Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study

Objective This study assessed the efficacy and safety of canakinumab, a fully human anti-interleukin 1 beta monoclonal antibody, for prophylaxis against acute gouty arthritis flares in patients initiating urate-lowering treatment.Methods In this double-blind, double-dummy, dose-ranging study, 432 patients with gouty arthritis initiating allopurinol treatment were randomised 1:1:1:1:1:1:2 to receive: a single dose of canakinumab, 25, 50, 100, 200, or 300 mg subcutaneously; 4 x 4-weekly doses of canakinumab (50 + 50 + 25 + 25 mg subcutaneously); or daily colchicine 0.5 mg orally for 16 weeks. Patients recorded details of flares in diaries. The study aimed to determine the canakinumab dose having equivalent efficacy to colchicine 0.5 mg at 16 weeks.Results A dose-response for canakinumab was not apparent with any of the four predefined dose-response models. The estimated canakinumab dose with equivalent efficacy to colchicine was below the range of doses tested. At 16 weeks, there was a 62% to 72% reduction in the mean number of flares per patient for canakinumab doses >= 50 mg versus colchicine based on a negative binomial model (rate ratio: 0.28-0.38, p <= 0.0083), and the percentage of patients experiencing >= 1 flare was significantly lower for all canakinumab doses (15% to 27%) versus colchicine (44%, p<0.05). There was a 64% to 72% reduction in the risk of experiencing >= 1 flare for canakinumab doses >= 50 mg versus colchicine at 16 weeks (hazard ratio (HR): 0.28-0.36, p <= 0.05). The incidence of adverse events was similar across treatment groups.Conclusions Single canakinumab doses >= 50 mg or four 4-weekly doses provided superior prophylaxis against flares compared with daily colchicine 0.5 mg

GAME-UP: Game-Aware Mode Enumeration and Understanding for Trajectory Prediction

Interactions between road agents present a significant challenge in trajectory prediction, especially in cases involving multiple agents. Because existing diversity-aware predictors do not account for the interactive nature of multi-agent predictions, they may miss these important interaction outcomes. In this paper, we propose GAME-UP, a framework for trajectory prediction that leverages game-theoretic inverse reinforcement learning to improve coverage of multi-modal predictions. We use a training-time game-theoretic numerical analysis as an auxiliary loss resulting in improved coverage and accuracy without presuming a taxonomy of actions for the agents. We demonstrate our approach on the interactive subset of Waymo Open Motion Dataset, including three subsets involving scenarios with high interaction complexity. Experiment results show that our predictor produces accurate predictions while covering twice as many possible interactions versus a baseline model.Comment: 10 pages, 6 figure

Metabolic and Crystal Arthropathies [70-72]: 70. Single Intramuscular Depot Methylprednisolone Injection: A Convenient, Efficacious and Safe Treatment for Gouty Arthritis in an Inpatient Setting

