Assessment and management of methotrexate hepatotoxicity in psoriasis patients: report from a consensus conference to evaluate current practice and identify key questions toward optimizing methotrexate use in the clinic

Experts in psoriasis, hepatology, pharmacokinetics and pharmacogenetics convened to discuss the safety and monitoring of methotrexate with respect to hepatotoxicity when used in the treatment of psoriasis. Methotrexate is an efficacious and cost‐effective treatment for psoriasis, but is associated with significant safety issues, particularly relating to hepatotoxicity. Current British, Dutch, German, EU and US guidelines for baseline evaluations, monitoring and prevention of hepatotoxicity in patients with psoriasis receiving methotrexate were evaluated. Liver safety monitoring is currently reliant upon multiple methods, including biopsy, serological tests for biomarkers such as type III procollagen amino terminal propeptide (PIIINP), and liver function tests based on liver enzymes. Monitoring of patients receiving long‐term therapy is expected to be improved by the utilization of serum biomarkers currently in development such as the Enhanced Liver Fibrosis (ELF) panel and other non‐invasive tests of hepatic architecture, such as fibroelastography, microbubbles and magnetic resonance imaging. Appropriate studies to determine optimal dosing to maximize efficacy and minimize toxicity, potentially utilizing pharmacogenetic principles, are clearly needed. Key questions for future research are identified including needs for optimal screening and monitoring, identification of appropriate biomarkers, assessment of relationships between dosing and safety, utility of liver biopsy, optimal dosing regimens (including route of administration), methods to measure methotrexate levels in blood, and use of methotrexate as a standardized active comparator in trials of experimental drugs used to treat psoriasis.     

Optical coherence tomography (OCT) study in Argentinean Huntington’s disease patients

Abstract

Background: Huntington’s disease (HD) is a genetic, rare and progressive neurodegenerative disorder that causes motor and cognitive impairment in midlife patients. Although retinal damage was observed in animal HD models and in patients with other neurodegenerative diseases, we still need confirmation of impairment in HD patients. Optical coherence tomography (OCT) is a non-invasive methodology that analyses the retinal nerve fibre layers (RNFL) and could reflect processes of neurodegeneration.

Methods: A cross-sectional study with 14?HD patients who underwent a spectral domain OCT. Results were compared with a control group. Demographic data were also obtained.

Results: Temporal and superior RNFL sectors in HD showed a significant RNFL thinning compared with a control group. However, no differences were identified in mean total RNFL thickness between HD patients and controls.

Conclusions: OCT is a rapid and non-invasive technique that can be investigated in larger cohorts of patients to assess its potential role as a biomarker in HD patients.     

Developments in the discovery of drugs for spinal muscular atrophy: successful beginnings and future prospects

Introduction: Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by mutations in a gene that produces a protein called survival motor neuron (SMN). SMN has an important role in snRNP assembly in all cells but that may not be its only role; the reasons for SMN deficiency resulting in neuromuscular dysfunction and motor neuron degeneration remain active areas of research. Besides increasing SMN, compensating for SMN deficiencies or neuroprotection may be therapeutic options for SMA. Age of onset and the rate of disease progression are variable and therapeutic strategies should be appropriate to subtypes of SMA patients.

Areas covered: The article discusses SMA, their targets and where these targets can be found. Additionally, the article reviews small molecules identified as disease modifiers and how these small molecules were discovered. The article also describes and discusses emerging concepts regarding the disease mechanisms. The author compiled this review using scientific literature, patent databases, company and patient association and government websites.

Expert opinion: Small molecules targeting various processes implicated in SMA are reaching the clinic. These molecules and targets, although not yet validated, are providing insight into the complexity of a ‘simple’ genetic disease such as SMA. SMA is not a single disease and so various therapeutic strategies are needed. Biomarkers and regulatory guidelines are required to select patients for clinical trials, decide when to initiate treatment and how to develop combinations of investigational drugs.     

