Hepatotoxicity associated with sulfasalazine in inflammatory arthritis: A case series from a local surveillance of serious adverse events

<p>Abstract</p> <p>Background</p> <p>Spontaneous reporting systems for adverse drug reactions (ADRs) are handicapped by under-reporting and limited detail on individual cases. We report an investigation from a local surveillance for serious adverse drug reactions associated with disease modifying anti-rheumatic drugs that was triggered by the occurrence of liver failure in two of our patients.</p> <p>Methods</p> <p>Serious ADR reports have been solicited from local clinicians by regular postcards over the past seven years. Patients', who had hepatotoxicity on sulfasalazine and met a definition of a serious ADR, were identified. Two clinicians reviewed structured case reports and assessed causality by consensus and by using a causality assessment instrument. The likely frequency of hepatotoxicity with sulfasalazine was estimated by making a series of conservative assumptions.</p> <p>Results</p> <p>Ten cases were identified: eight occurred during surveillance. Eight patients were hospitalised, two in hepatic failure – one died after a liver transplant. All but one event occurred within 6 weeks of treatment. Seven patients had a skin rash, three eosinophilia and one interstitial nephritis. Five patients were of Black British of African or Caribbean descent. Liver enzymes showed a hepatocellular pattern in four cases and a mixed pattern in six. Drug-related hepatotoxicity was judged probable or highly probable in 8 patients. The likely frequency of serious hepatotoxicity with sulfasalazine was estimated at 0.4% of treated patients.</p> <p>Conclusion</p> <p>Serious hepatotoxicity associated with sulfasalazine appears to be under-appreciated and intensive monitoring and vigilance in the first 6 weeks of treatment is especially important.</p

High-resolution microbiome analysis reveals exclusionary Klebsiella species competition in preterm infants at risk for necrotizing enterocolitis.

Intestinal colonization with Klebsiella has been linked to necrotizing enterocolitis (NEC), but methods of analysis usually failed to discriminate Klebsiella species or strains. A novel ~ 2500-base amplicon (StrainID) that spans the 16S and 23S rRNA genes was used to generate amplicon sequence variant (ASV) fingerprints for Klebsiella oxytoca and Klebsiella pneumoniae species complexes (KoSC and KpSC, respectively) and co-occurring fecal bacterial strains from 10 preterm infants with NEC and 20 matched controls. Complementary approaches were used to identify cytotoxin-producing isolates of KoSC. Klebsiella species colonized most preterm infants, were more prevalent in NEC subjects versus controls, and replaced Escherichia in NEC subjects. Single KoSC or KpSC ASV fingerprinted strains dominated the gut microbiota, suggesting exclusionary Klebsiella competition for luminal resources. Enterococcus faecalis was co-dominant with KoSC but present infrequently with KpSC. Cytotoxin-producing KoSC members were identified in most NEC subjects and were less frequent in controls. Few Klebsiella strains were shared between subjects. We conclude that inter-species Klebsiella competition, within an environment of KoSC and E. faecalis cooperation, appears to be an important factor for the development of NEC. Preterm infants seem to acquire Klebsiella primarily through routes other than patient-to-patient transmission

Darolutamide and health-related quality of life in patients with non-metastatic castration-resistant prostate cancer : An analysis of the phase III ARAMIS trial

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.BACKGROUND: In the ARAMIS trial, darolutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT significantly improved metastasis-free survival (MFS), overall survival (OS) and time to pain progression in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Herein, we present analyses of patient-reported health-related quality of life (HRQoL) outcomes. PATIENTS AND METHODS: This double-blind, placebo-controlled, phase III trial randomised patients with nmCRPC and prostate-specific antigen doubling time ≤10 months to darolutamide 600 mg (n = 955) twice daily or matched placebo (n = 554) while continuing ADT. The primary end-point was MFS; the secondary end-points included OS and time to pain progression. In this analysis, HRQoL was assessed by the time to deterioration using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) prostate cancer subscale (PCS) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer Module (EORTC QLQ-PR25) subscales. RESULTS: Darolutamide significantly prolonged time to deterioration of FACT-P PCS versus placebo (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.70-0.91; P = 0.0005) at the primary analysis (cut-off date: 3rd September 2018). Time to deterioration of EORTC QLQ-PR25 outcomes showed statistically significant delays with darolutamide versus placebo for urinary (HR 0.64, 95% CI 0.54-0.76; P < 0.0001) and bowel (HR 0.78, 95% CI 0.66-0.92; P = 0.0027) symptoms. Time to worsening of hormonal treatment-related symptoms was similar between the two groups. CONCLUSION: In patients with nmCRPC who are generally asymptomatic, darolutamide maintained HRQoL by significantly delaying time to deterioration of prostate cancer-specific quality of life and disease-related symptoms versus placebo.publishersversionPeer reviewe

