Real-world evidence on adherence, persistence, switching and dose escalation with biologics in adult inflammatory bowel disease in the United States: A systematic review.

WHAT IS KNOWN AND OBJECTIVE: The application of biologics to treat inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is well established. Our aim was to characterize the most recent five years of data on rates of adherence, persistence, switching and dose escalations with biologics used to treat IBD in the United States. METHODS: We systematically reviewed electronic databases MEDLINE, MEDLINE In-Process, EMBASE and Cochrane Library for 2012-2017 as well as conference proceedings for 2016-2017 published in English. RESULTS AND DISCUSSION: Of 449 records identified, 41 met all screening criteria. Published studies varied greatly in methodology, data sources, population studied, follow-up time and endpoint definitions, preventing meaningful comparisons across studies. Based on studies using a medication possession rate threshold of <80% or <86%, 38%-77% of patients were found non-adherent to biologics. Discontinuation within the first 3 months occurred in 0%-25% of patients in six studies; 7%-65% discontinued by 12 months in 13 studies. Among all patients who initiated an index biologic, the switch rate to another biologic ranged from 4.5% to 20% in 6 studies. Dose escalations were reported in only four studies; 8%-35% of patients had their dose escalated within the first year of therapy. WHAT IS NEW AND CONCLUSION: This study demonstrates variability in study design and methodology to assess adherence, persistence, switching and dose escalation with biologics among adults with IBD in the United States. Our findings suggest that real-world biologic use may be suboptimal and indicate new therapies and/or additional patient support may be needed.

Ethanol alters local cellular levels of (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP) independent of the adrenals in subcortical brain regions.

The neuroactive steroid (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP or allopregnanolone) is a positive modulator of GABAA receptors synthesized in the brain, adrenal glands, and gonads. In rats, ethanol activates the hypothalamic-pituitary-adrenal axis and elevates 3α,5α-THP in plasma, cerebral cortex, and hippocampus. In vivo, these effects are dependent on both the pituitary and adrenal glands. In vitro, however, ethanol locally increases 3α,5α-THP in hippocampal slices, in the absence of adrenal influence. Therefore, it is not known whether ethanol can change local brain levels of 3α,5α-THP in vivo, independent of the adrenals. To directly address this controversy, we administered ethanol (2 g/kg) or saline to rats that underwent adrenalectomy (ADX) or received sham surgery and performed immunohistochemistry for 3α,5α-THP. In the medial prefrontal cortex (mPFC), ethanol increased 3α,5α-THP after sham surgery, compared with saline controls, with no ethanol-induced change in 3α,5α-THP following ADX. In subcortical regions, 3α,5α-THP was increased independent of adrenals in the CA1 pyramidal cell layer, dentate gyrus polymorphic layer, bed nucleus of the stria terminalis, and paraventricular nucleus of the hypothalamus. Furthermore, ethanol decreased 3α,5α-THP labeling in the nucleus accumbens shore and central nucleus of the amygdala, independent of the adrenal glands. These data indicate that ethanol dynamically regulates local 3α,5α-THP levels in several subcortical regions; however, the adrenal glands contribute to 3α,5α-THP elevations in the mPFC. Using double immunofluorescent labeling we determined that adrenal dependence of 3α,5α-THP induction by ethanol is not due to a lack of colocalization of 3α,5α-THP with the cholesterol transporters steroidogenic acute regulatory protein (StAR) or translocator protein (TSPO).