Tophus burden reduction with pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy

INTRODUCTION: Two replicate randomized, placebo-controlled six-month trials (RCTs) and an open-label treatment extension (OLE) comprised the pegloticase development program in patients with gout refractory to conventional therapy. In the RCTs, approximately 40% of patients treated with the approved dose saw complete response (CR) of at least one tophus. Here we describe the temporal course of tophus resolution, total tophus burden in patients with multiple tophi, tophus size at baseline, and the relationship between tophus response and urate-lowering efficacy. METHODS: Baseline subcutaneous tophi were analyzed quantitatively using computer-assisted digital images in patients receiving pegloticase (8 mg biweekly or monthly) or placebo in the RCTs, and pegloticase in the OLE. Tophus response, a secondary endpoint in the trials, was evaluated two ways. Overall tophus CR was the proportion of patients achieving a best response of CR (without any new/enlarging tophi) and target tophus complete response (TT-CR) was the proportion of all tophi with CR. RESULTS: Among 212 patients randomized in the RCTs, 155 (73%) had ≥ 1 tophus and 547 visible tophi were recorded at baseline. Overall tophus CR was recorded in 45% of patients in the biweekly group (P = 0.002 versus placebo), 26% in the monthly group, and 8% in the placebo group after six months of RCT therapy. TT-CR rates at six months were 28%, 19%, and 2% of tophi, respectively. Patients meeting the primary endpoint of sustained urate-lowering response to therapy (responders) were more likely than nonresponders to have an overall tophus CR at six months (54% vs 20%, respectively and 8% with placebo). CONCLUSIONS: Pegloticase reduced tophus burden in patients with refractory tophaceous gout, especially those achieving sustained urate-lowering. Complete resolution of tophi occurred in some patients by 13 weeks and in others with longer-term therapy

Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: Two randomized controlled trials

Context Patients with chronic disabling gout refractory to conventional urate-lowering therapy need timely treatment to control disease manifestations related to tissue urate crystal deposition. Pegloticase, monomethoxypoly(ethylene glycol)–conjugated mammalian recombinant uricase, was developed to fulfill this need. Objective To assess the efficacy and tolerability of pegloticase in managing refractory chronic gout. Design, Setting, and Patients Two replicate, randomized, double-blind, placebo-controlled trials (C0405 and C0406) were conducted between June 2006 and October 2007 at 56 rheumatology practices in the United States, Canada, and Mexico in patients with severe gout, allopurinol intolerance or refractoriness, and serum uric acid concentration of 8.0 mg/dL or greater. A total of 225 patients participated: 109 in trial C0405 and 116 in trial C0406. Intervention Twelve biweekly intravenous infusions containing either pegloticase 8 mg at each infusion (biweekly treatment group), pegloticase alternating with placebo at successive infusions (monthly treatment group), or placebo (placebo group). Main Outcome Measure Primary end point was plasma uric acid levels of less than 6.0 mg/dL in months 3 and 6. Results In trial C0405 the primary end point was reached in 20 of 43 patients in the biweekly group (47%; 95% CI, 31%-62%), 8 of 41 patients in the monthly group (20%; 95% CI, 9%-35%), and in 0 patients treated with placebo (0/20; 95% CI, 0%-17%; P < .001 and <.04 for comparisons between biweekly and monthly groups vs placebo, respectively). Among patients treated with pegloticase in trial C0406, 16 of 42 in the biweekly group (38%; 95% CI, 24%-54%) and 21 of 43 in the monthly group (49%; 95% CI, 33%-65%) achieved the primary end point; no placebo-treated patients reached the primary end point (0/23; 95% CI, 0%-15%; P = .001 and < .001, respectively). When data in the 2 trials were pooled, the primary end point was achieved in 36 of 85 patients in the biweekly group (42%; 95% CI, 32%-54%), 29 of 84 patients in the monthly group (35%; 95% CI, 24%-46%), and 0 of 43 patients in the placebo group (0%; 95% CI, 0%-8%; P < .001 for each comparison). Seven deaths (4 in patients receiving pegloticase and 3 in the placebo group) occurred between randomization and closure of the study database (February 15, 2008). Conclusion Among patients with chronic gout, elevated serum uric acid level, and allopurinol intolerance or refractoriness, the use of pegloticase 8 mg either every 2 weeks or every 4 weeks for 6 months resulted in lower uric acid levels compared with placebo

Management of Peripheral Arthritis in Patients With Psoriatic Arthritis: An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations.