Background: Various modalities of treatment have been used and recommended in the treatment of acute gout. These include drugs such as colchicine, NSAIDs and oral prednisolone. Intramuscular depot methylprednisolone (im MP) is currently used in the treatment of rheumatoid arthritis as well as polymyalgia. However the response to im MP in acute gouty arthritis in an inpatient setting (where there are usually contraindications to NSAIDs) has not been previously described in literature. Methods: Eighteen case records of patients presenting with acute gouty arthritis and referred to Rheumatology, between October 2008 and October 2009, were reviewed. Results: Fourteen men and four women, with a mean age of 60 years (range 55-88 years) were seen. Of the 18, 14 patients had a previous history of chronic gout and 4 patients were newly diagnosed. Sixteen patients had polyarticular gout (mainly bilateral wrists and knees) and the remaining 2 had monoarticular gout (1 knee, 1 wrist). Seventeen patients had synovial fluid analysis, which revealed negatively birefringent urate crystals, and 1 patient refused joint aspiration. All patients had predisposing co-morbidities such as diabetes (10), hypertension (15), CCF (5), chronic kidney disease (8) and 2 patients had a history of chronic alcohol excess. Five patients initially received NSAIDs and 3 had concomitant colchicine with all 5 showing a delayed response. All patients were given im MP 120 mg in the gluteal region as a deep injection. All responded completely to im yMP within 2 days with resolution of pain and swelling of inflamed joints. All patients felt much improved and rated the treatment highly. Conclusions: The latest BSR guidelines recommends the use of steroids in the management of refractory cases of gout, i.e. patients intolerant of or having contraindications to NSAIDS or colchicine. This restricted indication is based mainly on the side effects to oral steroids or lack of expertise with intra-articular injections. We have shown that a single intramuscular methyl prednisolone injection is highly effective, very convenient, patient acceptable and safe treatment for gout particularly in elderly patients with multiple co-morbidities. As most cases of inpatient gout have comorbidities such as in our series with contraindications to NSAIDs, we recommend the use of im methyl prednisolone as the first-line treatment in such patients. It may be a less painful alternative to intra-articular steroid injections and safer than bigger doses of oral steroids (especially in diabetes). Disclosure statement: All authors have declared no conflicts of interes

The contribution of genetic variants to disease depends on the ruler

Our understanding of the genetic basis of disease has evolved from descriptions of overall heritability or familiality to the identification of large numbers of risk loci. One can quantify the impact of such loci on disease using a plethora of measures, which can guide future research decisions. However, different measures can attribute varying degrees of importance to a variant. In this Analysis, we consider and contrast the most commonly used measures-specifically, the heritability of disease liability, approximate heritability, sibling recurrence risk, overall genetic variance using a logarithmic relative risk scale, the area under the receiver-operating curve for risk prediction and the population attributable fraction-and give guidelines for their use that should be explicitly considered when assessing the contribution of genetic variants to disease

Case Report: Patient with Hepatitis C, p-ANCA, and Cryoglobulin Antibodies Presenting with Necrotizing Crescentic p-ANCA Glomerulonephritis

Hepatitis C (HCV) infection has a prevalence of 3 million infected individuals in the United States, according to recent Center for Disease Control reports, and can have various renal manifestations. Cryoglobulins, antibodies that precipitate at colder temperatures in vitro, are a relatively common cause of renal disease in HCV infection. The cryoglobulin proteins can form occlusive aggregates in small glomerular capillary lumina or deposit in other areas of the glomerulus, resulting in hypocomplementemia, proteinuria, hematuria, and renal injury. The typical biopsy pattern is that of membranoproliferative glomerulonephritis (MPGN). There are, however, other HCV-related patterns of glomerular injury. Anti-neutrophil cytoplasmic antibodies (ANCA) are known to exist in HCV-infected patients. In many reported cases, ANCA serologic testing may appear positive due to cross-reactivity of the immune assays; however, the biopsy findings do not support ANCA-associated crescentic glomerulonephritis (GN)/vasculitis as the primary cause of glomerular injury. There are rare reports of microscopic polyangiitis (MPA) p-ANCA vasculitis, in patients with HCV infection. In comparison with the MPGN pattern of cryoglobulinemic glomerular injury, biopsies from these HCV-infected patients with concomitant MPA revealed a crescentic GN, associated with normal serum complement levels. We present a case of HCV-associated glomerular disease with the surprising biopsy finding of necrotizing and crescentic p-ANCA GN, with a background, low-grade mesangial immune complex GN. Thus, p-ANCA disease should also be considered in HCV-infected patients, in addition to the more typical lesions of MPGN or cryoglobulinemic GN

Novel genetic analysis for case-control genome-wide association studies: quantification of power and genomic prediction accuracy

