation grants from Spanish Health Ministry, Basque Country Industry and Development Department, Spanish Foundation for Rheumatology, and Cruces Hospital Rheumatology Association. LKS has received consulting fees from AstraZeneca. AKT has received fees from Berlin-Chemie Menarini, Andrea Biosciences/AstraZeneca and Novartis. GM has received consulting and speaker fees from Menarini. MAC has received investigation grants and speakers fees from Menarini., (© 2016, American College of Rheumatology.)

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., (© 2015 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

There have been recent advances in the understanding of underlying mechanisms and treatment of gout and chronic hyperuricemia, making this an important time to review the current state of the disease. The goal of this article is to provide a practical review of the current standard of care as well as discuss some new developments in the management. There is an increasing prevalence of gout and hyperuricemia worldwide. Gout confers a significant individual and societal burden and is often under-treated. Appropriate diagnosis and treatment of acute gout should be followed by aggressive and goal-oriented treatment of hyperuricemia and other risk factors. Allopurinol remains as a first-line treatment for chronic hyperuricemia, but uricosuric agents may also be considered in some patients. Febuxostat, a non-purine xanthine-oxidase inhibitor, is a new agent approved for the treatment of hyperuricemia in patients with gout, which may be used when allopurinol is contraindicated. Gout and hyperuricemia appear to be independent risk factors for incident hypertension, renal disease and cardiovascular disease. Physicians should consider cardiovascular risk factors in patients with gout and treat them appropriately and aggressively.

Measurements of tophus size can be important in monitoring the course of gout therapy, as tophus resolution is proposed as one measure of success of treatment. This multicentre study assessed the intra- and interreader reproducibility of quantitative tophus volume measurements from magnetic resonance images (MRI) in subjects with palpable gouty tophi. Subjects first underwent radiographic imaging of a selected tophus followed by MRI before and at

The purpose of this work is to demonstrate the feasibility of T(1rho)-weighted magnetic resonance imaging (MRI) to quantitatively measure changes in proteoglycan content in cartilage. The T(1rho) MRI technique was implemented in an in vivo porcine animal model with rapidly induced cytokine-mediated cartilage degeneration. Six pigs were given an intra-articular injection of recombinant porcine interleukin-1beta (IL-1beta) into the knee joint before imaging to induce changes in cartilage via matrix metalloproteinase (MMP) induction. The induction of MMPs by IL-1 was used since it has been extensively studied in many systems and is known to create conditions that mimic in part characteristics similar to those of osteoarthritis. The contralateral knee joint was given a saline injection to serve as an internal control. T(1rho)-weighted MRI was performed on a 4 T whole-body clinical scanner employing a 2D fast spin-echo-based T(1rho) imaging sequence. T(1rho) relaxation parameter maps were computed from the T(1rho)-weighted image series. The average T(1rho) relaxation rate, R(1rho) (1/T(1rho)) of the IL-1beta-treated patellae was measured to be on average 25% lower than that of saline-injected patellae indicating a loss of proteoglycan. There was an average reduction of 49% in fixed charge density, measured via sodium MRI, of the IL-1beta-treated patellae relative to control corroborating the loss of proteoglycan. The effects of IL-1beta, primarily loss of PG, were confirmed by histological and immunochemical findings. The results from this study demonstrate that R(1rho) is able to track proteoglycan content in vivo.

Particulate polymethylmethacrylate debris has been implicated in the inflammatory response observed surrounding loosened cemented implants. The rat subcutaneous pouch model and the Howie implant model (used to study bone resorption) were used to quantify the response to mechanically produced endotoxin-free polymethylmethacrylate debris with and without 10% (wt/vol) BaSO4. In the rat subcutaneous pouch model, the inflammatory response to polymethylmethacrylate particles containing BaSO4 was greater than the response to plain polymethylmethacrylate particles of similar size. Increased inflammation was measured by leukocyte counts and levels of prostaglandin E2, tumor necrosis factor, and neutral metalloprotease. In addition, particulate polymethylmethacrylate with BaSO4 caused significantly greater bone resorption in the Howie model than did particulate plain polymethylmethacrylate. In in vitro studies, particulate polymethylmethacrylate with BaSO4 stimulated more prostaglandin E2, neutral metalloprotease, and tumor necrosis factor from human monocytes in culture and stimulated greater proliferation of synovial cells than did particulate plain polymethylmethacrylate. The presence of BaSO4 appears to significantly intensify the inflammatory response to polymethylmethacrylate debris.