OBJECTIVE We aimed to compile evidence for the efficacy and safety of therapeutic options for the peripheral arthritis domain of psoriatic arthritis (PsA) for the revised 2021 Group in Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations. METHODS A working group consisting of clinicians and patient research partners was convened. We reviewed the evidence from new randomized controlled trials (RCTs) for PsA treatment from February 19, 2013, to August 28, 2020. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE)-informed approach to derive evidence for the classes of therapeutic options for 3 patient groups: (1) naïve to treatment, (2) inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and (3) inadequate response to biologic DMARDs (bDMARDs). Recommendations were derived through consensus meetings. RESULTS The evidence review included 69 RCTs. We derived GRADE evidence for each class of therapeutic options and achieved consensus for the recommendations. For patients naïve to treatment, the working group strongly recommends csDMARDs (methotrexate, sulfasalazine, leflunomide) and phosphodiesterase 4 inhibitors, and emphasizes regular assessment and early escalation to achieve treatment target. bDMARDs (tumor necrosis factor inhibitors [TNFi], interleukin 17 inhibitors [IL-17i], IL-12/23i, IL-23i) and Janus kinase inhibitors (JAKi) are also strongly recommended. For patients with inadequate response to csDMARDs, we strongly recommend TNFi, IL-17i, IL-12/23i, IL-23i, and JAKi. For those who had prior experience with bDMARDs, we strongly recommend a second TNFi, IL-17i, IL-23i, and JAKi. The evidence supporting nonpharmacological interventions was very low. An expert panel conditionally recommends adequate physical activity, smoking cessation, and diet to control weight gain. CONCLUSION Evidence supporting optimal therapy for the peripheral arthritis domain of PsA was compiled for the revised 2021 GRAPPA treatment recommendations

Molecular, microbiological and clinical characterization of Clostridium difficile isolates from tertiary care hospitals in Colombia

In Colombia, the epidemiology and circulating genotypes of Clostridium difficile have not yet been described. Therefore, we molecularly characterized clinical isolates of C.difficile from patients with suspicion of C.difficile infection (CDI) in three tertiary care hospitals. C.difficile was isolated from stool samples by culture, the presence of A/B toxins were detected by enzyme immunoassay, cytotoxicity was tested by cell culture and the antimicrobial susceptibility determined. After DNA extraction, tcdA, tcdB and binary toxin (CDTa/CDTb) genes were detected by PCR, and PCR-ribotyping performed. From a total of 913 stool samples collected during 2013–2014, 775 were included in the study. The frequency of A/B toxins-positive samples was 9.7% (75/775). A total of 143 isolates of C.difficile were recovered from culture, 110 (76.9%) produced cytotoxic effect in cell culture, 100 (69.9%) were tcdA+/tcdB+, 11 (7.7%) tcdA-/tcdB+, 32 (22.4%) tcdA-/tcdB- and 25 (17.5%) CDTa+/CDTb+. From 37 ribotypes identified, ribotypes 591 (20%), 106 (9%) and 002 (7.9%) were the most prevalent; only one isolate corresponded to ribotype 027, four to ribotype 078 and four were new ribotypes (794,795, 804,805). All isolates were susceptible to vancomycin and metronidazole, while 85% and 7.7% were resistant to clindamycin and moxifloxacin, respectively. By multivariate analysis, significant risk factors associated to CDI were, staying in orthopedic service, exposure to third-generation cephalosporins and staying in an ICU before CDI symptoms; moreover, steroids showed to be a protector factor. These results revealed new C. difficile ribotypes and a high diversity profile circulating in Colombia different from those reported in America and European countries