Oxford consensus on primary cam morphology and femoroacetabular impingement syndrome: part 1—definitions, terminology, taxonomy and imaging outcomes

Introduction Primary cam morphology is a mostly benign bony prominence that develops at the femoral head-neck junction of the hip, but it is highly prevalent in many athlete populations. In the small proportion of athletes for whom it is not benign, the resulting hip osteoarthritis can be debilitating. Clinicians, athletes, patients and researchers do not yet agree on important primary cam morphology elements. We aimed to ascertain and improve the level of agreement on primary cam morphology definitions, terminology, taxonomy and imaging outcome measures. Methods To collect and aggregate informed opinions, an expert panel—the Young Athlete’s Hip Research Collaborative—rated primary cam morphology definition, terminology, taxonomy and imaging outcome statements through an online Delphi exercise followed by an online meeting to explore areas of tension and dissent. Reporting followed Conducting and REporting DElphi Studies. Results A diverse and inclusive Delphi panel (n=65 for rounds 1 and 2, representing 18 countries; 6 stakeholder groups; 40% women) agreed on 35 of 47 statements in 4 domains, while surfacing areas of tension and dissent. This Delphi panel agreed on four key issues essential to moving research and clinical care forward around primary cam morphology. They agreed on: (1) definition, confirming its conceptual attributes (tissue type, size, location, shape and ownership); (2) terminology—use ‘morphology’ and not terms with a negative connotation like ‘lesion’, ‘abnormality’ or ‘deformity’; (3) taxonomy, distinguishing between primary and secondary cam morphology, and (4) imaging outcomes, a continuous bone/cartilage alpha angle on radial femoral head-neck MRI for primary cam morphology aetiology research. Conclusion This consensus provides athletes, patients, clinicians and researchers with a strong foundation to guide more precise communication, better clinical decision-making and higher value research about primary cam morphology and its natural history

Oxford consensus on primary cam morphology and femoroacetabular impingement syndrome: part 1—definitions, terminology, taxonomy and imaging outcomes

INTRODUCTION: Primary cam morphology is a mostly benign bony prominence that develops at the femoral head-neck junction of the hip, but it is highly prevalent in many athlete populations. In the small proportion of athletes for whom it is not benign, the resulting hip osteoarthritis can be debilitating. Clinicians, athletes, patients and researchers do not yet agree on important primary cam morphology elements. We aimed to ascertain and improve the level of agreement on primary cam morphology definitions, terminology, taxonomy and imaging outcome measures. METHODS: To collect and aggregate informed opinions, an expert panel-the Young Athlete's Hip Research Collaborative-rated primary cam morphology definition, terminology, taxonomy and imaging outcome statements through an online Delphi exercise followed by an online meeting to explore areas of tension and dissent. Reporting followed Conducting and REporting DElphi Studies. RESULTS: A diverse and inclusive Delphi panel (n=65 for rounds 1 and 2, representing 18 countries; 6 stakeholder groups; 40% women) agreed on 35 of 47 statements in 4 domains, while surfacing areas of tension and dissent. This Delphi panel agreed on four key issues essential to moving research and clinical care forward around primary cam morphology. They agreed on: (1) definition, confirming its conceptual attributes (tissue type, size, location, shape and ownership); (2) terminology-use 'morphology' and not terms with a negative connotation like 'lesion', 'abnormality' or 'deformity'; (3) taxonomy, distinguishing between primary and secondary cam morphology, and (4) imaging outcomes, a continuous bone/cartilage alpha angle on radial femoral head-neck MRI for primary cam morphology aetiology research. CONCLUSION: This consensus provides athletes, patients, clinicians and researchers with a strong foundation to guide more precise communication, better clinical decision-making and higher value research about primary cam morphology and its natural history

