Updates on Pathophysiology of Pericarditis to Guide Development of Therapeutics

Purpose of the Review Pericarditis – the inflammation of the pericardial sac – has a generally benign course, although recurrences may occur in 15–30% of patients within 18 months, even after an initial uncomplicated course. For a long time, the scarcity of animal models has limited a deeper understanding of the pathophysiology of pericarditis. Recent Findings A number of stimuli, such as talc and bacterial products containing aluminum, were used in animal models to trigger the inflammation of the pericardial sac. Today, we know that such irritants represent canonical stimuli for the activation of the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome, an intracellular macromolecular complex responsible for the production and secretion of active interleukin-1 β (IL-1β), a pro-inflammatory cytokine that promotes pericardial inflammation. This evidence supports the central role of the NLRP3 inflammasome/IL-1β axis in driving acute inflammation of the pericardium and subsequent flares, as indirectly highlighted in seminal clinical trials of anakinra (AIRTRIP trial), rilonacept (RHAPSODY trial), and goflikicept. More recently, cannabidiol (CBD, derived from Cannabis sativa) has been found to block the NLRP3 inflammasome activation in vitro and in vivo. Preliminary positive findings have been reported in patients with ongoing recurrent pericarditis in the MAvERIC-Pilot study, while the phase III MAVERIC-2 trial is exploring the impact of CBD among patients with a history of recurrent pericarditis in stable control scheduled to discontinue an IL-1 blocker. Summary The activation of the NLRP3 inflammasome/IL-1β axis supports auto-inflammation as a central event driving recurrences, and its targeted therapeutic inhibition results as a game changer to reduce the risk of recurrences and improve patients’ quality of life. Accordingly, a shift moving from the prescription of glucocorticoids as second-line therapy in favor of IL-1 blockers, particularly in those patients presenting with an auto-inflammatory phenotype, is ongoing. To this end, an imaging-guided approach may help choosing the best treatment and monitoring its effects across time, thus allowing a personalized approach to patients with recurrent pericarditis. Graphical Abstract