The Early Data Release of the Dark Energy Spectroscopic Instrument

\ua9 2024. The Author(s). Published by the American Astronomical Society. The Dark Energy Spectroscopic Instrument (DESI) completed its 5 month Survey Validation in 2021 May. Spectra of stellar and extragalactic targets from Survey Validation constitute the first major data sample from the DESI survey. This paper describes the public release of those spectra, the catalogs of derived properties, and the intermediate data products. In total, the public release includes good-quality spectral information from 466,447 objects targeted as part of the Milky Way Survey, 428,758 as part of the Bright Galaxy Survey, 227,318 as part of the Luminous Red Galaxy sample, 437,664 as part of the Emission Line Galaxy sample, and 76,079 as part of the Quasar sample. In addition, the release includes spectral information from 137,148 objects that expand the scope beyond the primary samples as part of a series of secondary programs. Here, we describe the spectral data, data quality, data products, Large-Scale Structure science catalogs, access to the data, and references that provide relevant background to using these spectra

Association between transcatheter aortic valve replacement and subsequent infective endocarditis and in-hospital death

Importance Limited data exist on clinical characteristics and outcomes of patients who had infective endocarditis after undergoing transcatheter aortic valve replacement (TAVR). Objective To determine the associated factors, clinical characteristics, and outcomes of patients who had infective endocarditis after TAVR. Design, Setting, and Participants The Infectious Endocarditis after TAVR International Registry included patients with definite infective endocarditis after TAVR from 47 centers from Europe, North America, and South America between June 2005 and October 2015. EXPOSURE Transcatheter aortic valve replacement for incidence of infective endocarditis and infective endocarditis for in-hospital mortality. MAIN OUTCOMES AND MEASURES Infective endocarditis and in-hospital mortality after infective endocarditis. Results A total of 250 cases of infective endocarditis occurred in 20 006 patients after TAVR (incidence, 1.1% per person-year; 95% CI, 1.1%-1.4%; median age, 80 years; 64% men). Median time from TAVR to infective endocarditis was 5.3 months (interquartile range [IQR], 1.5-13.4 months). The characteristics associated with higher risk of progressing to infective endocarditis after TAVR was younger age (78.9 years vs 81.8 years; hazard ratio [HR], 0.97 per year; 95% CI, 0.94-0.99), male sex (62.0% vs 49.7%; HR, 1.69; 95% CI, 1.13-2.52), diabetes mellitus (41.7% vs 30.0%; HR, 1.52; 95% CI, 1.02-2.29), and moderate to severe aortic regurgitation (22.4% vs 14.7%; HR, 2.05; 95% CI, 1.28-3.28). Health care?associated infective endocarditis was present in 52.8% (95% CI, 46.6%-59.0%) of patients. Enterococci species and Staphylococcus aureus were the most frequently isolated microorganisms (24.6%; 95% CI, 19.1%-30.1% and 23.3%; 95% CI, 17.9%-28.7%, respectively). The in-hospital mortality rate was 36% (95% CI, 30.0%-41.9%; 90 deaths; 160 survivors), and surgery was performed in 14.8% (95% CI, 10.4%-19.2%) of patients during the infective endocarditis episode. In-hospital mortality was associated with a higher logistic EuroSCORE (23.1% vs 18.6%; odds ratio [OR], 1.03 per 1% increase; 95% CI, 1.00-1.05), heart failure (59.3% vs 23.7%; OR, 3.36; 95% CI, 1.74-6.45), and acute kidney injury (67.4% vs 31.6%; OR, 2.70; 95% CI, 1.42-5.11). The 2-year mortality rate was 66.7% (95% CI, 59.0%-74.2%; 132 deaths; 115 survivors). Conclusions and Relevance Among patients undergoing TAVR, younger age, male sex, history of diabetes mellitus, and moderate to severe residual aortic regurgitation were significantly associated with an increased risk of infective endocarditis. Patients who developed endocarditis had high rates of in-hospital mortality and 2-year mortality

