A randomised, double-blind, placebo-controlled study of the LAG-3-depleting monoclonal antibody GSK2831781 in patients with active ulcerative colitis.

Background: Selective depletion of T cells expressing LAG-3, an immune checkpoint receptor that is upregulated on activated T cells, has been investigated in pre-clinical models as a potential therapeutic approach in inflammatory and autoimmune diseases where activated T cells are implicated.

Aims: GSK2831781, a depleting monoclonal antibody that specifically binds LAG-3 proteins, may deplete activated LAG-3 cells in ulcerative colitis (UC).

Methods: Patients with moderate to severe UC were randomised to GSK2831781 or placebo.

Randomized Trial of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GSK2831781 in Healthy Japanese and White Participants.

This study investigated ethnic differences in the safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK2831781, an anti-lymphocyte activation gene 3 (LAG3) monoclonal antibody, in healthy participants, and determined local tolerability and bioavailability following subcutaneous (SC) administration. A double-blind, randomized study of (A) single intravenous (IV) doses of GSK2831781 450 mg or placebo in Japanese and White participants; and (B) single SC doses of GSK2831781 150 or 450 mg, or placebo in White participants, was conducted. Blood samples for analyses were collected before dosing and over 112 days after dosing.

A qualitative study to explore the symptoms and impacts of Crohn's disease and to develop the Crohn's Disease Diary.

Purpose: To explore symptoms and disease impacts of Crohn's disease and to develop a new patient-reported outcomes (PRO) measure according to industry best practices.

Methods: A conceptual model of relevant symptoms experienced by patients with Crohn's disease was developed following a literature review. Three rounds of combined qualitative semi-structured concept elicitation and cognitive debriefing interviews with 36 patients (≥ 16 years) with Crohn's disease and 4 clinicians were conducted to further explore the most commonly reported and most bothersome symptoms to patients.

A novel Streptococcus pneumoniae human challenge model demonstrates Treg lymphocyte recruitment to the infection site.

To investigate local tissue responses to infection we have developed a human model of killed Streptococcus pneumoniae challenge by intradermal injection into the forearm. S. pneumoniae intradermal challenge caused an initial local influx of granulocytes and increases in TNF, IL6 and CXCL8.

Depletion of LAG-3 T Cells Translated to Pharmacology and Improvement in Psoriasis Disease Activity: A Phase I Randomized Study of mAb GSK2831781.

Activated T cells drive a range of immune-mediated inflammatory diseases. LAG-3 is transiently expressed on recently activated CD4 and CD8 T cells. We describe the engineering and first-in-human clinical study (NCT02195349) of GSK2831781 (an afucosylated humanized IgG1 monoclonal antibody enhanced with high affinity for Fc receptors and LAG-3 and antibody-dependent cellular cytotoxicity capabilities), which depletes LAG-3 expressing cells.

Lymphocyte Activation Gene (LAG)-3 Is Associated With Mucosal Inflammation and Disease Activity in Ulcerative Colitis.

Background And Aims: Lymphocyte activation gene [LAG]-3 is an immune checkpoint and its expression identifies recently activated lymphocytes that may contribute to inflammation. We investigated the role of LAG-3 by analysing its expression and function in immune cells from blood and tissue of patients with ulcerative colitis [UC].

Methods: The phenotypic properties of LAG-3+ T cells were determined by flow cytometry, qRT-PCR and single-cell RNA-sequencing.

Outcomes from massive paracetamol overdose: a retrospective observational study.

Linked Article: This article is commented on by Bateman DN and Dear JW. Should we treat very large paracetamol overdose differently? Br J Clin Pharmacol 2017; 83: 1163-5. https://doi.

Severe alkalosis and hypokalemia with stanozolol misuse.

Stanozolol is a popular androgenic anabolic steroid, used by body builders and athletes for physical performance enhancement. There are few data on its potential adverse effects and no documented cases of it causing severe electrolyte imbalance. Here, we report a patient presenting to a tertiary care emergency department with reduced conscious level, profound hypokalemia, and severe metabolic alkalosis, resulting from stanozolol misuse.

Cyclooxygenase/lipoxygenase shunting lowers the anti-cancer effect of cyclooxygenase-2 inhibition in colorectal cancer cells.

Background: Arachidonic acid metabolite, generated by cyclooxygenase (COX), is implicated in the colorectal cancer (CRC) pathogenesis. Inhibiting COX may therefore have anti-carcinogenic effects. Results from use of non-steroidal anti-inflammatory drugs inhibiting only COX have been conflicting.

Thoracic empyema: a 12-year study from a UK tertiary cardiothoracic referral centre.

Background: Empyema is an increasingly frequent clinical problem worldwide, and has substantial morbidity and mortality. Our objectives were to identify the clinical, surgical and microbiological features, and management outcomes, of empyema.

Methods: A retrospective observational study over 12 years (1999-2010) was carried out at The Heart Hospital, London, United Kingdom.

Splenomegaly.

Splenomegaly is a common finding on clinical examination, and frequently features in postgraduate assessments. The spleen does not normally descend below the left costal margin. The routine abdominal examination will identify whether the spleen is palpable, and if so splenomegaly is almost universally present.

Cryptogenic colitis due to occult cytomegalovirus infection.

Colitis secondary to cytomegalovirus infection is well recognised and usually straightforward to diagnose. Here two cases are reported in whom all initial investigations failed to demonstrate the presence of virus, with potential adverse consequences for its treatment. A case is made for empirical antiviral therapy despite negative investigations if clinical suspicion is high.

Inflammatory bowel diseases in patients with adaptive and complement immunodeficiency disorders.

Crohn's disease and ulcerative colitis are idiopathic chronic inflammatory diseases that primarily affect the gastrointestinal tract. The underlying causes remain poorly understood, but there is a growing body of evidence advocating a likely primary pathogenic role for immunodeficiency in the development of Crohn's lesions. Concordantly, a number of congenital immunodeficiencies disrupting the cellular innate immune system strongly predispose to noninfectious, Crohn's-like inflammatory bowel disease.

Delayed resolution of acute inflammation in ulcerative colitis is associated with elevated cytokine release downstream of TLR4.

Background: Ulcerative colitis (UC) is widely viewed as a leukocyte-mediated disorder. Although strong evidence implicates an exuberant response to microbial components in its pathogenesis, no intrinsic immune defect has been identified and the underlying pathogenic mechanisms remain obscure.

Methodology/principal Findings: The acute immune response to bacterial injection was determined in UC patients with quiescent disease and directly compared to healthy control subjects.