Down-titration of biologics for the treatment of rheumatoid arthritis: A systematic literature review

Biologic therapies have improved the management of rheumatoid arthritis (RA) and the treat-to-target approach has resulted in many patients achieving remission. In the current treatment landscape, clinicians have begun considering dose reduction/tapering for their patients. Rheumatology guidelines in Asia, Europe, and the United States include down-titration of biologics but admit that the level of evidence is moderate. We conducted a systematic literature review to assess the published studies that evaluate down-titration of biologics in RA. The published literature was searched for studies that down-titrated the following biologics: abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Eligible studies included randomized controlled trials (RCTs), non-RCTs, observational, and pharmacoeconomic studies. The outcomes of interest were (1) efficacy and health-related quality of life, (2) disease flares, and (3) impact on cost. Eleven full-text publications were identified; only three were RCTs. Study results suggest that dosing down may be an option in many patients who have achieved remission or low disease activity. However, some patients are likely to experience a disease flare. Across the studies, the definition of disease flare and the down-titration criteria were inconsistent, making it difficult to conclude which patients may be appropriate and when to attempt down-titration. Studies have evaluated the practice of dosing down biologic therapy in patients with RA; however, a relatively small number of RCTs have been published. Although down-titration may be an option for some patients in LDA or remission, additional RCTs are needed to provide guidance on this practice

Application of the rainbow trout derived intestinal cell line (RTgutGC) for ecotoxicological studies: molecular and cellular responses following exposure to copper.

There is an acknowledged need for in vitro fish intestinal model to help understand dietary exposure to chemicals in the aquatic environment. The presence and use of such models is however largely restrictive due to technical difficulties in the culturing of enterocytes in general and the availability of appropriate established cell lines in particular. In this study, the rainbow trout (Oncorhynchus mykiss) intestinal derived cell line (RTgutGC) was used as a surrogate for the "gut sac" method. To facilitate comparison, RTgutGC cells were grown as monolayers (double-seeded) on permeable Transwell supports leading to a two-compartment intestinal model consisting of polarised epithelium. This two-compartment model divides the system into an upper apical (lumen) and a lower basolateral (portal blood) compartment. In our studies, these cells stained weakly for mucosubstances, expressed the tight junction protein ZO-1 in addition to E-cadherin and revealed the presence of polarised epithelium in addition to microvilli protrusions. The cells also revealed a comparable transepithelial electrical resistance (TEER) to the in vivo situation. Importantly, the cell line tolerated apical saline (1:1 ratio) thus mimicking the intact organ to allow assessment of uptake of compounds across the intestine. Following an exposure over 72 h, our study demonstrated that the RTgutGC cell line under sub-lethal concentrations of copper sulphate (Cu) and modified saline solutions demonstrated uptake of the metal with saturation levels comparable to short term ex situ gut sac preparations. Gene expression analysis revealed no significant influence of pH or time on mRNA expression levels of key stress related genes (i.e. CYP3A, GST, mtA, Pgp and SOD) in the Transwell model. However, significant positive correlations were found between all genes investigated suggesting a co-operative relationship amongst the genes studied. When the outlined characteristics of the cell line are combined with the division of compartments, the RTgutGC double seeded model represents a potential animal replacement model for ecotoxicological studies. Overall, this model could be used to study the effects and predict aquatic gastrointestinal permeability of metals and other environmentally relevant contaminants in a cost effective and high throughput manner

Diagnosis of reflux disease

There are numerous tests for which a diagnostic value in the context of gastro-oesophageal reflux disease has been claimed. Some of these tests (e.g. the acid perfusion test) have become obsolete after the advent of 24-hour oesophageal pH monitoring. With the latter rest not only can excessive reflux be identified, but also, and more importantly, a temporal relationship can be demonstrated between a patient's symptoms and reflux episodes. Radiographical examination of the oesophagus has largely been replaced by endoscopy, although the use of the former test is still indicated in certain circumstances (e.g. in the differentiation of sliding from paraoesophageal hiatus hernia). In clinical practice, the so-called proton pump inhibitor test has gained considerable popularity. Despite several studies on the specificity and sensitivity of this test, its value has not yet been established with sufficient accuracy. Conventional manometric evaluation of lower oesophageal sphincter pressure has been over-emphasized as a diagnostic test in gastro-oesophageal reflux disease

The role of hiatus hernia in gastro-oesophageal reflux disease

This article gives an overview of the role of sliding hiatus hernia in gastro-oesophageal reflux disease (GORD). The crural diaphragm acts as an external sphincter of the antireflux barrier. Contractions of the crural diaphragm increase lower-oesophageal-sphincter (LOS) pressure during each inspiration and in situations of increased abdominal pressure, whereas these contractions are inhibited when gas and/or a bolus has to pass the gastro-oesophageal junction. A hiatus hernia is associated with GORD symptoms, increased oesophageal acid exposure, and oesophagitis and its severity. In patients with hiatus hernia, the incidence of reflux episodes is increased during periods with low LOS pressure, straining and swallowing. These findings underline the importance of the crural diaphragm, which, when surrounding the LOS, protects against gastro-oesophageal reflux