The burden of osteoporosis in Latin America

Osteoporosis causes considerable morbidity, mortality and resource utilization in industrialized nations. Its burden is relatively well known in United States and Canada, but poorly studied in the rest of America. This study aimed to discover the burden of osteoporosis in Latin America through a review of literature and publicly available information. In this transversal and descriptive study, information from 20 countries in Latin American region was collected from diverse published and electronic sources. Rheumatologists and bone specialists were asked for additional information through a questionnaire created by consensus. In the year 2000, the population of the Latin America and Caribbean region was 524 million from diverse ethnic origins. On average, 5.5% of the population is 65 years and older. However, with life expectancy higher than 70 years in most countries, a significant growth in the elderly population is anticipated. Studies using World Health Organization's criteria for osteoporosis report 12-18% of women 50 years and older with vertebral osteoporosis and 8-22% with proximal femur osteoporosis. Community based studies in Argentina reported between 263 and 331 hip fractures per 100,000 people 50 years and older. Hospital based studies in Colombia, Chile, Brazil, Mexico, Panama, Peru and Venezuela reported between 40 and 362 hip fractures per 100,000 persons aged 50 and more. Between 17 and 37% of hip fracture sufferers die in the year following fracture. Prevalence of vertebral fractures in community-dwelling women aged 50 and more in Mexico is 19.35%. Data on other fractures are rare. Direct costs of a hip fracture ranged from $4500 to$6000. National gross income per capita in the region ranges from $410 to$7550. The burden of osteoporosis varies across countries with differences in populations and health resources. Considerable support for research is required, since numerous gaps in knowledge need to be filled to face the anticipated explosive growth in osteoporotic fractures

The burden of osteoporosis in Latin America

Osteoporosis causes considerable morbidity, mortality and resource utilization in industrialized nations. Its burden is relatively well known in United States and Canada, but poorly studied in the rest of America. This study aimed to discover the burden of osteoporosis in Latin America through a review of literature and publicly available information. In this transversal and descriptive study, information from 20 countries in Latin American region was collected from diverse published and electronic sources. Rheumatologists and bone specialists were asked for additional information through a questionnaire created by consensus. In the year 2000, the population of the Latin America and Caribbean region was 524 million from diverse ethnic origins. On average, 5.5% of the population is 65 years and older. However, with life expectancy higher than 70 years in most countries, a significant growth in the elderly population is anticipated. Studies using World Health Organization's criteria for osteoporosis report 12-18% of women 50 years and older with vertebral osteoporosis and 8-22% with proximal femur osteoporosis. Community based studies in Argentina reported between 263 and 331 hip fractures per 100,000 people 50 years and older. Hospital based studies in Colombia, Chile, Brazil, Mexico, Panama, Peru and Venezuela reported between 40 and 362 hip fractures per 100,000 persons aged 50 and more. Between 17 and 37% of hip fracture sufferers die in the year following fracture. Prevalence of vertebral fractures in community-dwelling women aged 50 and more in Mexico is 19.35%. Data on other fractures are rare. Direct costs of a hip fracture ranged from $4500 to$6000. National gross income per capita in the region ranges from $410 to$7550. The burden of osteoporosis varies across countries with differences in populations and health resources. Considerable support for research is required, since numerous gaps in knowledge need to be filled to face the anticipated explosive growth in osteoporotic fractures

Dermatomyositis exacerbated by abdominal Marlex® mesh implantation: Adjuvant effect?

We describe a 35-year-old woman with dermatomyositis, who four months after implantation of abdominal Marlex® mesh, developed a severe exacerbation of her disease with muscle weakness, elevated acute-phase reactants, a high level of muscle enzymes, and the appearance of dermal lesions with calcinosis. The Marlex® mesh implant may have triggered the flare-up of her underlying autoimmune disorder