Identifying Patient Candidates for IL-1 Inhibition: Lessons From Real-World Cases

A subgroup of patients with gouty arthritis have a chronic recurring form that is particularly difficult to treat. Such patients experience repeated flares and often have abundant tophi. Many also have underlying comorbidities, such as renal impairment, cardiovascular disease, gastrointestinal disorders, obesity, and hypertension, which contraindicate the use of standard anti-inflammatory medications. Five patients with difficult to treat gouty arthritis who were either candidates and/or treated with anti-IL therapy are described.info:eu-repo/semantics/publishedVersio

Correction to: Using CPAP in COVID-19 patients outside of the intensive care setting: a comparison of survival and outcomes between dialysis and non-dialysis dependent patients

Abstract: Background: SARS-CoV-2 (COVID-19) is a novel coronavirus associated with high mortality rates. The use of Continuous Positive Airway Pressure (CPAP) has been recognised as a management option for severe COVID-19 (NHS, Specialty guides for patient management during the coronavirus pandemic Guidance for the role and use of non-invasive respiratory support in adult patients with coronavirus (confirmed or suspected), https://www.nice.org.uk/guidance/ng159). We offered ward-based CPAP to COVID-19, dialysis patients not suitable for escalation to ICU. The aim of the study was to evaluate the use of CPAP for COVID-19 dialysis patients compared to non-dialysis COVID-19 patients outside of the intensive care setting. We further aimed to investigate factors associated with improved outcomes. Methods: Data was collected from a single centre (Royal Preston Hospital, UK), from March to June 2020. Treatment outcomes were compared for dialysis and non-dialysis dependent patients who received CPAP with limitations on their escalation and resuscitation status. Kaplan-Meier survival curves and Cox regression models were used to compare outcomes. The primary study outcome was 30 day mortality. Confounders including length of admission, systemic anticoagulation and ultrafiltration volumes on dialysis were also analysed. Results: Over the study period, 40 dialysis patients tested positive for COVID-19, with 30 requiring hospital admission. 93% (n = 28) required supplementary oxygen and 12% (n = 9) required CPAP on the ward. These patients were compared to a serial selection of 14 non-dialysis patients treated with CPAP during the same period. Results showed a significant difference in 30 day survival rates between the two groups: 88.9% in the dialysis group vs. 21.4% in the non-dialysis group. Statistical modelling showed that anticoagulation was also an important factor and correlated with better outcomes. Conclusion: This is to the best of our knowledge, the largest series of COVID-19 dialysis patients treated with CPAP in a ward-based setting. In general, dialysis dependent patients have multiple co-morbidities including cardiovascular disease and diabetes mellitus making them vulnerable to COVID-19 and not always suitable for treatment in ICU. We showed a significantly lower 30 day mortality rate with the use of CPAP in the dialysis group (11.1%) compared to the non-dialysis group (78.6%). Despite a small sample size, we believe this study provides impetus for further work clarifying the role of CPAP in treating COVID-19 dialysis dependent patients

A new era for understanding amyloid structures and disease

The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. The accumulation and deposition of amyloid fibrils, collectively known as amyloidosis, is associated with many pathological conditions that can be associated with ageing, such as Alzheimer disease, Parkinson disease, type II diabetes and dialysis-related amyloidosis. However, elucidation of the atomic structure of amyloid fibrils formed from their intact protein precursors and how fibril formation relates to disease has remained elusive. Recent advances in structural biology techniques, including cryo-electron microscopy and solid-state NMR spectroscopy, have finally broken this impasse. The first near-atomic-resolution structures of amyloid fibrils formed in vitro, seeded from plaque material and analysed directly ex vivo are now available. The results reveal cross-β structures that are far more intricate than anticipated. Here, we describe these structures, highlighting their similarities and differences, and the basis for their toxicity. We discuss how amyloid structure may affect the ability of fibrils to spread to different sites in the cell and between organisms in a prion-like manner, along with their roles in disease. These molecular insights will aid in understanding the development and spread of amyloid diseases and are inspiring new strategies for therapeutic intervention