Finding and sharing: new approaches to registries of databases and services for the biomedical sciences

The recent explosion of biological data and the concomitant proliferation of distributed databases make it challenging for biologists and bioinformaticians to discover the best data resources for their needs, and the most efficient way to access and use them. Despite a rapid acceleration in uptake of syntactic and semantic standards for interoperability, it is still difficult for users to find which databases support the standards and interfaces that they need. To solve these problems, several groups are developing registries of databases that capture key metadata describing the biological scope, utility, accessibility, ease-of-use and existence of web services allowing interoperability between resources. Here, we describe some of these initiatives including a novel formalism, the Database Description Framework, for describing database operations and functionality and encouraging good database practise. We expect such approaches will result in improved discovery, uptake and utilization of data resources. Database URL: http://www.casimir.org.uk/casimir_dd

Isolation of a Human Anti-HIV gp41 Membrane Proximal Region Neutralizing Antibody by Antigen-Specific Single B Cell Sorting

Broadly neutralizing antibodies are not commonly produced in HIV-1 infected individuals nor by experimental HIV-1 vaccines. When these antibodies do occur, it is important to be able to isolate and characterize them to provide clues for vaccine design. CAP206 is a South African subtype C HIV-1-infected individual previously shown to have broadly neutralizing plasma antibodies targeting the envelope gp41 distal membrane proximal external region (MPER). We have now used a fluoresceinated peptide tetramer antigen with specific cell sorting to isolate a human neutralizing monoclonal antibody (mAb) against the HIV-1 envelope gp41 MPER. The isolated recombinant mAb, CAP206-CH12, utilized a portion of the distal MPER (HXB2 amino acid residues, 673–680) and neutralized a subset of HIV-1 pseudoviruses sensitive to CAP206 plasma antibodies. Interestingly, this mAb was polyreactive and used the same germ-line variable heavy (VH1-69) and variable kappa light chain (VK3-20) gene families as the prototype broadly neutralizing anti-MPER mAb, 4E10 (residues 672–680). These data indicate that there are multiple immunogenic targets in the C-terminus of the MPER of HIV-1 gp41 envelope and suggests that gp41 neutralizing epitopes may interact with a restricted set of naive B cells during HIV-1 infection

BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (the BIO-FLARE study): protocol for a non-randomised longitudinal cohort study

Background Our knowledge of immune-mediated inflammatory disease (IMID) aetiology and pathogenesis has improved greatly over recent years, however, very little is known of the factors that trigger disease relapses (flares), converting diseases from inactive to active states. Focussing on rheumatoid arthritis (RA), the challenge that we will address is why IMIDs remit and relapse. Extrapolating from pathogenetic factors involved in disease initiation, new episodes of inflammation could be triggered by recurrent systemic immune dysregulation or locally by factors within the joint, either of which could be endorsed by overarching epigenetic factors or changes in systemic or localised metabolism. Methods The BIO-FLARE study is a non-randomised longitudinal cohort study that aims to enrol 150 patients with RA in remission on a stable dose of non-biologic disease-modifying anti-rheumatic drugs (DMARDs), who consent to discontinue treatment. Participants stop their DMARDs at time 0 and are offered an optional ultrasound-guided synovial biopsy. They are studied intensively, with blood sampling and clinical evaluation at weeks 0, 2, 5, 8, 12 and 24. It is anticipated that 50% of participants will have a disease flare, whilst 50% remain in drug-free remission for the study duration (24 weeks). Flaring participants undergo an ultrasound-guided synovial biopsy before reinstatement of previous treatment. Blood samples will be used to investigate immune cell subsets, their activation status and their cytokine profile, autoantibody profiles and epigenetic profiles. Synovial biopsies will be examined to profile cell lineages and subtypes present at flare. Blood, urine and synovium will be examined to determine metabolic profiles. Taking into account all generated data, multivariate statistical techniques will be employed to develop a model to predict impending flare in RA, highlighting therapeutic pathways and informative biomarkers. Despite initial recruitment to time and target, the SARS-CoV-2 pandemic has impacted significantly, and a decision was taken to close recruitment at 118 participants with complete data. Discussion This study aims to investigate the pathogenesis of flare in rheumatoid arthritis, which is a significant knowledge gap in our understanding, addressing a major unmet patient need