Genetic predisposition in recurrent pericarditis: from pathophysiology to precision therapy
F Veneziano, I Cavallari, M M Viscusi, N CoccoAbstract
Background
Recurrent pericarditis (RP) is a frequent cause of disease recurrence, repeated hospitalizations, and healthcare utilization. Although traditionally classified as idiopathic in most patients, accumulating evidence suggests that a clinically relevant subset of RP is driven by underlying genetic and autoinflammatory mechanisms. Variants affecting innate immune pathways may contribute to persistent inflammation, treatment resistance, and recurrent acute care presentations. Clarifying the genetic background of RP may therefore improve patient stratification and support more individualized therapeutic strategies.
Methods
A systematic literature review was conducted using MEDLINE, Embase, and Scopus databases from January 2012 to September 2025. A total of 742 records were identified. After duplicate removal and screening, 68 full-text articles were assessed, and 24 studies met inclusion criteria, including cohort studies, case series, and registry-based analyses. Extracted data focused on the prevalence and spectrum of germline genetic variants, associated clinical phenotypes, recurrence burden, hospitalization rates, and response to targeted anti-inflammatory therapies, particularly interleukin-1 (IL-1) inhibition.
Results
Across referral-center cohorts and observational series, variants in genes regulating innate immunity—most commonly MEFV, NLRP3, and TNFRSF1A—were identified in approximately 20–30% of patients with difficult-to-treat RP, with diagnostic yield increasing to 35–40% in early-onset disease. Genetic positivity was consistently associated with younger age at onset, systemic inflammatory manifestations such as fever or polyserositis, steroid dependence or colchicine resistance, and a two- to threefold higher risk of recurrence. Among studies reporting treatment outcomes, IL-1–targeted therapy achieved clinical remission in 70–80% of genetically positive patients, compared with less than 50% among genetically negative individuals, and was associated with a significant reduction in disease recurrences and hospital readmissions. No randomized trials stratified patients by genotype were identified.
Conclusions
Available evidence indicates that a genetically mediated autoinflammatory substrate contributes to disease severity, recurrence burden, and repeated hospitalizations in a substantial subset of patients with recurrent pericarditis. Selective genetic testing may support early identification of high-risk patients and guide timely initiation of IL-1–targeted therapy, with potential implications for reducing acute care utilization. Prospective genotype-guided multicenter studies are warranted to validate these findings and define their impact on clinical outcomes.