Genome-wide association studies (GWAS) are routinely conducted for both quantitative and binary (disease) traits. We present two analytical tools for use in the experimental design of GWAS. Firstly, we present power calculations quantifying power in a unified framework for a range of scenarios. In this context we consider the utility of quantitative scores (e.g. endophenotypes) that may be available on cases only or both cases and controls. Secondly, we consider, the accuracy of prediction of genetic risk from genome-wide SNPs and derive an expression for genomic prediction accuracy using a liability threshold model for disease traits in a case-control design. The expected values based on our derived equations for both power and prediction accuracy agree well with observed estimates from simulations

Optical Propagation and Communication

Contains research objectives and reports on four research projects.National Science Foundation (Grant ECS 85-09143)Maryland Procurement Office (Contract MDA 904-84-C-6037)National Science Foundation (Grant ECS 84-15580)U.S. Army Research Office - Durham (Contract DAAG29-84-K-0095)U.S. Navy - Office of Naval Research (Contract N00014-80-C-0941

Optical Propagation and Communication

Contains research objectives and reports on six research projects.National Science Foundation (Grant ECS 85-09143)Maryland Procurement Office (Contract MDA 904-84-C-6037)Maryland Procurement Office (Contract MDA 904-87-C-4044)National Science Foundation (Grant ECS 84-15580)National Science Foundation (Grant INT-86-14329)U.S. Navy - Office of Naval Research (Contract N00014-87-G-0198)U.S. Army Research Office - Durham (Contract DAAG29-84-K-0095)U.S. Army Research Office - Durham (Contract DAALO3-87-K-0117)U.S. Navy - Office of Naval Research (Contract N00014-80-C-0941_U.S. Air Force - Office of Scientific Research (Contract F49620-87-C-0043

Canakinumab relieves symptoms of acute flares and improves health-related quality of life in patients with difficult-to-treat Gouty Arthritis by suppressing inflammation: results of a randomized, dose-ranging study

INTRODUCTION: We report the impact of canakinumab, a fully human anti-interleukin-1β monoclonal antibody, on inflammation and health-related quality of life (HRQoL) in patients with difficult-to-treat Gouty Arthritis. METHODS: In this eight-week, single-blind, double-dummy, dose-ranging study, patients with acute Gouty Arthritis flares who were unresponsive or intolerant to--or had contraindications for--non-steroidal anti-inflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg) (N = 143) or an intramuscular dose of triamcinolone acetonide 40 mg (N = 57). Patients assessed pain using a Likert scale, physicians assessed clinical signs of joint inflammation, and HRQoL was measured using the 36-item Short-Form Health Survey (SF-36) (acute version). RESULTS: At baseline, 98% of patients were suffering from moderate-to-extreme pain. The percentage of patients with no or mild pain was numerically greater in most canakinumab groups compared with triamcinolone acetonide from 24 to 72 hours post-dose; the difference was statistically significant for canakinumab 150 mg at these time points (P < 0.05). Treatment with canakinumab 150 mg was associated with statistically significant lower Likert scores for tenderness (odds ratio (OR), 3.2; 95% confidence interval (CI), 1.27 to 7.89; P = 0.014) and swelling (OR, 2.7; 95% CI, 1.09 to 6.50, P = 0.032) at 72 hours compared with triamcinolone acetonide. Median C-reactive protein and serum amyloid A levels were normalized by seven days post-dose in most canakinumab groups, but remained elevated in the triamcinolone acetonide group. Improvements in physical health were observed at seven days post-dose in all treatment groups; increases in scores were highest for canakinumab 150 mg. In this group, the mean SF-36 physical component summary score increased by 12.0 points from baseline to 48.3 at seven days post-dose. SF-36 scores for physical functioning and bodily pain for the canakinumab 150 mg group approached those for the US general population by seven days post-dose and reached norm values by eight weeks post-dose. CONCLUSIONS: Canakinumab 150 mg provided significantly greater and more rapid reduction in pain and signs and symptoms of inflammation compared with triamcinolone acetonide 40 mg. Improvements in HRQoL were seen in both treatment groups with a faster onset with canakinumab 150 mg compared with triamcinolone acetonide 40 mg. TRIAL REGISTRATION: clinicaltrials.gov: NCT00798369