A plant-derived glucocorticoid receptor modulator attenuates inflammation without provoking ligand-induced resistance

Background: Acquired resistance to glucocorticoids constitutes a major clinical challenge, often overlooked in the search for improved alternatives to classic steroids. We sought to unravel how two glucocorticoid receptor-activating compounds, dexamethasone and Compound A, influence glucocorticoid receptor levels and how this can be correlated to their gene regulatory potential. Methods: Compound A and dexamethasone were applied in a short-term and long-term treatment protocol. By quantitative PCR analysis in fibroblast-like synoviocytes (FLS) the gene regulatory potential of both compounds in the two experimental conditions was analysed. A parallel Western blot assay revealed the glucocorticoid receptor protein levels in both conditions (ex vivo). In addition, this study examined the effect of systemic administration of dexamethasone and Compound A, in concentrations effective to inhibit collagen-induced arthritis, in DBA/1 mice on glucocorticoid receptor levels (in vivo). Results: Compound A does not induce a homologous downregulation of glucocorticoid receptor in vivo and ex vivo, thereby retaining its anti-inflammatory effects after prolonged treatment in FLS. This is in sharp contrast to dexamethasone, showing a direct link between prolonged dexamethasone treatment, decreasing glucocorticoid receptor levels, and the abolishment of inflammatory gene repression in FLS. It was also observed that the acquired low receptor levels after prolonged dexamethasone treatment are still sufficient to sustain the transactivation of endogenous glucocorticoid-responsive element-driven genes in FLS, a mechanism partly held accountable for the metabolic side-effects. Conclusion: Compound A is less likely to evoke therapy resistance, as it does not lead to homologous glucocorticoid receptor downregulation, which is in contrast to classic glucocorticoids

Surgical Management of Fistulating Perianal Crohn's Disease - A UK Survey.

AIM: Around one-third of patients with Crohn's disease are affected by Crohn's fistula-in-ano (pCD). It typically follows a chronic course and patients undergo long-term medical and surgical therapy. We set out to describe current surgical practice in the management of pCD in the UK. METHODS: A survey of surgical management of pCD was designed by an expert group of colorectal surgeons and gastroenterologists. This assessed acute, elective, multidisciplinary and definitive surgical management. A pilot of the questionnaire was undertaken at the Digestive Disease Federation 2015 meeting. The survey was refined and distributed nationally through the trainee collaborative networks. RESULTS: National rollout obtained responses from 133 surgeons of 179 approached (response rate 74.3%). At first operation, 32% surgeons would always consider drainage of sepsis and 31.1% would place a draining seton. At first elective operation, 66.6% would routinely insert of draining seton, and 84.4% would avoid cutting seton. The IBD multidisciplinary team was available to 87.6% respondents, although only 25.1% routinely discussed pCD patients. Anti-TNF-α therapy was routinely considered by 64.2%, although 44.2% left medical management to gastroenterology. Common definitive procedures were removal of seton only (70.7%), fistulotomy (57.1%), advancement flap (38.9%), fistula plug (36.4%) and ligation of intersphincteric track (LIFT) procedure (31.8%). Indications for diverting stoma or proctectomy were intractable sepsis, incontinence, and poor quality of life. DISCUSSION: This survey has demonstrated areas of common practice, but has also highlighted divergent practice including choices of definitive surgery and multimodal management. Practical guidelines are required to support colorectal surgeons in the UK. This article is protected by copyright. All rights reserved

Omineca Herald, May, 23, 1924

Background: LKB1 mutations are the underlying genetic abnormality causing Peutz-Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated. Methods: Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high-risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts. Results: Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49-year-old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52-year-old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse

1.5 Decades Later: Bearing fruits from the ACR/EULAR exchange Program

Imaging Science & TechnologyApplied Science

Pirfenidone in idiopathic pulmonary fibrosis: expert panel discussion on the management of drug-related adverse events

Pirfenidone is currently the only approved therapy for idiopathic pulmonary fibrosis, following studies demonstrating that treatment reduces the decline in lung function and improves progression-free survival. Although generally well tolerated, a minority of patients discontinue therapy due to gastrointestinal and skin-related adverse events (AEs). This review summarizes recommendations based on existing guidelines, research evidence, and consensus opinions of expert authors, with the aim of providing practicing physicians with the specific clinical information needed to educate the patient and better manage pirfenidone-related AEs with continued pirfenidone treatment. The main recommendations to help prevent and/or mitigate gastrointestinal and skin-related AEs include taking pirfenidone during (or after) a meal, avoiding sun exposure, wearing protective clothing, and applying a broad-spectrum sunscreen with high ultraviolet (UV) A and UVB protection. These measures can help optimize AE management, which is key to maintaining patients on an optimal treatment dose

Collecting New Peak and Intermediate Infliximab Levels to Predict Remission in Inflammatory Bowel Diseases

peer reviewedDataGreen - Fédération Wallonie Bruxelle

Compound A, a Dissociated Glucocorticoid Receptor Modulator, Inhibits T-bet (Th1) and Induces GATA-3 (Th2) Activity in Immune Cells

Background: Compound A (CpdA) is a dissociating non-steroidal glucocorticoid receptor (GR) ligand which has antiinflammatory properties exerted by down-modulating proinflammatory gene expression. By favouring GR monomer formation, CpdA does not enhance glucocorticoid (GC) response element-driven gene expression, resulting in a reduced side effect profile as compared to GCs. Considering the importance of Th1/Th2 balance in the final outcome of immune and inflammatory responses, we analyzed how selective GR modulation differentially regulates the activity of T-bet and GATA-3, master drivers of Th1 and Th2 differentiation, respectively. Results: Using Western analysis and reporter gene assays, we show in murine T cells that, similar to GCs, CpdA inhibits T-bet activity via a transrepressive mechanism. Different from GCs, CpdA induces GATA-3 activity by p38 MAPK-induction of GATA-3 phosphorylation and nuclear translocation. CpdA effects are reversed by the GR antagonist RU38486, proving the involvement of GR in these actions. ELISA assays demonstrate that modulation of T-bet and GATA-3 impacts on cytokine production shown by a decrease in IFN-c and an increase in IL-5 production, respectively. Conclusions: Taken together, through their effect favoring Th2 over Th1 responses, particular dissociated GR ligands, fo