Acute hydrothorax in a peritoneal dialysis patient: Long-term efficacy of autologous blood cell pleurodesis associated with small-volume peritoneal exchanges (multiple letters) [2]

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Dialysis-related amyloidosis: challenges and solutions

R Scarpioni, M Ricardi, V Albertazzi, S De Amicis, F Rastelli, L Zerbini Department of Nephrology and Dialysis, Azienda Unità Sanitaria Local (AUSL) Hospital “Guglielmo da Saliceto”, Piacenza, Italy Abstract: Amyloidosis refers to the extracellular tissue deposition of fibrils composed of low-molecular-weight subunits of a variety of proteins. These deposits may result in a wide range of clinical manifestations depending upon their type, location, and the amount of deposition. Dialysis-related amyloidosis is a serious complication of long-term dialysis therapy and is characterized by the deposition of amyloid fibrils, principally composed of β2 microglobulins (β2M), in the osteoarticular structures and viscera. Most of the β2M is eliminated through glomerular filtration and subsequent reabsorption and catabolism by the proximal tubules. As a consequence, the serum levels of β2M are inversely related to the glomerular filtration rate; therefore, in end-stage renal disease patients, β2M levels increase up to 60-fold. Serum levels of β2M are also elevated in several pathological conditions such as chronic inflammation, liver disease, and above all, in renal dysfunction. Retention of amyloidogenic protein has been attributed to several factors including type of dialysis membrane, prolonged uremic state and/or decreased diuresis, advanced glycation end products, elevated levels of cytokines and dialysate. Dialysis treatment per se has been considered to be an inflammatory stimulus, inducing cytokine production (such as interleukin-1, tumor necrosis factor-α, interleukin-6) and complement activation. The released cytokines are thought to stimulate the synthesis and release of β2M by the macrophages and/or augment the expression of human leukocyte antigens (class I), increasing β2M expression. Residual renal function is probably the best determinant of β2M levels. Therefore, it has to be maintained as long as possible. In this article, we will focus our attention on the etiology of dialysis-related amyloidosis, its prevention, therapy, and future solutions. Keywords: chronic inflammation, long-term dialysis, β2 microglobulin, high-flux dialysis membrane, mineral bone diseas

Renal involvement in secondary amyloidosis of Muckle-Wells syndrome: marked improvement of renal function and reduction of proteinuria after therapy with human anti-interleukin-1 monoclonal antibody canakinumab

Muckle-Wells syndrome (MWS) is a rare hereditary autoinflammatory disorder characterized by recurrent urticaria-like skin rashes, arthralgias, conjunctivitis, hypoacusia, and risk of reactive AA amyloidosis due to the progressive accumulation of amyloid fibrils in different organs. Its genetic defect lies in mutations in the NLRP3 gene, encoding the cryopyrin protein, and resulting in interleukin (IL)-1\u3b2 oversecretion. Renal involvement, in terms of proteinuria or renal insufficiency, can be observed in up to 25% of patients. Herein, we describe our experience with two Caucasian patients, father and son, aged 52 and 26 years, respectively, heterozygous for both V198M and R260W NLRP3 mutations who had AA amyloid deposits on renal biopsy. The fully human monoclonal antibody canakinumab, providing selective and prolonged IL-1\u3b2 blockade, was administered in both patients every 60 days over a period of 18 months. This treatment allowed to obtain amazing results: a rapid disappearance of any clinical symptoms, the stable normalization of serum amyloid-A and, furthermore, a marked improvement of glomerular filtration rate and proteinuria with no adverse events. Our data, though limited to only two patients, emphasize that therapeutic intervention with canakinumab, suppressing both inflammation and IL-1\u3b2-mediated manifestations, can contribute to improve kidney function in MWS with overt renal amyloidosis