Trikafta Rescues CFTR and Lowers Monocyte P2X7R-induced Inflammasome Activation in Cystic Fibrosis.

Rationale: Cystic fibrosis (CF) is caused by mutations in the CFTR (CF transmembrane conductance regulator) gene and is characterized by sustained inflammation. ATP triggers IL-1ß secretion via P2X7R (P2X7 receptor) and activation of the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome. Objectives: To explore the effect of the CFTR modulator elexacaftor/tezacaftor/ivacaftor (Trikafta) on CFTR expression and the ATP/P2X7R signaling axis in monocytes and on circulating proinflammatory markers. Methods: Inflammatory mediators were detected in blood from 42 patients with CF before and after 3 months of Trikafta therapy. Markers of inflammasome activation and IL-1ß secretion were measured in monocytes before and after stimulation with ATP and LPS, in the presence or absence of the P2X7R inhibitor A438079. Measurements and Main Results: P2X7R is overexpressed in CF monocytes, and receptor inhibition decreased NLRP3 expression, caspase-1 activation, and IL-1ß secretion. In vitro and in vivo, P2X7R expression is regulated by CFTR function and intracellular chloride (Cl-) levels. Trikafta therapy restored CFTR expression yet decreased P2X7R in CF monocytes, resulting in normalized Cl- and potassium efflux, and reduced intracellular calcium levels. CFTR modulator therapy decreased circulating levels of ATP and LPS and reduced inflammasome activation and IL-1ß secretion. Conclusions: P2X7R expression is regulated by intracellular Cl- levels and in CF monocytes promotes inflammasome activation. Trikafta therapy significantly increased CFTR protein expression and reduced ATP/P2X7R-induced inflammasome activation. P2X7R may therefore be a promising target for reducing inflammation in patients with CF who are noneligible for Trikafta or other CFTR modulator therapy.

What is the Impact of Outreach Services on Medication Adherence for COPD Patients? A Systematic Review.

Chronic obstructive pulmonary disease (COPD) patients have been known to have poor medication adherence rates. The purpose of this systematic review was to assess if outreach services could impact on medication compliance rates. CINAHL, Medline, Clinical Key and Cochrane library were all searched electronically along with grey literature for all eligible studies conducted on COPD patients in a non-acute hospital setting. Systematic review methodology was followed for data selection, extraction and risk of bias, validity testing and data analysis. Eight studies met all inclusion criteria. 4 randomised control trials and 4 quantitative intention-to-treat studies. 2 of the studies failed validity testing but due to a lack of articles, were included in the synthesis. Given the heterogeneity of data, a narrative synthesis was adopted. All 8 studies demonstrated the ability for an outreach service to improve medication adherence in the community setting. Secondary to this result, this systematic review showed the ability to reduce hospital admissions of exacerbations of COPD due to increased medication adherence. Quality of life was assessed but did not improve but importantly did not decrease. Medication adherence has the potential to be improved from an outreach programme but requires more high-quality research in the area to develop a standardised plan of care to identify the most effective way of educating patients on medication adherence. Medication adherence education should not be a once-off assessment, this systematic review has shown it must be continuous, re-checked and re-educated regularly.