Particulate debris, including that from polymethylmethacrylate (PMMA) cement, is observed commonly in the membrane surrounding loose joint prostheses. Such debris is assumed to cause an inflammatory response and contributes to osteolysis and failure of the implant. A subcutaneous rat air-pouch model was used to assess quantitatively the in vivo effects of the size, morphology, and surface area of PMMA particles on the acute inflammatory response. PMMA particles were divided into three groups. In Group A, mechanical grinding of cured bone cement produced irregularly shaped particles; Group B included spherical particles of PMMA powder (Simplex P); and Group C consisted of commercially prepared spherical latex particles. All three groups had two size distributions: < 20 microns and 50-350 microns. For a given mass or dose, the small, irregularly shaped mechanically produced particles in Group A elicited a significantly greater inflammatory reaction than the large particles in Group A, as expressed by the release of tumor necrosis factor (TNF), neutral metalloprotease (NMP), and prostaglandin E2 (PGE2) and the white blood cell (WBC) count within a 24-hour period. Similar findings were seen in Group B. Particles in Group C were used to compare the effect of absolute numbers of large and small particles and surface area. Large (10-126 microns) spherical PMMA particles at a dose of 1.7 x 10(6) particles/ml caused a significantly higher inflammatory response, as measured by WBC count and production of NMP and PGE2, than small (1-10 microns) spheres at a dose of 4 x 10(6) particles/ml. However, the production of TNF in the rats was significantly increased with small particles (p < 0.05) at a concentration 4-fold less than that with the large particles (4 x 10(5) compared with 1.7 x 10(6) particles/ml). This finding may reflect a different cellular mechanism for the TNF component of the inflammatory response than is measured by WBC counts or by levels of PGE2 and NMP. As the calculated surface area of the PMMA particles increased, a threshold level was reached, at which point the inflammatory response increased dramatically. The size of particles has a role in the prolongation and intensity of the release of specific cytokines. The total surface area of the particles appeared to be an important factor in determining the inflammatory response, as measured by WBC count, PGE2, TNF, and NMP.

Imprint preparations were performed on bone marrow biopsy specimens obtained from the posterior superior iliac spine of 310 consecutive patients. Bone marrow aspiration was attempted prior to biopsy. When aspiration was impossible or inadequate, imprint preparations were used in order to study cytologic detail and enhance interpretation of the biopsy specimen. Malignant infiltrates were present in 22 (7.1%) of the 310 biopsy specimens including: non-Hodgkin's lymphoma, 12 patients, metastatic carcinoma, 6; Hodgkin's disease, 1; multiple myeloma, 1; Waldenstrom's macroglobulinemia, 1; and Sezary's syndrome, 1. An aspirate could not be obtained in 8 (36%) of 22 cases, but malignant cells were found in imprint preparations of the biopsy specimens. This study demonstrates that imprint preparations of bone marrow biopsies are useful in evaluating patients with malignancy when bone marrow aspiration is inadequate.

Lymphoid cells from two patients with hand-mirror variant of acute lymphoblastic leukemia (ALL) were studied with various monoclonal antibodies in attempts to determine their derivation and differentiation. The predominant feature of the malignant bone marrow cells was strong reactivity with antibody 3A1, which stains the majority of normal T-cells and is apparently present on all T-ALL cells. In addition, a less intense binding was observed with antibody 4F2, which reacts with activated or rapidly dividing cells, and antibody 10.2, which reacts with all thymocytes and most peripheral T-cells. Most other antibodies with a wide variety of specificities were not reactive or, in the case of a few anti-T-cell antibodies showed, by fluorescence-activated cell sorter analysis only weak staining on some cells. Sequential bone marrow studies in one patient, before and during treatment with chemotherapy, revealed a reduction of 3A1-positive cells, concordant with a decrease of malignant cells in the marrow. When involved lymph nodes, peripheral blood, or marrow were studied, similar reactivity patterns were found in all locations. The data obtained suggest that in both patients with hand-mirror variant of ALL, the malignant lymphoid cells were immature cells of early T-lymphocyte lineage. The relation of phenotype by monoclonal antibody analysis to hand-mirror morphologic type and biologic function is discussed.

The local, articular, and systemic absorption of oral and topical salicylates was studied in dogs and humans using radioisotope techniques. Topical triethanolamine 14C-salicylate was found capable of percutaneous absorption into the knee joint and surrounding tissues. In dogs, topical salicylate application resulted in higher salicylate concentrations than oral aspirin in a number of tissues, despite lower blood levels. In patients with rheumatoid arthritis, intraarticular 14C-salicylate levels after triethanolamine 14C-salicylate cream were 60 per cent of those obtained with oral aspirin. Four of six patients reported equal improvement in local discomfort after oral and topical salicylates. A potential role for topical salicylate cream in the treatment of localized rheumatic disorders is suggested.

Qualitative and quantitative ultrastructural studies were performed on mitochondria of leukemic monoblasts from 15 patients with acute monoblastic leukemia. Similar comparative observations were made on mitochondria of myeloblasts from 14 hematologically normal controls. No significant quantitative differences were noted between normal and leukemic mitochondria. Area measurements were approximately equal. Qualitative differences between the two groups consisted of increased numbers of irregularly shaped mitochondria, damaged mitochondrial membranes, mitochondria with damaged matrix, and small granules in mitochondria in the leukemic group. Leukemic cells exhibited nuclear-mitochondrial contact and virus-like particles within damaged mitochondria. To confirm the presence of virus-like particles and to aid in our understanding of nuclear-mitochondrial interaction, a C-type virus producer MSV-MLV infected rat embryo cell culture was used for additional analysis. Mitochondrial abnormalities and increased frequency of virus in damaged mitochondria, often attached to mitochondrial membranes, were noted. Several lysosomes exhibited accumulations of virus and budding into lysosomes from lysosomal membranes. Mitochondria are important organelles in glycolytic-oxidative phosphorylation pathways, and carry extranuclear genetic information. Further studies of morphologic and biochemical abnormalities of leukemic mitochondria and the interaction between the mitochondria and the nuclei in leukemic cells are needed to provide researchers with data on extranuclear factors operating in oncogenesis.