Angiogenesis in salivary gland tumors: from clinical significance to treatment

Introduction: Salivary gland tumors (SGTs) represent a rare cancer entity, consisting of various morphological features that complicate diagnosis. Their diversity in terms of morphology and clinical course makes defining risk factors difficult, while the molecular steps responsible for SGT development remain unclear. Angiogenesis, a hallmark of cancer development, is considered as an attractive target.

Areas covered: This review aims to summarize the available research regarding angiogenesis in SGTs from clinical significance to treatment options.

Expert opinion: The available data suggest that microvessel density (MVD) evaluation may be capable of discriminating between benign and malignant SGTs, while the use of CD105 antibody seems to be the most suitable. Substantial evidence also suggests that MVD and VEGF expression could be used as prognostic factors in malignant SGTs. Although several agents have shown antiangiogenic activities in adenoid cystic carcinoma cells and xenograft tumors, limited effectiveness in the existing clinical trials was noted. Further studies are strongly recommended for the validation of already well-known and the identification of novel prognostic and predictive angiogenic markers. There is also a strong demand for relatively larger cohorts, homogenous samples referring to same histological SGT subtypes and including an equivalent number of low- and high-grade SGTs.     

An update in toxicology of ageing

The field of ageing research has been rapidly advancing in recent decades and it had provided insight into the complexity of ageing phenomenon. However, as the organism-environment interaction appears to significantly affect the organismal pace of ageing, the systematic approach for gerontogenic risk assessment of environmental factors has yet to be established. This puts demand on development of effective biomarker of ageing, as a relevant tool to quantify effects of gerontogenic exposures, contingent on multidisciplinary research approach.Here we review the current knowledge regarding the main endogenous gerontogenic pathways involved in acceleration of ageing through environmental exposures. These include inflammatory and oxidative stress-triggered processes, dysregulation of maintenance of cellular anabolism and catabolism and loss of protein homeostasis. The most effective biomarkers showing specificity and relevancy to ageing phenotypes are summarized, as well. The crucial part of this review was dedicated to the comprehensive overview of environmental gerontogens including various types of radiation, certain types of pesticides, heavy metals, drugs and addictive substances, unhealthy dietary patterns, and sedentary life as well as psychosocial stress. The reported effects in vitro and in vivo of both recognized and potential gerontogens are described with respect to the up-to-date knowledge in geroscience. Finally, hormetic and ageing decelerating effects of environmental factors are briefly discussed, as well.     

Pediatric liver transplantation: a North American perspective

Liver transplantation (LT) is an important component in the therapeutic armamentarium of managing end-stage liver disease. In North American children, biliary atresia remains the most common indication for LT compared to hepatitis C in adults, while hepatoblastoma is the most common liver tumor requiring LT, versus Hepatocellular carcinoma in adults. Rejection, lymphoproliferative disease, renal insufficiency, metabolic syndrome, recurrent disease, ‘de novo’ autoimmune hepatitis and malignancy require careful surveillance and prompt action in adults and children after LT. In children, specific attention to EBV viremia, growth, development, adherence and transition to the adult services is also required. Antibody mediated rejection and screening for donor specific antibodies is becoming important in managing liver graft dysfunction. Biomarkers to identify and predict tolerance are being developed. Machine perfusion and stem cells (iPS) to synthesize organs are generating interest and are a focus for research.     

Acute kidney injury in acute liver failure: a review

Acute liver failure is a rare and often devastating condition consequent on massive liver cell necrosis that frequently affects young, previously healthy individuals resulting in altered cognitive function, coagulopathy and peripheral vasodilation. These patients frequently develop concurrent acute kidney injury (AKI). This abrupt and sustained decline in renal function, through a number of pathogenic mechanisms such as renal hypoperfusion, direct drug-induced nephrotoxicity or sepsis/systemic inflammatory response contributes to increased morbidity and is strongly associated with a worse prognosis. Improved understanding of the pathophysiology AKI in the context of acute liver failure may be beneficial in a number of areas; the development of new and sensitive biomarkers of renal dysfunction, refining prognosis and organ allocation, and ultimately leading to the development of novel treatment strategies, these issues are discussed in more detail in this expert review.